Clinical trial NCT04862143
Conditions: Advanced Breast Cancer
Keywords: Decentralized clinical trial advanced breast cancer PIK3CA mutation alpelisib
Sponsor: Novartis Pharmaceuticals
Start date: 2022-03-08; Completion date: 2022-09-19
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study was designed to identify and register practical observations and experiences in connection with planning and implementing decentralized, patient-centered clinical trials at a geographic distance with virtual elements.

Detailed description:
The purpose of this open-label, single arm, multi-center, Phase II interventional pilot trial was to evaluate if a decentralized clinical trial (DCT) using a telemedicine platform offers a satisfactory, safe and suitable management for HR-positive/HER2-negative participants with advanced breast cancer harboring a PIK3CA mutation and treated with alpelisib plus fulvestrant. The trial utilized a hybrid DCT approach to reduce participant burden by bringing visits, services, and supplies closer to them.

The planned duration of treatment was 12 cycles of 28 days. Participants could discontinue treatment earlier due to unacceptable toxicity, disease progression and/or decision made at the discretion of the investigator or the participant.

On-site visits occurred during screening, at Cycle 1 Day 1 (baseline), and at end-of-trial. Visits at the local oncologist practice were planned on Day 1 of Cycle 2, Cycle 4, Cycle 7, and Cycle 10. Other visits were performed by a district nurse, either at home or at the local oncologist's practice, depending on the participant's preference.

During the on-site visit on Cycle 1, Day 1, participants were trained on using the telemedicine platform, and other monitoring devices used during remote participation: a glucometer and a smartphone with the telemedicine application installed. Study treatment was also initiated during this visit. The participants were then transitioned to remote participation enabled by the telemedicine platform with support of local healthcare providers (local oncologist, district nurse, or other qualified healthcare professional) under the investigator's oversight.

Discontinuation of remote participation was not a reason for trial termination. Participants who did not wish to continue with remote participation had the option to attend on-site visits.

The study planned to enroll approximately 20 participants, however the study was terminated prematurely with only 2 participants enrolled. The decision to terminate the study was due to delays during the start-up period and due to low enrollment. The decision to terminate was not related to any potential safety concern with alpelisib.

Arms: arm 1: Participants were administered alpelisib at a daily dose of 300 mg for 12 cycles of 28 days and fulvestrant at a dose of 500 mg via intramuscular injection on Cycle 1 Day 1 and Cycle 1 Day 15, and Day 1 of each subsequent cycle up to Cycle 12. Pre-menopausal women also received goserelin at a dose of 3.6 mg on Day 1 of each cycle.
Interventions: intervention 1: Alpelisib intervention 2: Fulvestrant intervention 3: Goserelin
Intervention descriptions: intervention 1: Participants received a daily oral dose of 300 mg of alpelisib film-coated tablets for a total of 12 cycles, with each cycle lasting 28 days. intervention 2: Participants were administered fulvestrant at a dose of 500 mg via intramuscular injection on Cycle 1 Day 1 and Cycle 1 Day 15, and on Day 1 of each 28-day cycle thereafter until Cycle 12. intervention 3: Pre-menopausal women were administered a dose of 3.6 mg of goserelin injection via intramuscular route, beginning on Cycle 1 Day 1. Subsequently, the same dose was administered on Day 1 of each 28-day cycle throughout the study.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
BYL719/Alpelisib 
Clinical Trial Protocol CBYL719A03201 / NCT04862143 
Open-label, multicenter, pilot-trial evaluating the safety and 
utility of a hybrid decentralized clinical trial (DCT) approach 
using a TELEmedicine platform in patients with HR-
positive/HER2-negative advanced breast cancer with a 
PIK3CA mutation treated with alpelisib – fulvestrant 
TELEPIK Trial 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-005882-15 
Version number: 
01 (clean) 
Clinical Trial Phase: 
II 
Release date: 
15-Jun-2021 (content final)
Property of Novartis Pharma AG 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 (25-May-2021) ........................................................................................... 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 17 
2 
Objectives, endpoints, and estimands ................................................................................ 18 
2.1 
Primary estimands ................................................................................................. 20 
2.2 
Secondary estimands ............................................................................................. 20 
3 
Trial design ........................................................................................................................ 21 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for trial design ....................................................................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of combination drugs ............................................................ 24 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 26 
4.5.1 
Potential risks to participants ................................................................ 26 
4.5.2 
Potential benefits for participants .......................................................... 27 
4.5.3 
Risk management strategies .................................................................. 27 
4.6 
Rationale for public health emergency mitigation ................................................. 28 
5 
Trial population ................................................................................................................. 29 
5.1 
Inclusion criteria .................................................................................................... 29 
5.2 
Exclusion criteria ................................................................................................... 31 
6 
Treatment ........................................................................................................................... 33 
6.1 
Trial treatments ...................................................................................................... 33 
6.1.1 
Additional trial treatments ..................................................................... 34 
6.1.2 
Treatment arms/group ........................................................................... 34 
6.1.3 
Treatment duration ................................................................................ 34 
6.2 
Other treatment(s) .................................................................................................. 34 
6.2.1 
Concomitant therapy ............................................................................. 34 
6.2.2 
Prohibited medication ........................................................................... 38 


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6.3 
Participant numbering, treatment assignment, randomization .............................. 38 
6.3.1 
Participant numbering ........................................................................... 38 
6.3.2 
Treatment assignment, randomization .................................................. 39 
6.4 
Treatment blinding ................................................................................................. 39 
6.5 
Dose escalation and dose modification .................................................................. 39 
6.5.1 
Follow-up for toxicities ......................................................................... 46 
6.6 
Additional treatment guidance ............................................................................... 51 
6.6.1 
Trial treatment compliance ................................................................... 51 
6.6.2 
Trial treatment accountability ............................................................... 51 
6.7 
Preparation and dispensation ................................................................................. 52 
6.7.1 
Handling of trial treatment and additional treatment ............................ 52 
6.7.2 
Instruction for prescribing and taking trial treatment ........................... 53 
7 
Informed consent procedures ............................................................................................ 54 
8 
Visit schedule and assessments ......................................................................................... 54 
8.1 
Screening ............................................................................................................... 59 
8.1.1 
Eligibility screening .............................................................................. 59 
8.1.2 
Information to be collected on screening failures ................................. 59 
8.2 
Participant demographics and other baseline characteristics ................................. 59 
8.3 
Efficacy .................................................................................................................. 60 
8.3.1 
Imaging tumor assessment .................................................................... 60 
8.3.2 
Performance status ................................................................................ 63 
8.3.3 
Appropriateness of efficacy assessments .............................................. 63 
8.4 
Safety and tolerability ............................................................................................ 63 
8.4.1 
Physical examination ............................................................................ 63 
8.4.2 
Vital signs.............................................................................................. 64 
8.4.3 
Laboratory evaluations .......................................................................... 64 
8.4.4 
Cardiac assessments .............................................................................. 65 
8.4.5 
Appropriateness of safety measurements .............................................. 66 
8.5 
Additional assessments .......................................................................................... 66 
8.5.1 
Participant reported outcomes ............................................................... 66 
8.6 
DCT elements included in the Trial....................................................................... 68 
8.6.1 
The telemedicine platform .................................................................... 68 
8.6.2 
Conduct of study visits away from the investigator site ....................... 69 
9 
Trial discontinuation and completion ................................................................................ 70 
9.1 
Discontinuation and completion ............................................................................ 70 
9.1.1 
Trial treatment discontinuation and trial discontinuation ..................... 70 


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9.1.2 
Withdrawal of informed consent ........................................................... 70 
9.1.3 
Lost to follow-up ................................................................................... 71 
9.1.4 
Early trial termination by the sponsor ................................................... 71 
9.2 
Trial completion and post-trial treatment .............................................................. 71 
10 Safety monitoring and reporting ........................................................................................ 72 
10.1 
Definition of adverse events and reporting requirements ...................................... 72 
10.1.1 
Adverse events ...................................................................................... 72 
10.1.2 
Serious adverse events .......................................................................... 74 
10.1.3 
Adverse events of interest ..................................................................... 74 
10.1.4 
SAE reporting........................................................................................ 75 
10.1.5 
Pregnancy .............................................................................................. 75 
10.1.6 
Reporting of trial treatment errors including misuse/abuse .................. 76 
10.2 
Additional safety monitoring ................................................................................. 76 
11 Data collection and database management ........................................................................ 76 
11.1 
Data collection ....................................................................................................... 76 
11.2 
Database management and quality control ............................................................ 77 
11.3 
Site monitoring ...................................................................................................... 77 
12 Data analysis and statistical methods ................................................................................ 79 
12.1 
Analysis sets .......................................................................................................... 79 
12.2 
Participant demographics and other baseline characteristics ................................. 79 
12.3 
Treatments ............................................................................................................. 79 
12.4 
Analysis of the primary endpoint .......................................................................... 79 
12.4.1 
Definition of primary endpoint ............................................................. 79 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 80 
12.5 
Analysis of secondary endpoints ........................................................................... 80 
12.5.1 
Patient retention on DCT approach ....................................................... 80 
12.5.2 
Safe and suitable remote management of patients on DCT approach .. 80 
12.5.3 
Compliance with treatment and adherence to procedures ..................... 80 
12.5.4 
Safety endpoints .................................................................................... 80 
12.5.5 
Participant reported outcomes: Global Health Status, Quality of 
Life, and Pain ........................................................................................ 82 
12.5.6 
Treatment effectiveness ........................................................................ 82 
12.6 
Analysis of exploratory endpoints ......................................................................... 82 
12.7 
Interim analyses ..................................................................................................... 82 
12.8 
Sample size calculation .......................................................................................... 82 
13 Ethical considerations and administrative procedures ...................................................... 82 


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13.1 
Regulatory and ethical compliance ........................................................................ 82 
13.2 
Responsibilities of the investigator and IEC ......................................................... 83 
13.3 
Publication of trial protocol and results ................................................................. 83 
13.4 
Quality control and quality assurance .................................................................... 83 
14 Protocol adherence ............................................................................................................ 84 
14.1 
Protocol amendments ............................................................................................. 84 
15 References ......................................................................................................................... 85 
16 Appendices ........................................................................................................................ 87 
16.1 
Appendix 1: Permitted medication to be used with caution .................................. 87 
16.1.1 
Permitted medication to be used with caution ...................................... 87 
16.1.2 
Prohibited Medication ........................................................................... 87 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 89 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 18 
Table 6-1 
Trial treatments ..................................................................................... 34 
Table 6-2 
Co-therapies .......................................................................................... 34 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation of 
alpelisib for adverse drug reactions ....................................................... 40 
Table 6-4 
Dose reduction steps for alpelisib1. ....................................................... 46 
Table 6-5 
Alternative causes of liver disease ........................................................ 51 
Table 8-1 
Assessment schedule ............................................................................. 56 
Table 8-2 
Imaging assessment collection plan ...................................................... 62 
Table 8-3 
WHO/ECOG performance status .......................................................... 63 
Table 8-4 
Laboratory evaluation collection plan ................................................... 65 
Table 8-5 
Participant reported outcomes collection plan ...................................... 67 
Table 10-1 
Guidance for capturing the trial treatment errors including 
misuse/abuse ......................................................................................... 76 
Table 16-1 
List of CYP450 substrates to be used with caution............................... 87 
Table 16-2 
List of prohibited strong inducers of CYP3A ....................................... 88 
Table 16-3 
List of prohibited BCRP inhibitors ....................................................... 88 
Table 16-4 
Liver event and laboratory trigger definitions ...................................... 89 
Table 16-5 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 90 
Table 16-6 
Follow up requirements for liver laboratory triggers ............................ 91 


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List of figures 
Figure 3-1 
Trial design ............................................................................................ 22 


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List of abbreviations 
 
ABC 
Advanced Breast Cancer 
ADA 
American Diabetes Association 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AKT 
Protein kinase B 
ALT 
Alanine aminotransferase 
ASIH 
Avancerad sjukvård i hemmet (Swedish acronym which means “advanced care at 
home” ) 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCRP 
Breast Cancer Resistance Protein  
BMI 
Body Mass Index 
BPI-SF 
Brief Pain Inventory Short Form 
C1 
Cycle 1 
CDK4/6i 
Cyclin-dependent kinases 4 and 6 inhibitors 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CMO&PS 
Chief Medical Office and Patient Safety  
CNS 
Central nervous system 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P 
D1 
Day 1 
DCT 
Decentralized Clinical Trial 
DDI 
Drug-drug interaction 
DILI 
Drug-induced liver injury 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EORTC 
QLQ C30 
European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire 
EOT 
End of Trial 
ePRO 
Electronic participant reported outcome 
ER 
Estrogen receptor 
ESMO 
European Society for Medical Oncology  
ESO 
European School of Oncology 
EU 
European Union 


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FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FG 
Fasting glucose 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GGT 
Gamma-Glutamyl Transferase 
hCG 
human chorionic gonadotropin 
HCP 
Healthcare Professional 
HER2 
Human Epidermal Growth Factor Receptor 2 
HR 
Hormone Receptor 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
LHRH 
Luteinizing Hormone-Releasing Hormone 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MPA 
Swedish Medical Product Agency 
MRI 
Magnetic Resonance Imaging 
mTOR 
mechanistic target of rapamycin 
NCI 
National Cancer Institute  
NTI 
Narrow Therapeutic Index 
OFS 
Ovarian function suppression 
ONJ 
Osteonecrosis of the Jaw 
PFS 
Progression-free survival  
PIK3 
Phosphatidylinositol-3-kinase 
PIK3CA 
Gene which encodes the p110alpha catalytic subunit of PI3K 
PR 
Progesterone receptor 
PRO 
Participant Reported Outcomes 
PT 
Preferred Term 
QOL 
Quality of life 
RANK 
Receptor activator of nuclear factor κ B 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SGLT2 
Sodium Glucose Co-Transporter 2 
SMBG 
Self-monitoring blood glucose 


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SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
TBIL 
Total bilirubin 
TFQ 
Trial Feedback Questionnaire 
ULN 
Upper Limit of Normal 
VAS 
Visual Analysis Scale 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the trial 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a trial participant  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Dosage 
Dose of the trial treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Decentralized 
Clinical Trial 
(DCTs) 
Trials executed through telemedicine and mobile/local healthcare providers, 
using processes and technologies that differ from the traditional clinical trial 
model. DCTs are conducted remotely, with participants remaining at home 
during a significant portion of the trial, also called partially decentralized or 
hybrid approaches, or all of the trial, called full DCTs. 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical trial data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant, i.e. 
the End of Trial (EOT) visit of the last ongoing patient (C12D28 or final visit for 
a patient early dropped) 
Enrollment 
Point/time of participant entry into the trial at which informed consent must be 
obtained  
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of 
the treatment effect reflecting the clinical question posed by the trial objective. 
It summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of 
an estimand include the population, variable (or endpoint) and treatment of 
interest, as well as the specification of how the remaining intercurrent events 
are addressed and a population-level summary for the variable. 
Medication 
number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the trial (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a trial used to evaluate specific objectives or contain different 
populations. For example, one trial could contain a single dose part and a 
multiple dose part, or a part in participants with established disease and in 
those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the trial for all data 
collected, sample labels, etc. 


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Patient-reported-
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about 
the status of a participant’s health condition, without amendment or 
interpretation of the patient’s report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the trial phases and will be 
used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, trial information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the trial prior to the planned 
completion of all trial drug administration and/or assessments; at this time all 
trial drug administration is discontinued and no further assessments are 
planned 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgement 
as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location within a participant’s locality 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the trial 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper 
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 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant 
Trial treatment 
Any drug or combination of drugs or intervention administered to the trial 
participants as part of the required trial procedures; includes investigational 
drug(s), control(s) or background therapy 
Trial treatment 
discontinuation 
When the participant permanently stops taking any of the trial drug(s) prior to 
the defined trial treatment completion date (if any) for any reason; may or may 
not also be the point/time of trial discontinuation  
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the trial treatment. 
Unscheduled in-
clinic visit 
Visits initially planned to be performed remotely but finally performed on site 
and unscheduled visits on site or at the local oncologist’s (regional hospital) 
will be considered as unscheduled in-clinic visits. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. 
Withdrawal of trial 
consent (WoC) 
Withdrawal of consent from the trial occurs only when a participant does not 
want to participate in the trial any longer and does not allow any further 
collection of personal data  


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Amended Protocol Version 01 
 
Protocol No. CBYL719A03201 
 
Amendment 1 (15-Jun-2021) 
Amendment rationale 
The protocol has been amended to address the request for supplementary information as 
described in the Deficiency letter received from the Swedish Health Authority (Medical 
Products Agency) on 22 April 2021 before the study started. The amended version is in 
accordance with the responses indicated by Novartis on 29 April 2021. 
Changes to the protocol 
Major changes to the protocol are listed below. Minor changes are highlighted in the track-
change version. 
• Section “Glossary of terms”: definition of “participant-reported outcomes (PRO)”, “Re-
screening” and “Remote” were added to match the most updated version of the Oncology 
protocol template. 
• Section 5.2 “Exclusion criteria”: criterion #26 was amended to exclude hormonal therapy 
as possible contraception method. 
• Section 6.2.2 “Prohibited medications”: the section was updated to specify that hormonal 
contraception is contraindicated for patients with ER positive breast cancer; therefore, it is 
not to be considered as contraception method for the trial. 
• Section 6.7 “Preparation and dispensation”: the sentence “Each shipment will be for a 
maximum of one cycle of trial treatment“ was eliminated to allow treatment continuity 
within the windows of assessments as per protocol. 
• Section 8 “Visit schedule and assessments”: section amended to include a clearer definition 
of local oncologists and district nurse, as well as the possibility to include other qualified 
healthcare professionals such as home-nursing professionals from ASIH (Swedish acronym 
meaning advanced care at home) performing standard of care procedures. Moreover, it was 
included the definition of “unscheduled visit” and the specification that, in case the 
participant cannot attend a final on site visit, they will be requested to return the study drug 
and the devices provided for the trial, through the courier. 
• Table 1-1 “Assessment schedule”: the assessment schedule was amended for the following 
assessments: 
• Included the continuous completion of e-diary by the participant. 
• e-PROs moved to Cycle 1, Day 1, specifying that they should be completed in the 
telemedicine platform, in the period between screening and Cycle 1, Day 1, before trial 
treatment administration. 
• for fasting plasma glucose (FPG) at Cycle 1, Day 1 and Cycle 1, Day 15, a note was 
added to reflect the last approved SmPC version (At Cycle 1, Day 1 and Cycle 1, Day 
15, if accepted by local approved SmPC, FPG evaluation could be replaced by self-
monitoring blood glucose (SMBG) assessment, and this will not be considered a 
protocol deviation). 
• SMBG: removed from screening and Cycle 1, Day 1, as FPG will be collected at those 
time points. SMBG will be started on Cycle 1, Day 2 


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• Considering the remote logistics and the allowed time-windows for the different 
assessments, a note was added to specify that CxD1 of each cycle is to be considered 
as the day of fulvestrant injection. 
• Participant satisfaction: TFQ questionnaire was replaced by collection of “participant 
satisfaction” and a note was added to specify that participant satisfaction will be 
collected on a quarterly basis (Day 1 of Cycles 4, 7, and 10) through Novartis standard 
Trial Feedback Questionnaire (TFQ) and, on the other Cycle x, Day 1 timepoints, 
through dedicated questions in the e-diary. 
• Sections 8.1, 8.2, 8.3, 8.4, and 8.5 were amended to reflect the above changes described in 
Table 8-1. 
• Section 8.6 “DCT elements included in the trial” was added as a new section, 
to include more operational information on the responsibilities and operational processes 
necessary to conduct the decentralized procedures/visits for participants at an off-site 
location. 
• Section 9.2 “Trial completion and post-trial treatment”: included the definition of End of 
trial, to reflect what is included in the glossary. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 
Not applicable. This is the first Protocol amendment. 
 
 
 
 
 
 
 
 
 


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Protocol summary 
 
Protocol number 
CBYL719A03201 
Full title 
Open-label, multicenter, pilot-trial evaluating the safety and utility of a 
hybrid decentralized clinical trial (DCT) approach using a TELEmedicine 
platform in patients with HR-positive/HER2-negative advanced breast 
cancer with a PIK3CA mutation treated with alpelisib – fulvestrant 
Brief title 
Study of safety and utility of a hybrid decentralized trial approach using a 
TELEmedicine platform in patients with HR-positive/HER2-negative 
advanced breast cancer with a PIK3CA mutation, treated with alpelisib – 
fulvestrant 
Sponsor and Clinical 
Phase 
Novartis Pharma AG 
Phase II 
Investigation type 
Other 
Trial type 
Interventional 
Purpose and rationale 
Novartis designed this pilot trial to answer Swedish Medical Product 
Agency’s call for launching pilot DCTs to identify and register pragmatic, 
empirical, and practical observations and experiences in connection with 
planning and implementing decentralized, patient-centered clinical trials 
at a geographic distance with virtual elements. 
Primary Objective  
To assess participant satisfaction with the DCT experience 
Secondary Objectives 
• 
To explore patient retention on DCT approach 
• 
To explore if the DCT approach ensures safe and suitable remote 
management of patients 
• 
Patient compliance to treatment 
• 
To assess adverse events (AEs) of special interest (AESIs) and AEs 
leading to in-clinic visits 
• 
To evaluate participant-reported global health status, quality of life 
(QOL) and pain 
• 
To assess the effectiveness of alpelisib plus fulvestrant 
 
Summary of qualitative research on the overall DCT experience from the 
Investigators and Clinical Trial Team will be also added in the Clinical 
Study Report. 
Trial design 
Open-label, single arm, multi-center, Phase II interventional pilot trial.  
Trial population 
Men, pre- and post-menopausal women with a HR-positive/HER2-
negative ABC (loco-regionally recurrent not amenable to curative therapy 
or metastatic) with a PIK3CA mutation, which progressed on or after 
endocrine-based treatment.  
Key Inclusion criteria 
1. Participant is an adult ≥18 years old at the time of consent 
2. Participant with ABC (loco-regionally recurrent or metastatic) not 
amenable to curative therapy. 
3. Participant with a histologically and/or cytologically confirmed 
diagnosis of ER-positive and/or PR-positive breast cancer by local 
laboratory. 
4. Participant with a confirmed HER2-negative ABC. 


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5. Participant with a pathology report confirming PIK3CA mutant status 
by a certified laboratory using a validated PIK3CA mutation assay 
(from either tissue or blood). 
6. Participant is a man or a pre- or post-menopausal woman. 
7. Participant is willing to operate a smartphone compatible with the 
software of the medical device and willing to manage applications 
8. Participant is willing to use the telemedicine platform and to follow the 
remote participant monitoring procedure. 
9. Participant has signed an informed consent form before any trial 
related activities and according to local guidelines. 
Key Exclusion criteria 
1. Participant has received prior treatment with any PI3K, mTOR, or 
AKT inhibitor. 
2. Participant with known hypersensitivity to alpelisib or fulvestrant, or to 
any of the excipients of alpelisib or fulvestrant. 
3. Participant participated in a prior investigational study within 30 days 
prior to the start of trial treatment or within 5 half-lives of the trial 
treatment, whichever is longer. 
Trial treatment 
Participants will receive alpelisib 300 mg daily and fulvestrant 500 mg 
administered intramuscularly on Cycle 1, Day 1 and Cycle 1, Day 15, and 
on Day 1 of each cycle thereafter until Cycle 12. 
Pre-menopausal women will receive goserelin 3.6 mg on Day 1 of each 
cycle. 
Treatment of interest 
Participants with risk factors for developing hyperglycemia may be 
treated, at the investigator's discretion, with SGLT2 with or without 
metformin if needed, as prophylactic treatment to prevent hyperglycemia. 
Prophylactic use of antihistamines could be considered for the treatment 
of trial drug inducted skin toxicity. 
Efficacy assessments 
Tumor imaging 
Key safety 
assessments 
Adverse event monitoring, Physical examinations, Vital signs, Monitoring 
of laboratory markers in blood, Health related quality of life using 
Participants reported outcomes 
Data analysis 
All analyses will be descriptive. 
Key words 
Pilot, Decentralized clinical trial. 


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1 
Introduction 
1.1 
Background 
Historically clinical trials rely heavily on close and frequent on-site contact between 
participants and investigators. Access to trial sites has been a challenge for patients living in 
remote and rural areas. This has contributed to a bias towards inclusion of patients living in 
urban areas. Nowadays, another way of conducting clinical trials is emerging, decentralized 
clinical trials (DCTs). The United States Food and Drug Administration (FDA) defines DCTs 
as trials executed through telemedicine and mobile/local healthcare providers, using processes 
and technologies that differ from the traditional clinical trial model. DCTs offer flexibility to 
patients participating in trials where they can remain at home for some or all visits in a trial. 
DCTs can be either full DCTs, where all activities occur away from the trial site, or Hybrid 
DCTs, where some activities remain at the trial site. DCTs have the potential to offer benefits 
to both patients and sites, but industry adoption of the model has been slow. There are several 
barriers to the uptake of DCTs including limited experience with the approach, and the 
perception of regulatory barriers with implementing and using data from DCTs 
(Apostolaros et al 2020). Industry regulations have been written for traditional trial models and 
drugs approvals to date, such as for alpelisib, were based on data collected from traditional 
trials. In light of the COVID-19 pandemic, there is a critical need to ensure continued participant 
safety, study oversight, assurance of data integrity, and continuity of treatment which provided 
an impetus to accelerate towards more patient-centric DCTs. The most common DCT 
components implemented during the pandemic were telemedicine, electronic informed consent, 
digital data collection tools, remote site monitoring, direct to patient shipping, home health 
visits, and local community-based laboratory utilization. Future trials need to capitalize on the 
increased adoption and learning from the use of DCT components that occurred in this time of 
crisis. 
On 28 May 2020, the European Medicines Agency’s (EMA’s) Committee for Medicinal 
Products for Human Use (CHMP) adopted a positive opinion recommending the granting of a 
marketing authorization for the medicinal product alpelisib (Piqray®). Alpelisib, an orally 
administered PI3K inhibitor that selectively inhibits the α‑isoform of PIK3, p110α, was 
developed to answer the need to treat postmenopausal women, and men, with hormone-receptor 
(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced 
or metastatic breast cancer with a PIK3CA mutation after disease progression following 
endocrine therapy. Marketing authorization was granted based on safety and efficacy data 
obtained through a traditional clinical trial, the SOLAR-1 trial. The SOLAR-1 trial was a 
randomized, double-blind, placebo-controlled Phase 3 trial where men and postmenopausal 
women with HR-positive/HER2-negative advanced breast cancer (ABC) were assigned to 
cohorts based on their tumor-tissue PIK3CA mutation status and randomized 1:1 to receive 
either treatment with alpelisib plus fulvestrant or placebo + fulvestrant. Participants in the 
SOLAR-1 trial were mandated to attend several on-site visits: Day 1, Day 8, and Day 15 of 
Cycle 1; Day 1 and Day 15 of Cycle 2; and Day 1 of subsequent cycles. 
SOLAR-1 trial primary endpoint was progression-free survival (PFS) in the PIK3CA-mutated 
cohort, as assessed by the investigator according to response evaluation criteria in solid tumors 
(RECIST) version 1.1. The trial showed a statistically significant improvement in PFS in favor 


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of the alpelisib plus fulvestrant arm (hazard ratio = 0.65; 95% confidence interval [CI]: 0.50, 
0.85), 1-sided p < 0.001). The median PFS was prolonged by 5.3 months, from 5.7 months 
(95% CI: 3.65, 7.36) in the placebo + fulvestrant arm to 11.0 months (95% CI: 7.5, 14.5) in the 
alpelisib plus fulvestrant arm. No PFS benefit was observed in patients without a PIK3CA 
mutation (Andre et al 2019). 
The safety profile of alpelisib plus fulvestrant is based on the combined PIK3CA mutant and 
non‑mutant cohort data of the SOLAR-1 trial. Medical dictionary for regulatory activities 
(MedDRA) preferred terms of any grade reported in at least 35% of the patients who received 
alpelisib plus fulvestrant were hyperglycemia (63.7%), diarrhea (57.7%), nausea (44.7%), 
decreased appetite (35.6%), and rash (35.6%) or maculopapular rash (14.1%). The most 
common adverse events (AEs) of grade 3 or 4, occurring in at least 5% of patients were 
hyperglycemia (36.6%), rash (9.9%), maculopapular rash (8.8%), and diarrhea (6.7%). 
Permanent discontinuation of alpelisib due to AEs occurred in 25.0% of patients receiving 
alpelisib plus fulvestrant. The most frequent AEs leading to the discontinuation of alpelisib 
were hyperglycemia (6.3%) and rash (3.2%) (Andre et al 2019). 
1.2 
Purpose 
DCTs will enable more diversity in clinical trials and increase enrollment of historically 
underrepresented patients in clinical research. In Sweden, the distribution of ABC patients is 
widespread and often there are limited sites options for clinical trial participation. The purpose 
of this pilot trial is to describe if the hybrid DCT approach is satisfactory, safe and suitable for 
ABC patients treated with alpelisib, which has a balanced safety profile. 
Additionally, the Swedish Medical Products Agency (MPA) is seeking to gain experience from 
DCT pilots with the aim to identify and register pragmatic, empirical, and practical observations 
and experiences in connection with planning and implementing decentralized, patient-centered 
clinical trials at a geographic distance with virtual elements. This trial was selected as a part of 
the MPA pilot program and is designed as a hybrid DCT. 


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2 
Objectives, endpoints, and estimands 
Table 2-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary Objective 
• 
To assess participant satisfaction with the 
DCT experience 
Endpoint for primary objective 
• 
Participant satisfaction, assessed at the start 
of the trial, every 12 weeks, and at the end 
of trial through the Trial Feedback 
Questionnaire (TFQ) 
Secondary Objectives 
• 
To explore patient retention on DCT 
approach 
 
Endpoints for secondary objectives 
• 
Proportion of participants on remote 
monitoring at 3, 6, 12 months for participants 
still on treatment. 
Statistical assumptions (descriptive): targeted 
proportion of patients remaining on remote monitoring 
after 6 months, 75% 
Note: unscheduled in-clinic visit does not exclude for 
DCT monitoring 
• 
To explore if the DCT approach ensures 
safe and suitable remote management of 
patients 
• 
Total number of unscheduled in-clinic visits 
because of safety reasons 
• 
Total number of unscheduled in-clinic visits 
and the reason 
• 
Number of unscheduled in-clinic visits per 
participant in the study 
• 
Discontinuation rate related to adverse 
events 
Note: Visits initially planned to be performed remotely 
but finally performed on site and unscheduled visits 
on site or at the local oncologist’s (regional hospital) 
will be considered as unscheduled in-clinic visits. 
Visits that require treating oncologists or district 
nurses assessments are considered unscheduled 
visits. 
• 
Patient compliance to treatment  
• 
Overall compliance 
• 
To assess AEs of special interest (AESIs) 
and AEs leading to in-clinic visits 
 
• 
Type, frequency and severity of AESIs 
(hyperglycemia, rash, and diarrhea) per 
Common Terminology Criteria for Adverse 
events (CTCAE) v4.03 (incidence 
proportion) 
• 
Number and proportion of AEs leading to in-
clinic visits 
 
• 
To evaluate participant-reported global 
health status, quality of life (QOL) and pain 
 
• 
Change in scores of participant reported 
outcome (PRO) questionnaire (within same 
participant) from baseline to each time point 
of questionnaire administration (every 12 
weeks) 
 


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Objectives 
Endpoints 
• 
To assess the effectiveness of alpelisib plus 
fulvestrant 
• 
PFS according to RECIST 1.1 


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2.1 
Primary estimands 
Primary estimands have not been described as trial is not planning any hypothesis testing. 
2.2 
Secondary estimands 
Secondary estimands have not been described as trial is not planning any hypothesis testing. 


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3 
Trial design 
This is an open-label, single arm, multi-center, Phase II interventional pilot trial conducted to 
evaluate if a DCT using a telemedicine platform offers a satisfactory, safe and suitable 
management for HR-positive/HER2-negative patients with ABC harboring a PIK3CA mutation 
and treated with alpelisib plus fulvestrant. 
In this pilot trial, approximately 20 participants living in a geographically well-defined region 
in Sweden will be treated with alpelisib plus fulvestrant after progression on an endocrine-based 
therapy. Upon enrollment in the trial (i.e., completion of the informed consent form [ICF]), 
participants will attend on-site visits for screening and on Cycle 1, Day 1. During the Cycle 1, 
Day 1 visit, participants will be trained on using the telemedicine platform and other monitoring 
devices to be used during remote participation: a glucometer and a smartphone with the 
telemedicine application installed. During this visit, participants will initiate treatment with 
alpelisib plus fulvestrant. Pre-menopausal women will be treated with goserelin, a luteinizing 
hormone-releasing hormone (LHRH) agonist, concomitantly with alpelisib plus fulvestrant. 
Participants with risk factors for developing hyperglycemia and participants who had a first 
fasting glucose level above the normal range (onset of hyperglycemia) may be treated, at the 
investigator's discretion, with sodium glucose co-transporter 2 (SGLT2 inhibitors) with or 
without metformin if needed, as prophylactic treatment to prevent hyperglycemia. 
Following this visit, investigators will transition participants to remote participation enabled by 
the telemedicine platform with support of local healthcare providers under the investigator’s 
oversight (see Section 8 “Visit schedule and assessments” for additional details on visit 
schedule during remote participation). Treatment with alpelisib plus fulvestrant will continue 
until end of trial, disease progression, intolerable toxicity or participants/investigators’ decision. 
Participants will be followed remotely up to 12 cycles of treatment or until treatment 
discontinuation, death, withdrawal of consent, or loss to follow-up, whichever occurs first. 
Discontinuation of remote participation is not a reason for trial discontinuation. Participants 
who do not wish to continue with remote participation will have the option to attend on-site 
visits. For each participant, the trial will conclude with an on-site end of trial (EOT) visit. 
Throughout the trial, investigators will be asked to provide their inputs on DCT approach on a 
regular basis. 


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Figure 3-1 
Trial design 
 
Screening 
28 days 
Trial Treatment 
C1, D1 
Visit 
Cycle 1 to Cycle 12 
EOT 
Visit 
On-Site 
Remote Participation 
Through telemedicine platform with support of a local oncologist and a district nurse 
On-Site 
 
 
+ goserelin in pre-menopausal women 
± SGLT2 inhibitors with or without metformin in participants at risk of 
hyperglycemia[a] and in participants who had a first fasting glucose level 
above the normal range (onset of hyperglycemia) (at the investigators 
discretion) 
 
[a] baseline BMI ≥ 30, baseline age ≥ 75 years, and baseline diabetic and pre-diabetic status have been found to 
be risk factors for hyperglycemia in patients treated with alpelisib. 
BMI= body mass index, C1, D1 = Cycle 1, Day 1; EOT = End of trial; SGLT2 = sodium glucose co-transporter 2 
alpelisib + fulvestrant 


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4 
Rationale 
4.1 
Rationale for trial design 
This trial is a single arm, open-label trial conducted in HR-positive/HER2-negative patients 
harboring a PIK3CA mutation and treated with alpelisib plus fulvestrant. This trial included a 
hybrid DCT approach to reduce participant burden of traveling to sites and enable enrollment 
of patients living far from investigative sites that may not have consented to participate in 
traditional clinical trials. Expected benefits of using a decentralized approach are (1) reduced 
burden on participants by bringing visits, services, and supplies closer to them, leading to 
increased access to trial (see Section 4.5.1 “Potential benefits for participants”), (2) potential 
improvement of participant recruitment (e.g., geographic diversity of recruitment), (3) potential 
to increase adherence to protocol and participant retention. 
Based on alpelisib safety profile, the following AESIs will be particularly looked at in this pilot 
trial: hyperglycemia, rash, and diarrhea. For hyperglycemia, a medical device will be used for 
blood glucose measurements. For rash, participants will take a photograph using the 
telemedicine application and upload the photograph to the platform for the investigator’s 
evaluation. Investigators will refer participants to the local oncologists when required. For 
diarrhea, participants will be trained to recognize signs and symptoms and will be instructed to 
contact investigators whenever they occur. 
Pain and health-related QOL will be surveyed using questionnaires administered through the 
telemedicine platform. 
Participants at risk of hyperglycemia and participants who had a first fasting glucose level above 
the normal range (onset of hyperglycemia) may be treated, at the investigator's discretion, with 
SGLT2 inhibitors with or without metformin as prophylactic treatment. Based on the data from 
the SOLAR-1 trial, baseline body mass index (BMI) ≥ 30, baseline age ≥ 75 years, and baseline 
diabetic and pre-diabetic status have been found to be risk factors for hyperglycemia in patients 
treated with alpelisib; these risk factors were present in 74.7% of patients with any grade of 
hyperglycemia and in 86.2% of patients with grade 3 or 4 hyperglycemia. As baseline diabetic 
and pre-diabetic status are defined based on baseline hemoglobin A1c (HbA1c) and fasting 
plasma glucose (FPG) values, these values will be closely monitored during the trial. 
Following expert opinion of the European School of Oncology (ESO) and European Society 
for Medical Oncology (ESMO) (Cardoso et al 2020), and from the Swedish guidelines for 
treatment of metastatic breast cancer (Cancercentrum 2019), it is recommended that young 
women with ER-positive ABC should have adequate ovarian function suppression (OFS) or 
ovarian function ablation. These young women should then be treated in the same way as 
postmenopausal women. Pre-menopausal women will be eligible for the trial even though this 
is outside of alpelisib label. These women will receive goserelin a LHRH agonist, as a co-
therapy to induce OFS. 
Participants with prior endocrine-based therapy with or without cyclin-dependent kinases 4 and 
6 inhibitors (CDK4/6i) will be eligible for trial participation; even though participants 
previously treated with concomitant CDK4/6i treatments are outside of alpelisib label. 
Endocrine 
therapy 
are 
considered 
the 
standard 
of 
care 
for 
patients 
with 
ER-positive/HER2-negative ABC, since it achieves substantial PFS benefit, significantly 


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increases OS and either maintains or improves QOL. The BYLieve study was originally 
designed to investigate the benefit:risk ratio of PIK3CA inhibitor treatment following prior use 
of CDK4/6 inhibitor treatments. BYLieve trial is a Phase II, multicenter, open-label, 3-cohort, 
non-comparative study of Piqray plus endocrine therapy (fulvestrant or letrozole) in men and 
women with ER-positive/HER2-negative, PIK3CA-mutated advanced breast cancer whose 
disease has progressed after prior therapy, including CDK4/6i (Rugo et al 2018). Results from 
the cohort of patients with CDK4/6i +aromatase inhibitor as an immediate prior treatment and 
centrally confirmed PIK3CA mutation (n = 121) have been published (Rugo et al 2020). The 
primary endpoint was the proportion of patients who are alive without disease progression at 6 
months (RECIST v1.1; local assessment). The AE analysis was based on preferred terms. Based 
on a median follow-up of 11.7 months, 50.4% of patients (95% CI: 41.2 to 59.6) met the primary 
endpoint. The most frequent all-grade AEs and grade ≥ 3 AEs in this BYLieve cohort were 
similar to those reported in SOLAR-1. 
4.2 
Rationale for dose/regimen and duration of treatment 
As alpelisib is already marketed in Europe, this protocol will mandate dosing follows the 
recommendations per the summary product characteristics (Piqray® SmPC, Novartis). Based 
on the 11.0-month median PFS in the alpelisib plus fulvestrant group in the cohort of patients 
with PIK3CA-mutated cancer (Andre et al 2019), trial duration is planned to be 12 cycles of 28 
days of treatment each. 
4.3 
Rationale for choice of combination drugs 
Fulvestrant 
Per alpelisib SmPC, alpelisib is indicated in combination with fulvestrant for the treatment of 
postmenopausal women, and men, with HR-positive/HER2-negative, locally advanced or 
metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine 
therapy. The combination of alpelisib and fulvestrant demonstrated increased anti-tumor 
activity compared to either treatment alone in xenograft models derived from estrogen receptor 
positive, PIK3CA mutated breast cancer cell lines (Piqray® SmPC, Novartis). 
Goserelin 
Endocrine treatment is a standard treatment option for pre-menopausal women with ABC. As 
it is generally admitted that pre-menopausal women exhibit a more aggressive disease with a 
poorer prognosis than other women and given that, despite several treatment options, resistance 
to endocrine therapy and disease progression occur in pre-menopausal women, there is a need 
for new therapeutic options. International ESO-ESMO guidelines and Swedish guidelines for 
treatment of metastatic breast cancer state that pre-menopausal women should be treated like 
post-menopausal women upon OFS (Cancercentrum 2019; Cardoso et al 2020). OFS can be 
induced, among other options, by administration of LHRH agonist. It is recommended to give 
LHRH agonists on an every 4 weeks basis to optimize OFS (Cardoso et al 2020). In the phase 
Ib B-YOND trial, pre-menopausal women with HR-positive ABC were treated with alpelisib 
and buparlisib. Interim data conducted in a small group of 16 patients treated with alpelisib in 
combination with tamoxifen and goserelin achieved 44% clinical benefit rate with 7 (44%) 


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patients achieving partial response per RECIST v1.1 as best overall response. Safety profile 
was generally manageable. These interim results led to conclusion that these pathways should 
also be further explored in this pre-menopausal population (Lu et al 2017). As goserelin is 
currently approved for the palliative treatment of pre-menopausal and peri-menopausal ABC, 
pre-menopausal women will be offered the possibility to be treated off-label with alpelisib plus 
fulvestrant with the addition of goserelin in this pilot trial. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not Applicable. 


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4.5 
Risks and benefits 
4.5.1 
Potential risks to participants 
This pilot hybrid DCT was designed using a registered drug with participants being managed 
according to clinical practice. Risks to participants will be limited as the investigator is able to 
anticipate possible reactions to trial treatment and efficiently manage any adverse drug 
reactions. For details on clinical safety, please refer to the latest version of alpelisib SmPC 
(Piqray® SmPC, Novartis) and fulvestrant SmPC (Faslodex® SmPC, Astra Zeneca). The 
addition of goserelin to premenopausal women is not expected to affect the metabolism of 
participants, or to be affected by co-administration of the other drugs (alpelisib in combination 
with fulvestrant), so no additional safety risks are expected with this combination. Risks will 
also be minimized by adherence to inclusion/exclusion selection criteria (see Section 5 “Trial 
Population”), avoidance of prohibited medication (see Section 6.2.2 “Prohibited medication”), 
close safety monitoring (see Section 6.5.1 “Follow-up for toxicities” and Section 10 “Safety 
monitoring and reporting”), adherence to dose adjustment guidelines (see Section 6.5 “Dose 
escalation and dose modification”), and training of site personnel. Participants will be trained 
to report symptoms via the telemedicine application as soon as possible as they occur. Safety 
management in a DCT is the same as in the traditional clinical trial. The investigator is 
responsible for identifying, managing, and assessing safety events reported and must use their 
medical judgment to determine the appropriate care needed to address any AEs. The platform 
will support the Investigator in overseeing the participant with summary reports and 
notifications. 
The participant can return to on-site visits at any time at the investigator’s and the participant’s 
discretion. 
Women of childbearing potential and sexually active males must be informed that taking this 
trial treatment may involve unknown risks to the fetus if pregnancy was to occur during the trial 
and up to the period required after the last dose of trial treatment. Based on findings in animals 
and its mechanism of action, alpelisib can cause fetal harm when administered to a pregnant 
woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and 
rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal 
mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal 
malformations at maternal exposures based on area under the curve that were ≥ 0.8 times the 
exposure in humans at the recommended dose of 300 mg/day. Pregnant women and females of 
reproductive potential should be advised of the potential risk to a fetus. Participants must 
therefore agree to adhere to the contraception requirements outlined in the exclusion criteria. If 
there is any question that the participant will not reliably comply, they should not be entered or 
continue in the trial. 
Sufficient training on the use of monitoring devices (glucometer and smartphone) is required to 
avoid any additional burden on participants. Participants in the SOLAR-1 trial had a median 
age of 63 years, the telemedicine platform was selected for its user-friendliness and specific 
inclusion criteria have been included to ensure that all enrolled participants will be able to 
adhere to the remote participation (see Section 4.5.3 “Risk management strategies” for 
additional details). 


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In DCTs, trial conduct is centered around the patient rather than the site, this means that each 
patient may have a different local oncologist and district nurse, to support care local to them. 
As such, this increases the number of parties that support data collection for the trial. Ensuring 
data privacy and security is essential, the telemedicine platform selected uses measures such as 
encryption, access controls and audit trails to ensure integrity, reliability and security of data 
flow (see Section 4.5.3 “Risk management strategies” for additional details). 
4.5.2 
Potential benefits for participants 
The hybrid approach is expected to reduce participant burden associated with traditional clinical 
trials, which involve frequent and lengthy on-site visits. The introduction of remote visits 
(facilitated by telemedicine, home health visits and direct-to-patient shipping of the trial 
medication) reduces the travel burden for participants; saving in turn participant’s time, effort, 
and possibly money. Use of remote visits can reduce geographic barriers to participation and 
allow for recruitment of a larger pool of participants, especially those in more remote (non-
urban) areas and/or those who do not drive and/or have easy access to transportation. This is 
particularly true for a geographically large country, such as Sweden, where patients oftentimes 
need to travel long distances to attend visits. 
It is anticipated that the reduced number of on-site visits will decrease participant burden and 
improve their satisfaction in taking part in this clinical trial, resulting in a lower drop-out rate. 
A survey conducted in 4,086 patients across the United States and Europe highlighted the 
importance for participants to keep relationships with site personnel and 40% of respondents 
indicated that they would prefer clinical trial tests to be performed through a hybrid design 
(Goller and Kinlaw 2020). The hybrid approach will allow participants to maintain contact with 
investigators, both face-to-face during clinic visits at site or through the telemedicine platform 
during remote participation. Participants will be closely monitored by the investigator via the 
telemedicine platform and the investigator will also have oversight of the local oncologist and 
district nurse. Investigators will keep the responsibility and authority to make decision for all 
aspects related to the management of participants during the entire clinical trial duration. 
4.5.3 
Risk management strategies 
Processes have been implemented to efficiently manage risks related to participants’ safety. 
Training of investigative staff and participants will be critical to ensure the success of remote 
participation. Prior to site initiation, investigational sites will be trained on the telemedicine 
platform, including both site and participant facing components, how to use the glucometer, and 
on processes unique to this DCT. At the Cycle 1, Day 1 Visit, participants will be trained by 
site staff on how to use the telemedicine application, in particular how to use the features to 
communicate with the site, and on how to use the glucometer. Investigators will ensure that 
participants feel at ease with the telemedicine application and are comfortable with the use of 
the glucometer prior to remote participation. Protocol selection criteria ensure enrolled 
participants are comfortable with the concept of remote participation. 
Processes mandated in the SmPC for patients with diabetes, pre-diabetes or a risk factor for 
hyperglycemia will be extended to all participants. Participants will be requested to perform 
daily self-assessment of their blood glucose levels using a glucometer during the first two weeks 
of treatment, or longer when the risk is higher, and to have their blood drawn for fasting plasma 


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glucose measurement at least once per cycle. Participants will be instructed to contact site 
personnel in case they identify a high glucose value using the glucometer (equal or higher than 
8.9 mmol/L) and the investigator will be able to monitor all reported glucose values in the 
telemedicine platform. Laboratory confirmation of self-measured high glucose values may be 
requested if deemed necessary by the investigator. The investigator will use clinical judgment 
to guide the management plan for each participant based on an individual benefit/risk 
assessment. See Section 6.5.1.3 “Guideline for the treatment of alpelisib-induced 
hyperglycemia” for additional details. 
Rash will be reported through the telemedicine platform. Site personnel will assess pictures of 
the rash uploaded by participants in the telemedicine platform. Site personnel will decide how 
the event should be managed or, if needed, will refer participants to the local healthcare provider 
for further assessment. See Section 6.5.1.2 “Guidelines for the treatment of trial drug induced 
skin toxicity”. 
Participants will be trained to recognize signs and symptoms of diarrhea and will be instructed 
to contact their investigator whenever they occur. Investigators will manage symptomatic 
treatment according to their current clinical practice. Process management of study drug to be 
followed in case of diarrhea is described in Table 6-3 “Criteria for dose reduction/interruption 
and re-initiation of alpelisib for adverse drug reactions”. 
Ensuring integrity, reliability and security of data flow is of the highest priority. Novartis 
assessed and qualified a telemedicine platform including direct capture of source data within a 
secure electronic environment. Data captured within this pilot trial will be stored in a robust and 
secure cloud-based back end; access to data will be role-based and restricted. The selected 
platform is a validated system complying with relevant International Conference for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Specific measures are built into 
the telemedicine platform to ensure integrity and security or data flow and storage, access 
control measures, and audit trail functionality will be described in a separate operational manual 
that will be provided to investigators. 
The glucometer that will be provided to participants is validated and CE marked, and will be 
employed in the study for its intended use. 
In light of the most recent guidelines, risks associated with the COVID-19 pandemic were 
evaluated and no additional risks were identified for this DCT. A COVID-19 test will not be 
mandated, but patients with COVID-19 symptoms at screening will not be enrolled in the trial. 
Specific measures will be taken according to local guidelines to prevent Sars-Cov-2 
contamination during home visits. 
Based on key anticipated benefits and potential risks, the benefit-risk balance is anticipated to 
be positive for the target population of this trial. 
4.6 
Rationale for public health emergency mitigation 
During a Public Health emergency declared by Local or Regional authorities, i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
should be implemented. Design of this protocol already meets Novartis guidelines in terms of 
Public Health Emergency Mitigation. Notification of the Public health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures, and 


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permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate. 
5 
Trial population 
The trial will include approximately 20 participants HR-positive/HER2-negative ABC (loco-
regionally recurrent not amenable to curative therapy or metastatic) with a PIK3CA mutation 
(refer to alpelisib SmPC for details on PIK3CA mutation, (Piqray® SmPC, Novartis), which 
progressed on or after endocrine-based treatment. Participants will be enrolled in a 
geographically well-defined region in Sweden. 
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 trial. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this trial must meet all of the following criteria: 
1. Participant is an adult ≥ 18 years old at the time of consent 
2. Participant with ABC (loco-regionally recurrent or metastatic) not amenable to curative 
therapy. 
3. Participant with a histologically and/or cytologically confirmed diagnosis of ER-positive 
and/or PR-positive breast cancer by local laboratory. 
4. Participant with a confirmed HER2-negative ABC. 
HER2-negative defined as a negative in situ hybridization test or an immunohistochemistry 
status of 0, 1+ or 2+. If immunohistochemistry is 2+, a negative in situ hybridization 
(Fluorescence In Situ Hybridization, Chromogenic In Situ Hybridization, or Silver In Situ 
Hybridization) test is required by local laboratory testing. 
5. Participant with a pathology report confirming PIK3CA mutant status by a certified 
laboratory using a validated PIK3CA mutation assay (from either tissue or blood). 
It is recommended the tumor sample is collected after the most recent progression or 
recurrence. 
6. Participant had progression of disease during or after endocrine-based therapy. 
Aromatase inhibitor therapy does not need to be the latest treatment regimen. 
7. Participant has a Performance Status at screening and at Cycle 1, Day 1 visit lower than or 
equal to 1 (ECOG/WHO PS ≤ 1) 
8. Participant has adequate bone marrow and organ function as defined in the following 
laboratory valued (as assessed by site laboratory for eligibility): 
• Absolute neutrophil count ≥ 1.5 × 109/L 
• Platelets ≥ 100 × 109/L 
• Hemoglobin ≥ 9.0 g/dL 
• Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ Grade 
1 according to National Cancer Institute (NCI)-CTCAE version 4.03 if judged clinically 
not significant by the investigator 
• International normalized ratio (INR) ≤ 1.5 


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• Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula 
• Total bilirubin < 2 × upper limit of normal (ULN; any elevated bilirubin should be 
asymptomatic at enrolment) except for participants with Gilbert’s syndrome who may 
only be included if total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN 
• Potassium within normal limits, or corrected with supplements 
• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) < 3 × ULN. If the participant has liver metastases, ALT and 
AST ≤ 5 × ULN (elevated ALT or AST values must be stable for 2 weeks, without 
evidence of biliary obstruction by imaging) 
• Fasting Serum amylase ≤ 2 × ULN 
• Fasting Serum lipase ≤ ULN 
• FPG ≤ 140 mg/dL (7.7 mmol/L) and Glycosylate Hemoglobin (HbA1c) ≤ 6.4% (both 
criteria have to be met) 
9. Participant is a man or a pre- or post-menopausal woman 
Post-menopausal status is defined either by: 
• Prior bilateral oophorectomy or 
• Age ≥ 60 or 
• Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH) 
and/or estradiol in the post-menopausal range per local normal range. If patient is taking 
tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should be 
in post-menopausal range per local normal range. 
Note: For women using therapy-induced amenorrhea other than ovarian radiation or 
goserelin, serial measurements (per local guidelines) of FSH and/or estradiol are needed 
to ensure menopausal status. 
Pre-menopausal status is defined as either: 
• Patient had last menstrual period within the last 12 months 
OR 
• If on tamoxifen or toremifene during the past 14 days, plasma estradiol and FSH must 
be in the premenopausal range per local normal range, 
OR 
• In case of therapy-induced amenorrhea, plasma estradiol and/or FSH must be in the 
premenopausal range per local normal range 
10. Participant is willing to operate a smartphone including the telemedicine application and a 
medical device (glucometer) 
11. Participant is willing to follow the requirements for remote participation. 
12. Participant has signed ICF before any trial related activities and according to local 
guidelines. 


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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this trial. 
1. Participant has received prior treatment with any PI3K, mTOR, or AKT inhibitor. 
2. Participant with known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients 
of alpelisib or fulvestrant. 
3. Participant has had major surgery within 14 days prior to trial treatment start and/or has not 
recovered from major side effects. 
4. Participant with inflammatory breast cancer at screening. 
5. Participant with an established diagnosis of diabetes mellitus type I or not controlled type 
II (based on fasting glucose [FG] and HbA1c, see inclusion criterion 8) 
6. Participant with impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of the trial treatments (e.g., ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection) based on investigator discretion. 
7. Participant has currently documented pneumonitis/interstitial lung disease (the chest 
Computerized Tomography (CT) scan performed at baseline for the purpose of tumor 
assessment should be reviewed to confirm that there are no relevant pulmonary 
complications present). 
8. Participant with Child Pugh score B or C. 
9. Participant with uncontrolled hypertension defined by a Systolic Blood Pressure 
≥ 160 mmHg and/or Diastolic Blood Pressure ≥ 100 mmHg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is 
allowed prior to screening. 
10. Participant with clinically significant, uncontrolled heart disease and/or recent cardiac 
events including any of the following: 
• History of angina pectoris, coronary artery bypass graft, symptomatic pericarditis, or 
myocardial infarction within 6 months prior to the start of trial treatment 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• History of Left Ventricular Ejection Fraction < 50% 
• Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left 
bundle branch block, high grade atrioventricular (AV) block (e.g. bifascicular block, 
Mobitz type II and third degree AV block without pacemaker in place) 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or Fredericia QT correction formula (QTcF) > 470 msec at screening 
11. Participant with any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, contraindicate participant participation in the clinical 
trial (e.g., chronic active hepatitis, [testing not mandatory unless required by local 
regulations or requirements] confirmed pneumonitis etc.). 
12. Participant is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to the start of the treatment: 
• Strong cytochrome P (CYP)3A4 inducers  


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• Inhibitors of breast cancer resistance protein (BCRP) 
13. Participant has a history of acute pancreatitis within 1 year of screening or past medical 
history of chronic pancreatitis. 
14. Participant with unresolved osteonecrosis of the jaw. 
15. Participant has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome, 
Erythema Multiforme, or Toxic Epidermal Necrolysis, or Drug Reaction with Eosinophilia 
and Systemic Symptoms. 
16. Participant with evidence of disease progression during the pre-trial induction therapy and 
prior to first dose of alpelisib. 
17. Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation 
≤ 2 weeks prior to trial treatment initiation, and who has not recovered to grade 1 or better 
from related side effects of such therapy (with the exception of alopecia). 
18. Participant is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior 
to starting trial treatment, or who have not fully recovered from side effects of such 
treatment. 
Note: The following uses of corticosteroids are permitted: single doses, topical applications 
(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular). 
19. Participant participated in a prior investigational study within 30 days prior to the start of 
trial treatment or within 5 half-lives of the trial treatment, whichever is longer. 
20. Participant has not recovered from all toxicities related to prior anticancer therapies to NCI 
CTCAE version 4.03 Grade ≤ 1. Exception to this criterion: participants with any grade of 
alopecia are allowed to enter the trial. 
21. Participant has a concurrent malignancy or malignancy within 3 years of start of trial 
treatment, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer, or curatively resected cervical cancer. 
22. Participant has central nervous system (CNS) involvement which was not previously treated 
and not fulfilling the following 3 criteria to be eligible for the trial: 
• Completed prior therapy (including radiation and/or surgery) for CNS metastases 
≥ 28 days prior to the start of trial entry and 
• CNS tumor is clinically stable at the time of screening and 
• Participant is not receiving steroids and/or enzyme inducing anti-epileptic medications 
for brain metastases. 
23. Participant has a known history of Human Immunodeficiency Virus infection (testing not 
mandatory unless required by local regulations or requirements). 
24. Participant is not able to understand and to comply with trial instructions and requirements, 
including oral administration of trial treatment. 
25. Participant is a nursing (lactating) or pregnant woman as confirmed by a positive serum 
(hCG) test prior to initiating trial treatment. 
26a. Participant is a woman of child-bearing potential defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of contraception 
during trial treatment and at least for 2 years after the last dose of any trial treatment. Highly 
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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking 
trial treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
trial the vasectomized male partner should be the sole partner for that participant 
Note: Hormonal contraception is contraindicated for patients with ER positive breast 
cancer, therefore it is not to be considered as a contraception method for the trial. 
Note: Women are considered postmenopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., 
age appropriate, history of vasomotor symptoms. Women are considered not of child 
bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 
weeks before starting trial treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
If local regulations to prevent pregnancy deviate from the contraception methods listed 
above, local regulations apply and will be described in the ICF. 
27. Participant is a sexually active male unwilling to use a condom during intercourse while 
taking trial treatment, and for 2 years after the last dose of trial treatment. A condom is 
required for all sexually active male participants to prevent them from fathering a child 
AND to prevent delivery of trial treatment via seminal fluid to their partner. In addition, 
male participants must not donate sperm during the trial and up to the time period specified 
above. 
28. Participants with active infections, including a COVID-19-related diagnosis. 
6 
Treatment 
6.1 
Trial treatments 
Participants will be administered alpelisib 300 mg daily (2 × 150 mg film-coated tablets) for 
12 cycles of 28 days and fulvestrant 500 mg administered intramuscularly on Cycle 1, Day 1 
and Cycle 1, Day 15, and on Day 1 of each cycle thereafter until Cycle 12 (see Table 6-1). 


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Table 6-1 
Trial treatments 
Drugs 
 
Pharmaceutical Form and 
route of administration 
Dose 
Frequency and/or regimen 
MAH 
Alpelisib 
(Piqray®) 
Film coated tablet for oral use 
300 mg 
Daily (continuous) starting Cycle 
1, Day 1 
Novartis 
Fulvestrant 
(Faslodex®) 
Injection for intra-muscular 
administration 
500 mg 
Days 1 and Day 15 on Cycle 1 
and Day 1 at each cycle 
thereafter 
AstraZeneca 
AB 
MAH= Marketing Authorization Holder 
6.1.1 
Additional trial treatments 
Depending on menopausal status, women participants may be prescribed goserelin as co-
therapy with alpelisib and fulvestrant to induce OFS (see Table 6-2). 
Table 6-2 
Co-therapies 
Drugs 
 
Pharmaceutical Form and 
route of administration 
Dose 
Frequency and/or regimen 
Goserelin 
Injection for intra-muscular 
administration 
3.6 mg 
Starting Cycle 1, Day 1 and Day 
1 at each cycle thereafter 
6.1.2 
Treatment arms/group 
All participants enrolled within this trial will receive the same treatment. 
6.1.3 
Treatment duration 
The planned duration of treatment is 12 cycles of 28 days. Participants may be discontinued 
from treatment earlier than the planned treatment duration due to unacceptable toxicity, disease 
progression and/or decision made at the discretion of the investigator or the participant. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
6.2.1.1 
Permitted concomitant medications 
The use of any concomitant medications/non-drug therapies deemed necessary to treat AEs, 
manage cancer symptoms, concurrent diseases and supportive care agents, such as pain 
medications, anti-emetics and anti-diarrheal are allowed, except if specifically prohibited (See 
Section 6.2.2 “Prohibited medication”). 
All medications, procedures, and significant non-drug therapies (including vitamins, physical 
therapy, herbal/natural medications and blood transfusions) administered within 30 days prior 
to the start of trial treatment must be recorded on the appropriate electronic Case Report Form. 
The investigator should instruct the participant to notify the trial site about any new medications 
and/or non-drug therapies/procedures he/she takes after signing the informed consent. Each 
concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 


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already enrolled, contact Novartis to determine if the participant should continue participation 
in the trial. 
Oral anti-diabetics 
Participants who develop hyperglycemia during the trial should be treated according to the 
ADA (American Diabetes Association) guidance. 
Consultation with a diabetologist or healthcare provider experienced in the management of 
hyperglycemia is highly recommended for better assessment and management of alpelisib-
induced hyperglycemia. It is recommended to start treatment with metformin, however SGLT2 
inhibitors may be a suitable alternative or add-on therapy to metformin. SGLT2 inhibitors are 
a class of diabetic medications that improve hyperglycemia primarily by promoting urinary 
glucose excretion. 
In the SOLAR-1 study, among the 284 participants who were randomized to receive alpelisib 
plus fulvestrant, 190 participants (67%) developed hyperglycemia, with 18 patients (6%) 
discontinuing alpelisib treatment due to hyperglycemia, as of 30-Sep-2019. 
Among those with hyperglycemia, 166 participants received concomitant anti-diabetic 
medications, primarily consisting of metformin (87%). However, in addition to metformin, 
6 participants also received an SGLT2 inhibitor, consisting of empagliflozin, ipragliflozin, or 
dapagliflozin. All 6 participants had ≥ 1 risk factor at baseline for developing hyperglycemia, 
defined as prediabetes (n = 4; 1 of whom had documented history of type 2 diabetes), diabetes 
(n = 2), and obesity (n = 2). The most severe hyperglycemia in these participants was grade (G) 
3 (n = 5). After initiating an SGLT2 inhibitor, all subsequent hyperglycemia events were G 1/2, 
except one G 3 event with steroids as a confounding factor. The duration of alpelisib ranged 
from 9.5 to 27.7 months in these 6 participants who discontinued alpelisib; and notably, 2 
participants were continuing to receive alpelisib after 37.0 and 40.0 months, respectively. None 
of the 6 participants discontinued alpelisib due to hyperglycemia. 
Based on these data, participants may benefit from the initiation of an SGLT2 inhibitor with 
metformin, which is available as a single oral combination pill or as two separate medications. 
Particularly in participants with at least one risk factor for the development of severe 
hyperglycemia, defined as prediabetes/diabetes, and/or obesity (BMI ≥ 30), and/or age 
≥ 75 years, early or prophylactic initiation of an SGLT2 inhibitor alone or in combination with 
metformin may help to reduce the incidence and frequency of severe hyperglycemia events. 
The decision to initiate an SGLT2 inhibitor alone or in combination with metformin 
prophylactically or at the onset of hyperglycemia (first fasting glucose level above the normal 
range) is at the discretion of the investigator. Since SGLT2 inhibitors may increase the risk of 
euglycemic diabetic ketoacidosis, serum ketones levels will be assessed throughout the trial in 
participants treated with SGLT2 inhibitors at screening, Day 1 of each cycle, and at EOT. For 
additional details on management of alpelisib induced hyperglycemia, please refer to 
Section 6.5.1.3 “Guidelines for the treatment of alpelisib induced hyperglycemia”. 
Participants receiving oral anti-diabetics which are predominantly metabolized by CYP2C9 and 
CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and tolbutamide, 
should be monitored with respect to their effectiveness as alpelisib was found to be an inducer 
of CYP2C9 in vitro. 


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Gastric protection agents 
Alpelisib is characterized by a pH-dependent solubility but can be co-administered with acid 
reducing agents (e.g. proton-pump inhibitors, H2-antagonists and antacids), as long as it is taken 
after food. In a joint food effect and acid reducing drug-drug interactions (DDI) study, food 
exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH 
value leading to a net decrease in area under the curve of on average by 21% when administered 
after a meal. 
Palliative radiotherapy 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required. Participants requiring initiation of palliative radiotherapy during the course of 
the trial should be assessed by appropriate image modalities to exclude disease progression per 
RECIST 1.1 and the reason for its use must be clearly documented. If disease progression is 
documented, the participant should discontinue trial treatment. No dose modification of trial 
treatment is needed during radiotherapy. 
Hematopoietic growth factors 
Hematopoietic growth factors may be used according to American Society of Clinical Oncology 
guidelines. 
Corticosteroids 
Chronic dosing of high levels of corticosteroids such as dexamethasone and prednisone may 
prolong or aggravate hyperglycemia (steroid-induced diabetes). Hyperglycemia is a common 
adverse event for PI3K inhibitors like alpelisib, so corticosteroids should therefore be used with 
caution and participants should be closely monitored. 
Rash Management 
Prophylactic use of antihistamines could be considered, refer to Section 6.5.1.2 “Guidelines for 
the treatment of trial drug inducted skin toxicity”. 
6.2.1.2 
Permitted concomitant therapy requiring caution and/or action 
Medications to be used with caution during combined alpelisib and combination drug in this 
trial are listed below and in Appendix 1 “Permitted medication to be used with caution”. This 
list is not comprehensive and is only meant to be used as a guide. The investigator may contact 
Novartis for any questions regarding the use of permitted concomitant therapy requiring caution 
and/or action. 
These medications should be excluded from participant use if possible. If they must be given, 
based on the investigator’s judgment, then use with caution and consider an alpelisib and/or 
combination drug interruption, as appropriate, if the concomitant medication is only needed for 
a short time. 


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Medications to be used with caution: 
• CYP2C9 substrates with narrow therapeutic index (NTI) (e.g. anticoagulants): In vitro 
evaluations indicated that pharmacological activity may be reduced by the CYP2C9 
induction effects of alpelisib. In the absence of clinical data, caution is recommended with 
therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants as alpelisib may reduce the clinical activity of such drugs (Table 16-1 “List 
of CYP450 substrates to be used with caution”). Alternatively, therapeutic anticoagulation 
may be accomplished using low-molecular weight heparin or Direct Thrombin inhibitors, 
and Factor Xa inhibitors. 
• CYP2B6 sensitive substrates or CYP2B6 substrates with NTI: Based on a static 
mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a reduction 
of exposure by up to 3-fold can be expected when co-administered with alpelisib. In absence 
of clinical data, CYP2B6 sensitive substrates (e.g. bupropion, evafirenz) or CYP2B6 
substrates with a narrow therapeutic window should be used with caution in combination 
with alpelisib, as alpelisib may reduce the clinical activity of such drugs (Table 16-1 “List 
of CYP450 substrates to be used with caution”). 
• Selected CYP3A4 substrates: Alpelisib can be co-administered with sensitive CYP3A4 
substrates (e.g. everolimus, midazolam) and CYP3A4 substrates with narrow therapeutic 
window (e.g. fentanyl). Caution is recommended when alpelisib is used in combination with 
CYP3A4 substrates that also possess an additional time dependent inhibition and induction 
potential on CYP3A4 that affects their own metabolism (e.g. ribociclib, encorafenib, refer 
to Table 16-2 “List of prohibited strong inducers of CYP3A”). Systemic exposures of such 
CYP3A4 auto inhibitors and auto inducers may be either decreased or increased depending 
on the drug and nature of auto-perpetrator potential, respectively, when alpelisib is co 
administered, based on PBPK simulations. 
• Herbal Medications: The use of herbal preparations/medications and dietary supplements 
are permitted with caution unless explicitly prohibited (see Section 6.2.2 “Prohibited 
Medication”) for being strong inducers of CYP3A such as St. John’s Wort (Hypericum 
perforatum) and avasimibe (see Table 16-2 “List of prohibited strong inducers of CYP3A”) 
or BCRP inhibitors such as curcumin (see Table 16-3 “List of prohibited BCRP inhibitors”). 
Medications such as kava, ephedra (ma huang), Gingko biloba, dehydroepiandrosterone, 
yohimbe, saw palmetto, black cohosh and ginseng should be avoided if possible due to their 
potential for complex interactions. Since cannabinoids have been shown to inhibit BCRP in 
vitro, medical cannabis should be used with caution. Participants closely monitored for 
increased adverse reactions (as the relevance of this interaction in vivo is currently 
unknown). In case of unexpected toxicities, participants should stop using all herbal 
medications. Use of all such medications (including frequency of administration) should be 
documented. 
6.2.1.3 
Use of bisphosphonates/RANK-ligand inhibitors 
The use of bisphosphonates/Receptor activator of nuclear factor κ B (RANK)-ligand inhibitors 
(e.g. denosumab) regardless of indication is allowed provided participants have been on stable 
doses for at least 2 weeks prior to trial treatment initiation. Stable dose should be maintained 
during the treatment period. 


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Bisphosphonates may be given according to the local prescribing information and routine 
clinical practice, at the investigator’s discretion. 
Participants taking bisphosphonates prior to entering the trial should continue with the same 
bisphosphonate treatment, given as per local medical practice. 
Participants requiring initiation of bisphosphonate/RANK-ligand inhibitors treatment during 
the course of the trial should be assessed by appropriate image modalities to exclude disease 
progression; if disease progression is documented, the participant should discontinue trial 
treatment. If bisphosphonate therapy/RANK-ligand inhibitors therapy is to be started after the 
first dose of trial treatment, the reason for its use must be clearly documented. 
Osteonecrosis of the jaw (ONJ) is a known adverse reaction for bisphosphonates/RANK-ligand 
inhibitors. In SOLAR-1, ONJ was reported in 4.2% subjects (12/284) in the alpelisib plus 
fulvestrant arm compared to 1.4% subjects (4/287) in the placebo plus fulvestrant arm. All 
subjects experiencing ONJ were also exposed to prior or concomitant bisphosphonates (e.g. 
zoledronic acid). Therefore, in participants receiving alpelisib and bisphosphonates, an 
increased risk of development of ONJ cannot be excluded. For prevention and clinical 
management of ONJ, prescribing information of bisphosphonates should be followed. 
6.2.2 
Prohibited medication 
The following medications are prohibited during combined alpelisib plus fulvestrant treatment 
in this trial (see in Appendix 2 “Prohibited Medication”, this list is not comprehensive and is 
only meant to be used as a guide. Please contact the medical monitor with any questions): 
• Strong inducers of CYP3A4: Avoid co-administration of alpelisib with a strong CYP3A4 
inducer as it could potentially reduce the effectiveness of alpelisib, refer to Table 16-2 “List 
of prohibited strong inducers of CYP3A”. 
• Inhibitors of BCRP: Avoid the use of BCRP inhibitors in participants treated with 
alpelisib. If unable to use alternative drugs, closely monitor for increased adverse reactions, 
refer to Table 16-3 “List of prohibited BCRP inhibitors”. 
• Other investigational and antineoplastic therapies. 
• Hormonal contraception: hormonal contraception is contraindicated for patients with ER 
positive breast cancer, therefore it is not to be considered as contraception method for the 
trial. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the trial by a Participant Number (Participant No.) assigned 
when the participant is enrolled for screening and is retained for the participant throughout 
his/her participation in the trial. 
The Participant No. consists of the Center Number (Center No.; assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant’s 
participation is numbered uniquely across the entire database. Upon signing the ICF, the 
participant is assigned to the next sequential Participant No. available. 


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6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this trial. Only one cohort of participants will be enrolled 
in this trial. 
6.4 
Treatment blinding 
Treatment will be open to participants, investigator staff, personnel performing the assessments, 
and the clinical trial team. 
6.5 
Dose escalation and dose modification 
No dose escalations or dose modifications are allowed with fulvestrant. 
No dose escalation will be allowed for alpelisib as alpelisib is to be started at the maximum 
recommended daily dose according to the SmPC. For participants who do not tolerate the 
protocol-specified dosing schedule, dose interruptions, and/or reductions are either 
recommended or mandated in order to allow participants to continue the trial treatment. Dose 
modifications are summarized in Table 6-3“Criteria for dose reduction / interruption and re-
initiation of alpelisib for adverse drug reactions”. A maximum of 2 dose reductions will be 
allowed after which treatment must be discontinued as indicated in Table 6-4 “Dose Reduction 
Steps for Alpelisib”. Deviations to stepwise dose reductions are not allowed. 
These dose changes must be recorded on the appropriate eCRF 
AEs for alpelisib are graded according to CTCAE v4.03 since this version is more objective 
with regard to hyperglycemia grading since it is based on laboratory values. Clinical judgment 
of the investigator, including confirmation of laboratory values if deemed necessary, should 
guide the management plan of each participant based on individual benefit/risk assessment. 
After treatment is resumed at a lower dose: 
• If the same toxicity reoccurs with the same severity, then the next treatment re-initiation 
must resume at a lower dose irrespective of duration, except if specified in Table 6-3 
“Criteria for dose reduction/interruption and re-initiation of alpelisib for adverse drug 
reactions”. 
• Once the alpelisib dose has been reduced by the investigator, no re-escalation is allowed, 
even upon resolution of AE. 
If a participant requires a withholding of alpelisib dose, the participant could continue 
fulvestrant, per investigator discretion. All scheduled assessments will continue to be performed 
as per protocol. 
Permanent treatment discontinuation is mandatory for specific events indicated as such in Table 
6-3 “Criteria for dose reduction/interruption and re-initiation of alpelisib for adverse drug 
reactions” or listed in Section 9.1“ Discontinuation and completion”. These dose changes must 
be recorded on the appropriate eCRF. 


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Table 6-3 
Criteria for dose reduction / interruption and re-initiation of alpelisib 
for adverse drug reactions 
Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Investigations (Fasting Glucose) 
Hyperglycemia (see also Section 6.5.1.3 “Guidelines for the treatment of alpelisib induced hyperglycemia”) 
Consultation with a diabetologist or HCP experienced in the management of hyperglycemia is highly 
recommended for better assessment and management of alpelisib-induced hyperglycemia. Always 
recommend/reinforce on lifestyle changes as per American Diabetes Association (ADA) and/or European 
Association for the study of Diabetes (EASD), i.e. exercise and dietary advice (e.g. controlled carbohydrate 
intake, high fiber, low process food intake. Three macronutrient-balanced meals and 2 optional small snacks 
rather than one large meal). 
Note: this table provides dose management recommendations. Dose modifications and management should 
only be based on fasting glucose (FG) values (fasting plasma glucose or fasting blood glucose). Fasting 
glucose values can be obtained using a glucometer (self-measured) or through laboratory investigation. 
Laboratory confirmation of self-measured high glucose values may be requested by the investigator if deemed 
necessary. The investigator will use clinical judgment to guide the management plan of each participant based 
on individual benefit/risk assessment. 
As metformin is widely available, it is an appropriate choice as initial therapy for alpelisib-induced 
hyperglycemia. However, SGLT2 inhibitors are acceptable as well and may be administered alone or in 
combination with metformin. Refer to Section 6.5.1.3 “Guidelines for the treatment of alpelisib induced 
hyperglycemia” for additional details regarding the use SGLT2 inhibitors. In case of intolerance to or 
unavailability of metformin, investigator’s judgment should be exercised and other oral anti-diabetic agents such 
as thiazolidinediones or dipeptidyl peptidase-4 Inhibitors can be used. 
As SGLT2 inhibitors may increase the risk of euglycemic diabetic ketoacidosis, monitoring of serum ketones will 
be mandated in participants treated with SGLT2 inhibitors/ 
Grade 1 (FG > ULN - 160 mg/dL) 
[> ULN - 8.9 mmol/L] 
For participants with baseline values 
between > ULN - 140 mg/dL 
(ULN - 7.7 mmol/L) this applies only for 
values > 140 mg/dL (7.7 mmol/L) 
• 
Maintain dose level, and remind participant on lifestyle 
changes*. 
• 
Start/intensify metformin as per guidance below or in 
cooperation with a healthcare expert experienced in 
hyperglycemia management or a diabetologist. 
 
Metformin 500 mg orally once daily with dinner. If no 
gastrointestinal (GI) intolerance after several days, increase to 
500 mg 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.  
Titrate to the MTD over a period of 3 weeks. 
 
• 
Alternatively, consider starting an SGLT2 inhibitor alone or in 
combination with metformin, especially in participants at risk 
for developing severe hyperglycemia (See Section 6.5.1.3 
“Guidelines for the treatment of alpelisib induced 
hyperglycemia”). Starting dose and titration should be in 
accordance with the local prescribing information and 
consistent with local practice. 
 
• 
Monitor fasting glucose levels as clinically indicated and at 
least twice weekly for 8 weeks, then continue checking at 
least weekly until FG is within baseline values. 
 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Grade 2 (FG > 160 to 250 mg/dL) [> 8.9 to 
13.9 mmol/L] 
 
 
• 
Maintain dose level and remind subject on lifestyle changes*, 
exclude confounding factors like e.g. urinary tract infection, 
and consider consultation with a healthcare expert 
experienced in hyperglycemia management or a 
diabetologist. 
• 
Start/intensify oral anti-diabetic treatment with metformin or 
alternatively start an SGLT2 inhibitor alone or in combination 
with metformin.  
• 
Additional oral anti-diabetic agents may be initiated, if needed. 
If fasting glucose levels are still rising on maximum tolerated 
dose of metformin or persistently > 160 mg/dl (> 8.9 mmol/L), 
add an SGLT2 inhibitor if available, e.g. empagliflozin up to 
25 mg (max. dose). Alternatively an insulin-sensitizer, e.g. 
pioglitazone 30 mg (max. dose) can be added. 
• 
Monitor fasting glucose levels as clinically indicated and at 
least weekly until FG resolves to ≤ Grade 1. 
• 
If FG does not resolve to ≤ Grade 1 within 21 days after 
institution of appropriate anti-diabetic treatment, reduce 
alpelisib by 1 dose level. 
• 
Continue with anti-diabetic treatment and check fasting 
glucose levels at least weekly for 8 weeks, then continue 
checking at least every 2 weeks, alert treating physician if 
FG > 250 mg/dL. 
 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Grade 3 (FG > 250 to 500 mg/dL) [> 13.9 
to 27.8 mmol/L] 
 
• 
Omit alpelisib and confirm fasting status of the assessment. If 
non-fasting, re-check within 24 hours. 
Regardless of fasting status, consider IV fluids if symptoms of 
hyperglycemia or signs of volume depletion. 
Exclude confounding factors like e.g. urinary tract and consider 
consultation with a diabetologist. 
Administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as clinically 
appropriate. Insulin may be used for 1 to 2 days until 
hyperglycemia resolves, however this may not be necessary in 
the majority of alpelisib-induced hyperglycemia given the short 
half-life of alpelisib. 
Start or further intensify oral anti-diabetic treatment and titrate as 
outlined for Grade 2. 
Monitor fasting glucose levels as clinically indicated and at least 
twice weekly until FG resolves to ≤ Grade 1. 
• 
If FG resolves to ≤ 160 mg/dL within 3 to 5 days, while off 
alpelisib and on metformin, re-start alpelisib and reduce 
1 dose level, continue with anti-diabetic treatment. A second 
and third oral hypoglycemic agent may be initiated 
concomitantly, if needed, in consultation with a diabetologist. 
Check FG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks, alert treating physician if 
FPG > 250 mg/dL. 
• 
If FG does not resolve to ≤ 160 mg/dL within 3 to 5 days while 
off alpelisib and on metformin, consultation a diabetologist for 
management of diabetes is strongly recommended.  
• 
If FG does not resolve to ≤ 160 mg/dL within 21 days after 
institution of appropriate anti-diabetic treatment in 
cooperation with diabetologist and exclusion of confounding 
factors e.g. urinary tract infection, permanently discontinue 
participant from alpelisib treatment. 
Grade 4 (FG > 500 mg/dL) [≥ 27.8 
mmol/L] 
 
• 
Omit alpelisib confirm fasting status of the assessment. If 
non-fasting, re-check within 24 hours. 
Regardless of fasting status, consider IV fluids. 
• 
Exclude confounding factors like e.g. urinary tract infection. 
• 
Consult with diabetologist, initiate or intensify medication with 
appropriate anti-diabetic treatment (see Grade 3), re-check 
within 24 hours. 
• 
If grade improves then follow specific grade recommendations 
• 
If FG is confirmed as > 500 mg/dL and confounding factors 
could be excluded, permanently discontinue participant from 
alpelisib. 
 
CTCAE v 4.03 is modified to allow fasting blood glucose values in addition to fasting plasma glucose values.  
* For specific recommendations please see Section 6.5.1.3 “Guidelines for the treatment of alpelisib induced 
hyperglycemia” 
Investigations (Hepatic). Note: this is for newly occurred or worsened from baseline 
 
Isolated total Bilirubin elevation 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Grade 1 (> ULN - 1.5 × ULN) 
• 
No dose adjustment is required. Initiate appropriate medical 
therapy and monitor as clinically indicated. 
Grade 2 (> 1.5 to 3.0 × ULN) 
• 
Interrupt dose until recovery to Grade ≤ 1 and resume at the 
same dose if resolved in ≤ 14 days or resume at the next 
lower dose level if resolved in > 14 days. 
Grade 3 (> 3.0 to 10.0 × ULN) 
• 
Interrupt dose until recovery to Grade ≤ 1, then resume at the 
next lower dose level. 
Grade 4 (> 10.0 × ULN) 
• 
Permanently discontinue. 
 
Isolated AST or ALT elevation 
Grade 1 (> ULN - 3.0 × ULN) 
Grade 2 (> 3.0 to 5.0 × ULN) 
• 
No dose adjustment is required. Initiate appropriate medical 
therapy and monitor as clinically indicated. 
Grade 3 (> 5.0 to 20.0 × ULN) 
• 
Interrupt dose until recovery to Grade ≤ 1, then decrease dose 
level. 
Grade 4 (> 20.0 × ULN) 
• 
Permanently discontinue. 
Combined ALT/AST and TBIL elevation 
• 
Please see specific instructions in Section 6.5.1.5 “Follow up 
on potential drug-induced liver injury (DILI) cases” 
Gastrointestinal 
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements. 
Grade 1 (Increase of < 4 stools per day 
over baseline; mild increase in ostomy 
output compared to baseline) 
• 
Maintain dose level but initiate appropriate medical therapy 
and monitor as clinically indicated. 
Grade 2 (Increase of 4 to 6 stools per day 
over baseline; moderate increase in 
ostomy output compared to baseline; 
limiting instrumental Activities of Daily 
Living (ADL)) 
• 
Omit dose until resolved to ≤ Grade 1, then restart at same 
dose. 
• 
If diarrhea returns as ≥ Grade 2, then omit dose until resolved 
to ≤ Grade 1, then decrease 1 dose level 
• 
Initiate or intensify appropriate medical therapy and monitor as 
clinically indicated. 
Grade 3 (Increase of ≥ 7 stools per day 
over baseline; hospitalization indicated; 
severe increase in ostomy output 
compared to baseline; limiting self-care 
ADL) 
• 
Omit dose until resolved to ≤ Grade 1, then decrease dose 
level. 
• 
Manage according to local standard of care medical 
management, including electrolyte monitoring, administration 
of antiemetics and antidiarrheal medicinal products and/or 
fluid replacement and electrolyte supplements, as clinically 
indicated. 
Grade 4 (Life-threatening consequences; 
urgent intervention indicated) 
• 
Discontinue participant from treatment. 
• 
Manage according to local standard of care medical 
management, including electrolyte monitoring, administration 
of antiemetics and antidiarrheal medicinal products and/or 
fluid replacement and electrolyte supplements, as clinically 
indicated. 
Investigations (Pancreatic) 
Pancreatitis 
Grade 2 or Grade 3 
Omit dose until resolved to Grade ≤ 1, then resume treatment 
at decreased dose level. If toxicity recurs, permanently 
discontinue participant from alpelisib 
Skin and subcutaneous tissue disorders 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Consultation with a dermatologist is highly recommended for better assessment and management of alpelisib-
induced skin toxicity. (see also Section 6.5.1.2 “Guidelines for the treatment of trial drug induced skin toxicity”). 
Dermatologist consultation is mandated for serious cutaneous reactions (i.e. fulfilling seriousness criteria for AE 
Reporting) and for severe cutaneous reactions like Stevens-Johnson-Syndrome, Toxic Epidermal Necrolysis, 
Erythema Multiforme, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). 
Rash 
Grade 1 ( < 10% body surface area  
(BSA) with active skin toxicity*) 
• 
Maintain dose level. 
• 
Initiate topical corticosteroids 3 to 4 times daily, preferred 
compounds to use are triamcinolone, betamethasone for up 
to 28 days, as long as skin toxicity is active. 
• 
If active rash is not resolved within 28 days of appropriate 
treatment, add low dose systemic corticosteroid 
(20 to 40 mg/d), such as prednisone 10 mg 3 times daily. 
For participants with symptoms like burning and/or pruritus add a 
non-sedating anti-histamine such as cetirizine once daily during 
daytime and a sedating antihistamine such as diphenhydramine 
once daily at night 
 
Grade 2 (10 to 30% BSA with active skin 
toxicity*) 
 
• 
Maintain dose level. 
• 
Initiate or intensify topical corticosteroids 3 to 4 times daily, 
preferred compounds to use are triamcinolone or 
betamethasone for up to 28 days, as long as skin toxicity is 
active. 
• 
Add systemic corticosteroids 20 to 40 mg/d. 
If rash improves to ≤ Grade 1 within 10 days systemic 
corticosteroid may be discontinued. For participants with 
symptoms like burning, stinging and/or pruritus add a non-
sedating anti-histamine such as cetirizine once daily during 
daytime and a sedating anti-histamine such as diphenhydramine 
once daily at night. 
 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Grade 3 (> 30% BSA with active skin 
toxicity*)  
• 
Omit alpelisib dose until rash /skin toxicity has improved to 
≤ Grade 1 or resolved, recommend documentation by 
photography and consider performing a skin biopsy. 
• 
Initiate topical corticosteroids 3 to 4 times daily, preferred 
compounds to use are triamcinolone or betamethasone for at 
least 28 days. 
• 
Add systemic corticosteroids 20 to 40 mg/d. 
• 
If rash improves to ≤ Grade 1 within 10 days systemic 
corticosteroid may be discontinued. 
• 
Re-start alpelisib dose once rash /skin toxicity is fading but no 
longer active (Grade 1): 
- at reduced dose in case of first occurrence 
- If rash/skin toxicity still active in up to 10% BSA after more than 
14 days, continue oral corticosteroid for at least 48 hours upon re-
challenge with alpelisib; if rash and/or pruritus do not reoccur 
within 48 hours after re-challenge with alpelisib, systemic 
corticosteroid may be discontinued. 
For participants with symptoms like burning, stinging and/or 
pruritus, add a non-sedating antihistamine such as cetirizine once 
daily during daytime and a sedating antihistamine such as 
diphenhydramine once daily at night. Antihistamine regimen 
should be continued for a minimum of 28 days after re-challenge 
with alpelisib. 
 
Grade 4 
(any % BSA associated with extensive 
superinfection, with IV antibiotics 
indicated; life-threatening consequences) 
• 
Permanently discontinue subject from alpelisib 
• 
Consult a dermatologist, ensure documentation by 
photography, and obtain a skin biopsy.  
• 
Treatment may follow guidelines for Grade 3 above with the 
exception of rechallenge. 
• 
Additional measures may be taken as per local treatment 
guidance. 
 
Any Grade of Stevens-Johnson-
Syndrome/Toxic Epidermal Necrolysis/ 
Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS) or other 
SJS/TEN/DRESS like severe skin 
reactions   
• 
Permanently discontinue participant from alpelisib.  
• 
Consult a dermatologist, ensure documentation by 
photography and obtain skin biopsy. 
• 
Follow local treatment guidelines for SJS/TEN/DRESS. 
* “Active” skin toxicities:  If there are no new lesions or new areas of involvement developing, and if lesion 
appearance is changing color from red to pale or light brown, it is likely the skin toxicity has begun to fade and is 
not to be considered “active” any longer. Treatment reduction can be considered for these areas. The 
appearance of skin toxicity may fade slowly, over 10 days or more but not requiring ongoing therapy. 
Immune system disorders 
Hypersensitivity 
Please see specific instructions in Section 6.5.1.6 “Guidelines for hypersensitivity” 
Investigations (Pulmonary disorders) 
Pneumonitis 
Please see specific instructions in Section 6.5.1.1 “Management of Pneumonitis/Interstitial lung disease” 
Investigations (Metabolic) 


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Dose Modifications for alpelisib as specified below. Combination drug may be continued while alpelisib 
dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib 
Asymptomatic amylase and/or lipase elevation (see also Section 6.5.1.4 “Follow-up on amylase or lipase 
elevation (≥ CTCAE Grade 3”) 
Grade 1 (> ULN - 1.5 × ULN) 
• 
Maintain dose level. 
Grade 2 (> 1.5 to 2.0 × ULN) 
• 
Maintain dose level. 
Grade ≥ 3 (> 2.0 × ULN) 
• 
Omit dose until resolved to baseline, then 
• 
If resolved in ≤ 14 days, maintain dose level. 
• 
If resolved in > 14 days, then decrease dose level. 
Note: 
• 
In cases of isolated amylase elevations only, dosing may be 
maintained provided amylase fractionation demonstrates that 
pancreatic amylase is ≤ Grade 1. Monitor total amylase (and 
continue to assess fractionated amylase) as specified in 
Section 6.5.1.4 “Follow-up on amylase or lipase elevation (≥ 
CTCAE Grade 3” 
Note: Withhold trial treatment for acute onset of new or progressive unexplained abdominal symptoms, such as 
severe pain or vomiting; and perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude 
pancreatic pathology. 
Investigations (any other) 
Other adverse events 
Grade 1 or 2 
• 
Maintain dose level. 
Grade 3 
• 
Omit dose until resolved to ≤ Grade 1, then decrease dose 
level. 
Grade 4 
• 
Permanently discontinue participant from alpelisib. 
• 
Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only if 
the vomiting or nausea cannot be controlled with optimal 
antiemetic (as per local practice). 
Table 6-4 
Dose reduction steps for alpelisib1. 
Alpelisib dose level 
Dose and schedule 
Number and strength of tablets 
Starting dose  
300 mg/day continuously 
2 × 150 mg tablets 
First dose reduction 
250 mg/day continuously  
1 × 200 mg tablet and 1 × 50 mg tablet 
Second dose reduction 
200 mg/day continuously 
1 × 200 mg tablet 
1 Only one dose reduction is permitted for pancreatitis. 
 
6.5.1 
Follow-up for toxicities 
Participants, whose treatment is interrupted or permanently discontinued due to an AE or a 
clinically significant laboratory value, must be followed until resolution or stabilization of the 
event (and/or up to EOT visit), whichever comes first. Further guidelines and recommendations 
for the management of specific trial treatment combination-induced toxicities are provided 
below. 


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6.5.1.1 
Management of pneumonitis/interstitial lung disease 
Alpelisib is associated with pneumonitis/interstitial lung disease. Closely monitor all 
participants for signs and symptoms of pneumonitis. 
All participants will be routinely asked about and observed for the occurrence of AEs including 
new or changed pulmonary symptoms (consistent with lung abnormalities). 
Participants who are suspected to have developed pneumonitis should interrupt (alpelisib and 
combination drug) immediately and undergo appropriate imaging (high resolution CT scan) and 
broncho-alveolar lavage; 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 trial treatment. 
After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently 
discontinue treatment with alpelisib and promptly initiate appropriate treatment and supportive 
measures. 
6.5.1.2 
Guidelines for the treatment of trial drug-induced skin toxicity 
Skin toxicity is a class-effect AE observed with PI3K inhibitors agents. 
Close monitoring of potential skin reactions will be performed and will be reported as AE (see 
Section 4.5.3 “Risk Management Strategies”). 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 co-
medication and treatment interruption if needed. Skin reactions may improve over several 
weeks. Consultation with a dermatologist is highly recommended for better assessment and 
management of alpelisib-induced skin toxicity at any grade, and mandated if severe cutaneous 
reaction like Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Erythema Multiforme 
or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected. 
Workup for skin toxicity events may include a complete blood count with differential, and a 
full chemistry panel. 
Antihistamines administered prior to rash onset may decrease incidence and severity of rash 
based on Study CBYL719C2301; therefore, at the investigator’s discretion, non-sedating 
antihistamines (e.g. cetirizine (Zyrtec®), fexofenadine (Allegra®), loratadine (Claritin®)) may 
be used as prophylactic treatment starting at Cycle 1, Day 1 to reduce severity of rash in all 
participants and especially for participants with a history of atopy such as allergic rhinitis, 
asthma, atopic dermatitis, or drug allergies. 
Recommended therapies for skin toxicity events of all grades and as clinically indicated include: 
• Mid to high potency topical steroids: triamcinolone 0.01% or fluocinonide 0.05% twice 
daily for at least 28 days. Recommend spray, lotion, or cream preparation for ease of 
application on trunk. For scalp involvement, recommend a foam or solution preparation. 


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• Gamma-aminobutyric acid agonists: gabapentin 300 mg every 8 hours, pregabalin 
50 to 75 mg every 8 hours (to adjust of renal impairment). Depending on participant’s 
clinical condition, be aware of potential and common side effects observed with gamma-
aminobutyric acid agonists such as: somnolence, dizziness (both drugs) and peripheral 
edema (gabapentin) among others AEs. 
For grade 4 skin events or any grade of severe cutaneous reactions (including Stevens-Johnson 
syndrome, Toxic epidermal necrolysis, Erythema multiforme, DRESS), alpelisib treatment 
must be permanently discontinued without any re-challenge. 
If dry skin is reported, it is recommended that participants with dry skin use mild and fragrance-
free soaps and detergents. 
Although preclinical experiments demonstrated that alpelisib have no potential phototoxic 
effect, participants should avoid sun exposure during treatment with alpelisib, especially when 
they already have experienced rash or other skin toxicities as the increased blood flow of the 
skin may worsen skin symptoms. Participants should be advised to take measures to protect 
themselves from direct exposure to sunlight, including the wearing of sunglasses as well as the 
regular use of sunscreen, hats, long-sleeve shirts, and long pants when outdoors. 
6.5.1.3 
Guidelines for the treatment of alpelisib-induced hyperglycemia 
Alpelisib, like other PI3K inhibitors, may affect glucose homeostasis which could result in 
increases of plasma glucose and insulin resistance (Busaidy et al 2012). Alpelisib induced 
hyperglycemia is generally manageable with adequate anti-diabetic treatment. Alpelisib 
induced hyperglycemia typically occurs within the first month of treatment. Participants with 
pre-diabetes (i.e. FG 100 to 125 mg/dl; 5.6 to 6.9 mmol/L) and those with an established 
diagnosis of type 2 diabetes mellitus should be monitored carefully, thus allowing an early 
detection and prompt management of increases in fasting glucose while on alpelisib treatment. 
However all participants, even those with fasting glucose within normal limits at screening, 
may develop alpelisib-induced hyperglycemia which is an on-target effect seen with PI3K 
inhibitors. Participants should always be instructed to follow dietary guidelines provided by the 
ADA and/or the European Association for the study of Diabetes, e.g. small frequent meals, low 
carbohydrate content, high fiber, balancing carbohydrates over the course of the day; three small 
meals and 2 small snacks rather than one large meal and exercise, as appropriate. 
Detailed guidelines for management of alpelisib induced hyperglycemia is provided in 
Table 6-3 “Criteria for dose reduction/interruption and re-initiation of alpelisib treatment for 
adverse drug reactions” and detailed guidelines on use of oral anti-diabetics is provided in 
Section 6.2.1.1 “Permitted concomitant medications”. In brief, this includes early 
administration of metformin or a SGLT2 inhibitor (alone or in combination with metformin). 
Metformin may be titrated to a daily dose of 1000 mg twice a day. Since SGLT2 inhibitors may 
increase the risk of euglycemic diabetic ketoacidosis, serum ketones levels will be assessed 
throughout the trial in participants treated with SGLT2 inhibitors at screening, Day 1 of each 
cycle, and at end of trial. 
Local standard clinical practice may be followed for monitoring and managing hyperglycemia. 
Fasting glucose testing will be performed both locally (at home using a glucometer or at a local 
laboratory) and/or at the investigative site for rapid availability for safety evaluation and 


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management guidance. Laboratory confirmation of self-measured high glucose values may be 
requested if deemed necessary by the investigator. The investigator will use clinical judgment 
to guide the management plan of each participant based on individual benefit/risk assessment. 
Special attention should be paid to the risk of hypoglycemia in participants interrupting alpelisib 
treatment and concomitantly receiving insulin and/or sulfonylureas. Due to the short half-life 
of alpelisib, all glucose lowering medications should be discontinued when alpelisib is stopped. 
If metformin or an anti-diabetic agent is interrupted for radiologic assessments or another 
reason, then alternative hyperglycemia management should be considered for those days to 
ensure optimal hyperglycemia management. 
Consultation with a diabetologist or HCP experienced in the management of hyperglycemia is 
highly recommended for better assessment and management of alpelisib-induced 
hyperglycemia. 
6.5.1.4 
Follow-up on amylase or lipase elevation (≥ CTCAE Grade 3) 
Participants with amylase or lipase elevation ≥ CTCAE Grade 3 must be tested weekly (or more 
frequently if clinically indicated) until ≤ 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). 
Participants who discontinue trial treatment due to pancreatic toxicity must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ Grade 1 or 
stabilization occurs (no CTCAE v4.03 grade change over 4 weeks). 
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold trial treatment, then perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. 
See also dose modification guidelines described in Table 6-3 “Criteria for dose 
reduction/interruption and re-initiation of alpelisib for adverse drug reactions”. 
6.5.1.5 
Follow up on potential drug-induced liver injury cases 
Participants with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential drug-induced liver injury (DILI), and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most 
likely cause of the observed laboratory abnormalities. 
In general, any increase of serum aminotransferases to > 3 × ULN should be followed by repeat 
testing within 48 to 72 hours. 


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If total bilirubin is elevated > 2 × ULN, fractionation into direct and indirect bilirubin is 
required. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBIL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and TBIL value at baseline: AST or 
ALT > 3.0 × ULN combined with TBIL > 2.0 × ULN 
• For participants with elevated AST or ALT or TBIL value at baseline: [AST or 
ALT > 3.0 × baseline] OR [AST or ALT > 8.0 × ULN], whichever occurs first, combined 
with [TBIL > 2 × baseline AND > 2.0 × ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as medical review needs to ensure that 
liver test elevations of ethanol consumption, concomitant medications, herbal remedies, 
supplement consumption, history of any pre-existing liver conditions or risk factors, should be 
collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), glutamate dehydrogenase, prothrombin time/INR, alkaline 
phosphatase, albumin, and creatine kinase. 
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion - e.g. using CT, 
magnetic resonance imaging (MRI), or duplex sonography. 
Perform 
relevant 
examinations 
(ultrasound 
or 
MRI, 
Endoscopic 
Retrograde 
Cholangiopancreatography) as appropriate, to rule out an extrahepatic cause of cholestasis. 
Cholestasis is defined as an ALP elevation > 2.0 × ULN with R value < 2 in participants without 
bone metastasis, or elevation of the-specific ALP isoenzyme in participants with bone 
metastasis. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
(R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury. In clinical situations where 
it is suspected that ALP elevations are from an extrahepatic source, the GGT can be used if 
available. GGT may be less specific than ALP as a marker of cholestatic injury, since GGT can 
also be elevated by enzyme induction or by ethanol consumption. It is more sensitive than ALP 
for detecting bile duct injury (livertox.nih.gov/rucam.html). 
If DILI confirmed: permanently discontinue trial treatment. 
If DILI is unlikely: interrupt treatment. Treat identified cause according to institutional 
guidelines. If resolved, reduce by one dose level. Re-administration of trial treatment should be 
considered only if the investigator assesses benefit to outweigh the risk. Any decision regarding 
re-administration of trial drug/s and dose regimen should be discussed with the Novartis 
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Table 6-5 “Alternative causes of liver disease” provides guidance on specific clinical and 
diagnostic assessments which can be performed to rule out possible alternative causes of 
observed liver function test abnormalities. 
Table 6-5 
Alternative causes of liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
Cytomegalovirus (CMV), Herpes Simplex Virus 
(HSV), Epstein-Barr virus (EBV) infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, gammaGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or 
MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Following appropriate causality assessments, as outlined above, the causality of the drug is estimated as 
“probable” i.e. > 50% likely, if it appears greater than all other causes combined. The term “drug-induced” 
indicates probably caused by the drug, not by something else, and only such a case can be considered a DILI 
case and should be reported as an SAE. 
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e. > 50% likely, if it appears greater than all other causes combined. 
The term “drug-induced” indicates probably caused by the drug, not by something else, and 
only such a case can be considered a DILI case and should be reported as a serious AE (SAE). 
6.5.1.6 
Guidelines for hypersensitivity 
Alpelisib and combination drug are associated with hypersensitivity reactions, including 
anaphylaxis. These are manifested by symptoms including, but not limited to, dyspnea, 
flushing, rash, fever or tachycardia. Alpelisib and/or combination drug should be permanently 
discontinued and should not be re-introduced in participants with serious hypersensitivity 
reactions. Appropriate treatment should be promptly initiated. 
6.6 
Additional treatment guidance 
6.6.1 
Trial treatment compliance 
Participants or caregivers will complete a medication diary during the entire trial through the 
telemedicine application to report compliance. 
6.6.2 
Trial treatment accountability 
The dispatch of trial treatment from the site to the participant’s home remains under the 
responsibility of the investigator. The investigator or designee must maintain an accurate record 


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of the shipment and dispensing of trial treatment in a treatment accountability log. Participants 
will be asked to return all unused trial treatment and packaging at the end of the trial or at the 
time of trial treatment discontinuation either directly to the site during the EOT visit or by a 
courier company. In case a courier company is used, site personnel will organize the shipment. 
At trial close-out, and when appropriate during the course of the trial, the investigator will ship 
all remaining trial treatment to the central pharmacy for destruction. Verification of the 
accountability should be performed by the clinical research associate prior to shipping to the 
central pharmacy. Processes will be described in details in the Monitoring Plan. A certificate of 
destructions will be provided by the central pharmacy to be filed in the investigator folder. 
6.7 
Preparation and dispensation 
At Cycle 1, Visit 1, participants will receive their first dose of trial treatment on site, and will 
be provided with one cycle of supply of alpelisib for self-administration at home, including 
instructions for administration. After the Cycle 1, Visit 1, participants will receive trial 
treatment on an outpatient basis with trial treatment delivered at their home by a courier 
company. The investigator or responsible site personnel must instruct the participant or 
caregiver to take the trial treatment per protocol (promote compliance). Fulvestrant, and if 
applicable goserelin, will be injected by either a district nurse at the participants’ homes, at the 
district nurse clinic, or by the local oncologist when a visit is planned at time of drug 
administration (i.e. on Day 1 of Cycle 4, Cycle 7, and Cycle 10). All dosages prescribed to the 
participant and all dose changes during the trial must be recorded on the Dosage Administration 
Record CRF. 
6.7.1 
Handling of trial treatment and additional treatment 
6.7.1.1 
Handling of trial treatment 
Trial treatment will be labeled at a central pharmacy in Sweden. The dispatch of trial treatment 
from the site to the participant’s home remains under the responsibility of the investigator. Site 
personnel will order trial treatment from the central pharmacy and organize the delivery of the 
treatment to individual participants by direct contact with the courier company. Such process 
will ensure that no personal data is disclosed to Novartis as the Sponsor of the clinical trial as 
only site personnel will have knowledge of participant’s details and the courier will only have 
access to the minimum require information to provide the service (name and address). The chain 
of custody for trial treatment will be documented in the Investigator Folder and includes at a 
minimum pick-up times from the clinical trial site, time of receipt confirmed by the participant 
at home, and temperature control log. Participants will be informed about the planned delivery 
to ensure secure receipt of the trial treatment. 
Processes set in place for handling of trial treatment are compliant with measures approved for 
COVID-19 pandemic procedures. Additional information will be included in the Site 
operational manual. 
6.7.1.2 
Handling of additional treatment 
Goserelin, SGLT2 inhibitors, metformin and any other additional drugs, such as antihistamines, 
prescribed by the investigator will be reimbursed through standard reimbursement coverage. 


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6.7.2 
Instruction for prescribing and taking trial treatment 
Alpelisib is dosed on a flat scale of mg/day and not by weight or body surface area. There will 
be no breaks between dosing cycles. Participants should be instructed to take the dose of 
alpelisib at approximately the same time each day immediately after food (preferably in the 
morning), except on the days blood collection is scheduled at the clinic. On those days, local 
oncologists will instruct participants to take alpelisib according to their current practice at their 
regional hospital. 
Alpelisib tablets should be swallowed whole (tablets should not be chewed, crushed or split 
prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should not be 
ingested. 
On the days of combination drug administration, alpelisib tablets should be taken 1 hour prior 
to the infusion of combination drug. 
Should any participant enrolled on the trial miss a scheduled dose of alpelisib, the participant 
will be allowed to take immediately the missed scheduled dose up to a maximum of 9 hours 
after that scheduled dose time. If greater than 9 hours after the scheduled dose time, the missed 
dose should not be taken, and the participant should take their allotted dose at the next scheduled 
time. 
If the participant vomits after taking the alpelisib dose, the participant should not take an 
additional dose on that day and should resume the usual dosing schedule the next day at the 
usual time. 
On days when pre-dose fasting blood samples are collected, participants should be instructed 
to arrive at the laboratory in fasted state. The following additional guidelines should be 
followed: 
• The participants must be fasting overnight for at least 8 to 12 hours prior to the blood 
collection for fasting glucose. Water, coffee/tea (unsweetened and without milk) is allowed 
during all fasting periods; however juice is not permitted during the fasting period. 
• On days when participants have a fasting blood sample collected, participants must have 
their blood sample collected prior to taking their trial treatment  
• The participants must take alpelisib immediately after having breakfast. 
Fulvestrant 500 mg will be given at Cycle 1, Day 1 and 15 after randomization and then at 
Day 1 of each subsequent cycle during the randomized treatment phase (± 3 days). 
Fulvestrant is administered intramuscularly into the buttocks slowly as two 5 mL injections, 
one in each buttock. No dose modification is allowed for fulvestrant. Please refer to the local 
approved prescribing information. Any planned variance from these guidelines in the view of 
the patient safety must be previously discussed with the Sponsor unless there is an urgent need 
for action. 


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7 
Informed consent procedures 
Eligible participants may only be included in the trial after providing (witnessed, where required 
by law or regulation) independent Ethics committee (IEC)-approved informed consent. If 
applicable, in cases where the participants' representative(s) gives consent (if allowed according 
to local requirements), the participant must be informed about the trial to the extent possible 
given his/her understanding. If the participant is capable of doing so, he/she must indicate 
agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any trial-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the ICH GCP guidelines, regulatory requirements, and applicable data privacy guidelines, and 
is considered appropriate for this trial. Any changes to the proposed ICF suggested by the 
investigator must be agreed by Novartis before submission to the IEC. 
Information about common side effects already known about the trial treatment can be found 
in the SmPC (Piqray® SmPC, Novartis; Faslodex® SmPC, Astra Zeneca). This information will 
be included in the participant ICF and should be discussed with the participant during the trial 
as needed. Any new information regarding the safety profile of the trial treatment that is 
identified between SmPC updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the ICF and then must be discussed with the participant. 
A main trial consent will be included in this trial, including a subsection that requires a separate 
signature for the ‘Optional Consent for Additional Research’ to allow future research on data 
collected during this trial. 
A copy of the approved version of all consent forms must be provided to Novartis after IEC 
approval. 
8 
Visit schedule and assessments 
On-site visits will occur during screening, at Cycle 1, Day 1, and at EOT. Any other  
assessments are planned to be performed remotely supported by a telemedicine platform, local 
oncologists and district nurses. 
Local oncologists are defined in this protocol as oncologist working in a regional hospital. The 
support for the participant at home could include district nurses, or other qualified healthcare 
professionals such as home-nursing professionals from ASIH performing standard of care 
procedures. 
Participants will be visited by district nurse on Cycle 1, Day 15 and Day 1 of each cycle from 
Cycle 3 onwards, except when meeting with the local oncologist. 
This visit can occur at the participant’s home or, alternatively, patients can visit district nurse 
at the local health center, depending on patient preference. 
 


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Visits at the local oncologist practice will occur on Day 1 of Cycle 2, Cycle 4, Cycle 7, and 
Cycle 10. Depending on clinical practice and feasibility, participants may either: 
• Go to the local oncologist and have their blood drawn, and imaging and medical evaluation 
assessment performed on the same day. In this case, the investigator will review results 
remotely to decide whether participant should continue treatment or not. If the decision is 
made for the participant to continue, then the district nurses will be informed by the 
investigator to inject fulvestrant. 
• Have their blood drawn and imaging assessments performed in the week preceding the visit 
to the local oncologist. In that case, the investigator will review the results prior to the visit 
with the local oncologist and confirm whether or not the participant should continue with 
treatment. If the decision is made for the participant to continue, then the participant will 
attend the visit with the local oncologist per schedule and, if there are no medical concerns, 
they will receive fulvestrant injection at the end of the visit. 
The Assessment Schedule (Table 8-1) lists all of the assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants will attend visits and perform assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. For visits a general ± 7 days 
window is allowed, except when specified otherwise. Laboratory evaluations and Fulvestrant 
injection should be performed in a ± 3 days window. Missed or rescheduled visits should not 
lead to automatic discontinuation. Participants who no longer wish to participate remotely will 
be offered the possibility to attend on-site visits. 
Visits initially planned to be performed remotely but finally performed on site and unscheduled 
visits on site or at the local oncologist’s (regional hospital) will be considered as unscheduled 
in-clinic visits. Visits that require treating oncologists or district nurses assessments are 
considered unscheduled visits. Additional contacts or visit performed by the Investigator 
through the telemedicine platform are not to be considered unscheduled visits. 
Participants who wish to prematurely discontinue the trial for any reason should be scheduled 
for an on-site visit as soon as possible, at which time all of the assessments listed for the EOT 
visit will be performed. At this EOT visit, all dispensed trial treatment should be reconciled, 
and the AEs and concomitant medications recorded on the dedicated CRFs. 
If the participants is not able to attend the visit on site, Investigators should make every effort 
to collect safety follow-up information and should ask the patient availability to return the study 
drug and the devices provided for the trial, through the courier. 
 


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Table 8-1 
Assessment schedule 
Period 
Scr. 
Treatment Period 9 
EOT 
Cycle 
Day 
 
C1 
D1 
C1 
D15 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
End of 
C12 
Assessment 
Location 
Site 
Site 
Remote 
Site 
DN 
LO 
DN 
LO 
DN 
DN 
LO 
DN 
DN 
LO 
DN 
DN 
 
Participant informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telemedicine platform (use, 
interaction and e-diary completion) 
X1 
X1 
 continuous  
X 
Patient History 
Demographic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status (WHO/ECOG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging Assessment4 
Tumor assessment and response 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Participant Reported Outcomes5 
EORTC QLQ-C30 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
BPI-SF 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Participant Satisfaction  
 
X7 
 
X6 
X6 
X7 
X6 
X6 
X7 
X6 
X6 
X7 
X6 
X6 
X7 


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Period 
Scr. 
Treatment Period 9 
EOT 
Cycle 
Day 
 
C1 
D1 
C1 
D15 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
End of 
C12 
Assessment 
Location 
Site 
Site 
Remote 
Site 
DN 
LO 
DN 
LO 
DN 
DN 
LO 
DN 
DN 
LO 
DN 
DN 
 
Laboratory Assessments8 
Serum Pregnancy test  
(pre-menopausal women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Chemistry Profile  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FPG3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMBG 
 
Daily in the first two weeks, starting from Cycle 1 Day 2, and then as clinically indicated 
 
HbA1c 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Treatments 
Previous and concomitant medication 
X 
Continuous 
X 
Fulvestrant 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Alpelisib 
 
Daily 
 
Goserelin (pre-menopausal women only) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment compliance 
 
Continuous 
 
Safety review 
ECG 
X 
When clinically indicated, at the discretion of the investigator 
Adverse events 
X 
Continuous, up to the EOT Visit 
BPI-SF= Brief Pain Inventory Short Form; DN = District nurse; ECG = electrocardiogram; EORTC QLQ-C30 = European Organization for Research and Treatment of 
Cancer’s Core Quality of Life Questionnaire; FPG = fasting plasma glucose; HbA1c = Glycosylated hemoglobin; LO = Local oncologist; Scr. = Screening; SMBG = self-
monitoring blood glucose; TFQ = Trial Feedback questionnaire; WBC = white blood count. X = assessment to be recorded in the clinical database or received 
electronically from a vendor 
1. Participant training and registration in the telemedicine platform 
2. ER/PR status, HER2 status, and PIK3CA status will be collected as part of medical history 
3. Assessment can be performed as clinically indicated in addition to the scheduled assessments. At Cycle 1, Day 1 and Cycle 1, Day 15, if accepted by local approved 
SmPC and according to Investigator’s opinion, FPG evaluation could be replaced by SMBG assessment, and this will not be considered protocol deviation. 


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4. Imaging assessments at baseline to be performed from −28 days to −1 day before Cycle 1, Day 1. Depending on clinical practice and feasibility, assessments 
scheduled at Day 1 of Cycle 4, Cycle 7, and Cycle 10 can be either performed on the day of the visit or in the week prior to the visit. Tumor assessment and response 
will be performed by RECIST v1.1 criteria 
5. During treatment period, questionnaires to be performed in the week preceding Day 1 of Cycle 4, Cycle 7, and Cycle 10. The baseline completion, should occur 
between screening and  Cycle 1, Day 1,  before trial treatment administration 
6. Through dedicated questions in the e-diary 
7. Through Novartis standard Trial feedback Questionnaire (TFQ) administration 
8. Laboratory assessments at baseline to be performed from -14 days to -1 day before Cycle 1, Day 1. Depending on clinical practice and feasibility, laboratory 
assessments are scheduled at Day 1 of Cycle 4, Cycle 7, and Cycle 10 can be either performed on the day of the visit or in a 3 day window prior to the visit. 
9. During treatment period, the Day 1 of each cycle is considered as the day of fulvestrant injection.  


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8.1 
Screening 
8.1.1 
Eligibility screening 
Participant eligibility will be checked by investigators once all screening procedures are 
completed. The investigator site will then be allowed to initiate treatment for the participant. 
Please refer and comply with detailed guidelines in the eligibility check user guidelines for the 
manual process. 
It is permissible to re-screen a participant once if s/he fails the initial screening on laboratory 
values. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an ICF and are subsequently found to be ineligible will be considered a 
screening failure. The following CRFs must be completed for a screen failure patient: 
• Screening phase disposition page of CRF (including reason for not being started on 
treatment) 
• Informed consent 
• Inclusion/Exclusion criteria 
• Demography 
• AEs (only if the participant experienced a SAE during the screening period after signing the 
ICF (see Section 10 “Safety monitoring and reporting” for SAE reporting details) 
• Withdrawal of consent, if applicable 
• Death, if applicable 
No other data will be entered into the clinical database for participants who are screen failures. 
Participants who sign an ICF and are considered eligible but fail to initiate treatment for any 
reason will be considered an early terminator. The reason for early termination should be 
captured on the appropriate disposition CRF. 
8.2 
Participant demographics and other baseline characteristics 
The following baseline characteristics will be collected and assessed on-site at screening or at 
the Cycle 1, Day 1 visit: 
• Demographic data (age and gender) 
• Height and weight 
• Medical history (e.g., important medical, surgical, and allergic conditions from the 
participant’s medical history which could have an impact on the participant’s evaluation, 
mutational status [ER, PR, HER2, and PIK3CA status]) and current medical conditions 
(e.g., all relevant current medical conditions which are present at the time of signing ICF). 
• Ongoing medical conditions, symptoms, and disease that are recorded on the Medical 
History CRF should include the toxicity grade. 
• Patient-reported outcome questionnaires (EORTC QLQ-C30, EQ-5D-5L, Brief pain 
inventory-short form [BPI-SF], and TFQ Section A) (see Section 8.5.1 “Participant 


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Reported Outcomes”) should be completed by the participant in the period between 
screening and Cycle 1, Day 1 before treatment administration. This will enable the 
participant to gain confidence with the telemedicine platform. 
• Prior and concomitant medications: 
• All prior antineoplastic therapies including surgical interventions and chemo-, 
biologic-, immunologic- and radiation-therapies provided as treatment for cancer prior 
to the administration of trial treatment. 
• All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded on the Prior and Concomitant medication 
or Surgical and medical procedures CRF page and updated on a continual basis if there 
are any new changes to the medications. 
• Laboratory evaluations (e.g. hemoglobin, white blood count with differential, platelets, full 
chemistry profile, fasting plasma glucose, glycosylated hemoglobin, and pregnancy) 
• Imaging assessments (see Section 8.3.1 “Imaging tumor assessment”) 
• ECG (see Section 8.4.4.1 “Electrocardiogram”), and other cardiac assessment if clinically 
indicated, at the discretion of the treating physician 
• Furthermore the following assessments will be performed: 
• Physical examination 
• Vital signs 
• Performance Status (World Health Organization [WHO]/Eastern Cooperative 
Oncology Group [ECOG]) 
8.3 
Efficacy 
8.3.1 
Imaging tumor assessment 
Imaging will be performed on-site at screening and at EOT. During the remote participation 
period, imaging will be performed at the local oncologist facilities. Once available, source 
imaging data will be made accessible to investigators and site personnel per current practice as 
allowed per country regulation. Additional details on transfer of source documents will be 
detailed in a separate operational manual. Site radiologist will assess tumor response according 
to the Novartis guideline version 3.1 (Appendix 3) based on RECIST 1.1 
(Eisenhauer et al 2009). The imaging assessment collection plan is presented in Table 8-2. 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days prior to start of 
trial treatment (Day −28 to Day −1 prior to Cycle 1, Day 1). The whole body scan can be 
performed within 42 days prior to start of trial treatment. Any imaging assessments already 
completed during the regular work-up of the participant within 28 days prior to start of treatment 
(42 days for the whole body scan), including before signing the main trial ICF, can be 
considered as the baseline images for this trial. Any imaging assessments obtained after 
treatment initiation cannot be considered as baseline images. The following assessments are 
required at screening/baseline: 


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• Chest, abdomen and pelvis CT or MRI 
• Brain CT or MRI, if clinically indicated 
• Whole body bone scan 
• Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI 
• Color photography for any skin lesions present 
• CT or MRI of other metastatic sites (e.g., neck), if clinically indicated 
If a participant is known to have a contraindication to CT i.v. contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (MRI is not recommended due 
to respiratory artifacts, however if CT is not feasible per local regulations, MRI can be 
performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and pelvis should 
be performed. 
If brain metastases are suspected at baseline, brain MRI or CT should be completed. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then MRI without 
contrast or CT with/without contrast is acceptable. 
At baseline all participants will undergo, a whole body bone scan per institutional standard of 
care [e.g., Tc-99 bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission 
tomography (FDG-PET) or sodium fluoride (NaF) PET], thereafter whole body scan should be 
performed as clinically indicated. Localized CT, MRI or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed. 
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Each lesion that is measured at baseline must be measured by the same method (either same 
radiologic/nuclear method or by physical exam) throughout the trial so that the comparison is 
consistent. Criteria required for determining partial or complete response should be present for 
at least 4 weeks. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
Post-baseline imaging assessments 
Imaging assessments described in Table 8-2 should be performed using the same imaging 
modality used at baseline, irrespective of trial treatment interruption or actual dosing (see 
Table 8-1). Imaging assessments for response evaluation will be performed every 12 weeks 


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(± 7 days) after treatment initiation (Cycle 1, Day 1), and at the EOT visit. The 12-week interval 
should be respected regardless of whether trial treatment is temporarily withheld or unscheduled 
assessments are performed. 
Additional imaging assessments may be performed at any time during the trial at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the trial so that the comparison is consistent. If an off-schedule 
imaging assessment is performed because progression is suspected, subsequent imaging 
assessments should be performed in accordance with the original imaging schedule. 
Combined Positron Emission Tomography/Computed Tomography (PET/CT) may be used 
only if the CT is of similar diagnostic quality as a CT performed without PET, including the 
utilization of IV contrast media. At the discretion of the investigators, FDG-PET scans may be 
performed to document progressive disease per RECIST 1.1. 
Table 8-2 
Imaging assessment collection plan 
Procedure 
Screening 
Day -28 to Day -1 
Treatment phase 
End of Trial 
 Visit 
CT or MRI (Chest, 
Abdomen, Pelvis)  
Mandated 
Mandated every 12 weeks 
after 
Mandated* 
CT or MRI for any site of 
disease 
Mandated if suspected 
lesion at screening 
If lesion at screening: 
every 12 weeks after 
treatment initiation 
Mandated if 
lesion at 
screening* 
Brain CT or MRI (only if 
existing or suspected brain 
metastasis) 
Mandated at screening only 
if existing or suspected 
brain metastasis 
If brain lesion at 
screening: every 12 weeks 
after treatment initiation  
Mandated only if 
brain lesion at 
screening* 
Whole Body Bone scan** 
Mandated, within 42 days (6 
weeks) prior to 
randomization. 
As clinically indicated 
As clinically 
indicated 
Bone X-ray, CT or MRI 
Mandated at screening only 
if skeletal abnormalities 
identified by bone scan at 
screening 
If bone lesion at 
screening: every 12 weeks 
after treatment initiation 
Mandated only if 
bone lesion at 
screening* 
Skin color photography 
Mandated if skin lesions at 
screening 
If skin lesions at screening 
every 12 weeks after 
treatment initiation 
Mandated if skin 
lesions at 
screening* 
* Mandated for participants who discontinue trial treatment before the first scheduled post-screening tumor assessment and 
for participants whose previous tumor assessment did not demonstrate PD and was done more than 21 days prior to end of 
trial visit. In addition, EOT tumor assessment should be done in patients who discontinue due to clinical progression (e.g. 
investigator decision) to confirm disease progression by RECIST. 
** Type of whole body bone scan according to institutional guidelines 
*** If CT or MRI scan available before signing of ICF but within 28 days of first dose, no need to repeat the procedures 
Note: All scans will be acquired and analyzed for primary endpoint locally. 
 


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8.3.2 
Performance status 
Performance status scale will be assessed as described in Table 8-3. 
Table 8-3 
WHO/ECOG performance status 
Grade 
WHO/ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
8.3.3 
Appropriateness of efficacy assessments 
Imaging assessments are standards and were the ones performed during the SOLAR-1 clinical 
trial (Andre et al 2019). 
8.4 
Safety and tolerability 
Safety will be monitored by assessing physical examination, vital signs, ECG (if available), 
laboratory evaluations for hematology and biochemistry including but not limited to glucose 
monitoring as well as collecting of the AEs at every visit. Whenever necessary, the trial team 
will be able to assess rash and diarrhea symptoms through the telemedicine platform. For details 
on AE collection and reporting, refer to Section 10 “Safety monitoring and reporting”. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
8.4.1 
Physical examination 
A complete physical examination will be performed at: 
• Screening (Day −28 to Day −1) and at Cycle 1, Day 1 by the investigator. 
• Day 1 of Cycle 2, Cycle 4, Cycle 7 and Cycle 10 by the local oncologist, 
• The EOT visit by the investigator. 
Whenever clinically indicated, additional physical examination can be performed by 
investigators or local oncologists. 
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 trial site if the visit is an on-
site visit or at the practice of the local oncologist. Once available, source documents from the 


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practice of the local oncologist will be made accessible to investigators and site personnel per 
current practice as allowed per country regulation. Additional details on transfer of source 
documents will be detailed in a separate operational manual. 
Significant findings that were present prior to the signing of ICF must be included in the 
Medical History page on the patient’s CRF. Significant new findings that begin or worsen after 
signing of ICF must be recorded on the AE page of the participant’s CRF. 
8.4.2 
Vital signs 
Vital signs (temperature, blood pressure [supine position preferred when optional ECG is 
collected] and pulse) will be monitored at: 
• Screening (Day −28 to Day −1) and Cycle 1, Day 1 by the investigator, 
• Day 1 of Cycle 2, Cycle 4, Cycle 7 and Cycle 10 by the local oncologist, 
• Day 1 of Cycle 3, Cycle 5, Cycle 6, Cycle 8, Cycle 9, Cycle 11, and Cycle 12 by a district 
nurse, 
• EOT visit by the investigator. 
Additional vital signs assessments can be performed as clinically indicated by the investigator, 
the local oncologist or the district nurse. Blood pressure (systolic and diastolic) and pulse should 
be measured after the participant has been sitting for five minutes. 
8.4.3 
Laboratory evaluations 
Clinical laboratory analyses are to be performed on-site at Screening (Day −28 to Day −1), 
Cycle 1, Day 1, and at the EOT visit, and at a local laboratory during remote participation. 
SMBG will be performed by the participant. Novartis must be provided with a copy of all the 
laboratories’ certification (if applicable), and a tabulation of the normal ranges and units of each 
parameter collected in the CRF. Any changes regarding normal ranges and units for laboratory 
values assessed during the trial must be reported via an updated tabulation indicating the date 
of revalidation. 
The laboratory evaluation collection plan is presented in Table 8-4. Visit windows of ± 3 days 
are allowed for laboratory evaluations. 
The investigator is responsible for reviewing all laboratory reports for participants in the trial 
and evaluating any abnormalities for clinical significance. Clinically significant abnormalities 
must be recorded as either medical history/current medical conditions or AEs as appropriate. 
At any time during the trial, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with trial treatment (e.g., require dose modification and/or 
interruption of trial treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the CTCAE version 4.0.3. 
Unscheduled assessments may be performed if medically indicated to assess a (potential) AE 
or when needed by the treating physician for decision making (e.g. dose modifications). 


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Table 8-4 
Laboratory evaluation collection plan 
Test Category 
Test Name 
Screening 
Day -14 to 
Day -1 
Treatment phase 
End of Trial Visit 
Hematology 
Hemoglobin, White blood 
cells, Differential 
(Leukocytes, Neutrophils, 
Thrombocytes), and 
Platelets. 
Mandated 
D1 of Cycle 2, and 
thereafter Day 1 of each 
cycle 
Mandated 
Chemistry 
For all participants:  
C-Reactive Protein, 
Albumin, Alkaline 
Phosphatase, alanine 
aminotransferase, 
Aspartate 
aminotransferase, Bilirubin, 
Creatinine, Sodium, 
Potassium, Cancer Antigen 
15-3, Lactate 
Dehydrogenase (LDH). 
For participants treated with 
SGLT2 inhibitors with or 
without metformin: ketones 
Mandated 
D1 of Cycle 2, and 
thereafter Day 1 of each 
cycle 
Mandated 
Fasting Plasma Glucose 
Mandated 
Day 1, and Day 15 of 
Cycle 1, Day 1 of Cycle 2, 
and thereafter Day 1 of 
each cycle 
Day 1 and Day15 of Cycle 
1, if accepted by local 
approved SmPC, FPG 
evaluation could be 
replaced by SMBG 
assessment, and this will 
not be considered protocol 
deviation. 
Mandated. 
 
SMBG 
- 
Daily from Day 2 to Day 
14 of Cycle 1, and 
thereafter as clinically 
indicated 
 
Glycosylated hemoglobin 
(HbA1c) 
Mandated 
Day 1 of Cycle 2, Cycle 5, 
Cycle 8, and Cycle 11 
Mandated 
Serum pregnancy test 
Mandated 
- 
- 
Note: All laboratory analyses will be performed locally. 
SMBG=self-monitoring blood glucose 
8.4.4 
Cardiac assessments 
Cardiac assessments will only be performed if clinically indicated by the investigator or the 
local oncologist. 
8.4.4.1 
Electrocardiogram 
A standard 12-lead ECG will be performed on-site at screening and thereafter only if clinically 
indicated. ECG will be performed after the participant has been resting for 5 to 10 min. The 
interpretation of the tracing must be made by a qualified physician and documented in the ECG 


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section of the CRF. Each ECG tracing should be labeled with the Participant No, date, and kept 
in the source documents at the trial site. If an ECG is performed during the screening period, 
clinically significant abnormalities present when the participant signed ICF should be reported 
on the Medical History CRF page. Clinically significant findings must be discussed with the 
Novartis Medical Monitor prior to enrolling the participant in the trial. New or worsened 
clinically significant findings occurring after signing of ICF must be recorded on the AEs CRF 
page. 
8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this participant population. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this trial, apart from collection 
of participant-reported outcomes (PROs). 
8.5.1 
Participant reported outcomes 
The following electronic participant-reported outcomes (ePROs) EORTC QLQ-C30, EQ-5D-
5L and BPI-SF will be used to evaluate participant-reported outcome measures of health-related 
quality of life, functioning, disease symptoms, treatment-related side effects, global health 
status, and cancer related pain. The Trial Feedback questionnaire (TFQ) will be used to assess 
participant satisfaction throughout the conduct of the trial. The ePRO assessment collection 
plan is presented in Table 8-5. 
All ePRO data will be collected using the telemedicine platform: the baseline collection will be 
done between screening visit and Cycle 1, Day 1 visit, before trial treatment administration. 
The next ePROs will be collected at home during the week preceding the visits with the local 
oncologist, i.e. prior to Day 1 of Cycle 4, Cycle 7, and Cycle 10. ePROs will be administered 
in Swedish. All ePRO measures will be administered before any trial treatment administration 
at the time-point indicated. Participants should be given sufficient space and time to complete 
all trial questionnaires. During the remote participant monitoring period, participants will 
receive a reminder that ePROs are available to be completed through their device. 
All administered questionnaires should be reviewed for completeness. When applicable, if 
missing responses are noted, participants should be encouraged to complete any missing 
responses. Attempts should be made to collect responses to all questionnaires for all 
participants, including from those who discontinue prior to the trial evaluation completion visit, 
however, if participants refuse to complete questionnaires, this should be documented in trial 
source records. 
Participant’s refusal to complete trial questionnaires are not protocol deviations. 
Completed questionnaires must be reviewed and assessed by the investigator for responses 
which may indicate potential AEs or SAEs. This review should be documented in trial source 
records. 
If an AE or SAE is confirmed then the physician should record the event as instructed in 
Section 10 “Safety monitoring and reporting” of this protocol. 


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Investigators should not encourage the participants to change responses reported in 
questionnaires. 
Table 8-5 
Participant reported outcomes collection plan 
Participant 
Questionnaires 
Baseline 
collection 
(between 
Screening and 
C1D1) 
Treatment phase 
In the week preceding 
End of Trial 
EORTC QLQ-C30 
Mandated 
Day 1 of Cycle 4, Cycle 7, and Cycle 10 
Mandated 
EQ-5D-5L 
Mandated 
Day 1 of Cycle 4, Cycle 7, and Cycle 10 
Mandated 
BPI-SF 
Mandated 
Day 1 of Cycle 4, Cycle 7, and Cycle 10 
Mandated 
TFQ 
Mandated  
(Section A) 
Day 1 of Cycle 4, Cycle 7, and Cycle 10 
(Section B) 
Mandated 
(Section C) 
Note: If questionnaires are to be completed on the same day than other assessments, they should be completed prior to 
any clinical assessment, drug dosing or diagnostic testing. 
BPI-SF = Brief Pain Inventory Short Form; C1D1 = Cycle 1, Day 1; EORTC QLQ-C30 = European Organization for 
Research and Treatment of Cancer’s Core Quality of Life Questionnaire; TFQ = Trial Feedback Questionnaire 
 
8.5.1.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single 
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson et al 1993). 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a 
high/healthy level of functioning; a high score for the global health status/QoL represents a high 
QoL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers 2001). 
8.5.1.2 
EQ-5D-5L 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal. Whatever 
the version of the EQ-5D questionnaire, the EQ-5D essentially consists of 2 pages: the EQ-5D 
descriptive system and the EQ visual analogue scale (EQ VAS). The patient is asked to indicate 
his/her health state by ticking the box next to the most appropriate statement in each of the five 
dimensions. The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale, where the endpoints are labeled ‘The best health you can imagine’ and ‘The worst health 
you can imagine. 
The 5-level EQ-5D version (EQ-5D-5L) was introduced by the EuroQol Group in 2009 to 
improve the instrument’s sensitivity and to reduce ceiling effects, as compared to the EQ-5D-
3L. The EQ-5D descriptive system comprises of the 5 following dimensions: mobility, self-


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care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems. 
8.5.1.3 
Brief Pain Inventory 
The BPI-SF is a self-administered assessment tool validated to assess pain (Atkinson et al 2011; 
Philip et al 1998). The basic aim of the BPI is to provide the information on the intensity of 
pain, along with the degree to which the pain interferes with the everyday functioning of life. 
The BPI uses simple numeric rating scales from 0 to 10. Since pain can vary to a considerable 
measure over a day, the BPI asks the patients to rate their pain at the time of responding to the 
questionnaire. In addition, the questionnaire also asks the respondent to specify the pain at its 
worst, least and average over the previous week. The short version of the BPI is completed in 
5 min. 
No scoring algorithm have been developed for the BPI, but "worst pain" or the arithmetic mean 
of the four severity items can be used as measures of pain severity; the arithmetic mean of the 
seven interference items can be used as a measure of pain interference. 
The BPI has been validated in a patient population with breast cancer (Castel et al 2007) and 
has been linguistically validated in Swedish. 
8.5.1.4 
Trial Feedback Questionnaire 
The Trial Feedback Questionnaire (TFQ) is a brief, validated patient questionnaire designed to 
capture patient trial experience independent of disease and treatment. The face and content 
validity of the questionnaire was tested and confirmed by research conducted by Adelphi, 
PatientsLikeMe and HRM using established Patient Reported Outcome (PRO) methodology 
through cognitive debriefing with participants from phase I-III studies for various conditions 
(Brohan et al 2014). The questions have been further tested quantitatively and qualitatively 
through electronic administration and/or in depth interviews with >400 trial experienced 
patients (Manson et al 2015). Therefore, the questionnaire can be considered to have face and 
content validity in clinical trial participants. 
Participants will be asked to complete the TFQ to provide feedback on their clinical trial 
experience. TFQ is divided in 3 parts: Part A – Participant experience before they started the 
trial; Part B – Participant experience during the trial; and Part C – Participant experienced at 
the end of the trial. 
Individual participant level responses will not be reviewed by investigators. 
8.6 
DCT elements included in the Trial 
8.6.1 
The telemedicine platform 
The Sponsor has qualified and contracted a third party vendor who provides the telemedicine 
platform technology for this hybrid DCT. Trial participants can interact with site personnel 
using online communication tools built into the platform. The telemedicine platform includes 
the following key capabilities: 
• Secure videoconferencing, which allows the patient to directly connect with the investigator 
and site staff 


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• ePROs and e-Diaries (for capturing information such as compliance with study drug, self-
reporting glucose level and events), to be completed by the trial participant 
• Reminders, to be automatically sent to participants to ensure timely completion of ePROs 
and the e-Diary 
• Electronic Data Capture for sites data entry from source clinical information 
• Automated summary reports for the investigator and site staff, to support participant 
management and for maintaining study oversight 
Additional details are available in the Site Operational Manual. 
8.6.2 
Conduct of study visits away from the investigator site 
Participants in the study agree during enrollment to participate in visits supported by local 
oncologists, district nurses, local laboratory facilities and specialized radiology centers and to 
connect 
with 
the 
site 
staff 
using 
the 
telemedicine 
platform, 
based 
on the visit/assessment schedule summarized in Section 8. Roles and responsibilities of local 
oncologists and district nurses will be fully defined in a written agreement with the investigative 
site. 
The main aspects of the remote visits and activities are: 
• Investigative site: the investigator will maintain oversight and accountability for 
participant’s treatment and safety as defined in the protocol, oversee local oncologist and 
district nurse activities, and maintain regular contact with the participant to ensure their 
safety and well-being. On an ongoing basis, the investigator will review the data reported 
by the participant (trial medication compliance, ePRO, e-diaries etc.) directly in the platform 
and will assess and report accordingly any AEs/SAEs as defined in Section 10. 
• Local oncologist: the investigator is responsible to engage with qualified local oncologists 
who are willing to support remote study visits during the study participation. The local 
oncologist will support the investigator by performing clinical practice procedures and will 
make medical records pertaining to remote visits available to the investigator. Any changes 
to the participant’s medical health will also be shared, in addition to any performed 
laboratory assessments, but any trial-related decisions will remain under the responsibility 
of the investigator. 
• District nurse: as per local process, the investigator could request the assistance and support 
of a district nurse (or ASIH program) to conduct specific assessments. These delegated 
assessments may include vital signs collection, administration of fulvestrant (Faslodex® 
500 mg i.m.), concomitant medication when prescribed by the investigator, and assisting 
participants on the use of the glucometer. After each assisted visit, the district nurse will 
document the visit as per local process, and make them available to the investigator. 
• Participant: Participants will perform remote visits with the investigator via the telemedicine 
platform, and will attend in-person assessments (with the local oncologist or district nurses 
or at the local lab or radiologist centers) in accordance with the schedule defined in 
Section 8. 
Participants will also be requested to complete PRO assessments and electronic diaries using 
the telemedicine application (by providing the participant with a smartphone or by using 
their own device, at the participant’s request). In addition, participants will receive 


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automated notifications within the telemedicine platform, to remind them to complete the 
required assessments in a timely manner. 
• Other facilities: Laboratory and radiology center appointments may also be ordered by the 
investigator, as per local process, to conduct these standard assessments. The investigator 
should discuss and arrange for direct access to these reports. 
Participants will be instructed to contact the site at any time if they have questions 
about the completion of activities, regarding functionality of the telemedicine application, and 
also if  there are any changes to their health status. 
The telemedicine platform can generate regular summary reports, to support the investigator’s 
assessment and participant’s safety management on an ongoing basis. 
9 
Trial discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Trial treatment discontinuation and trial discontinuation 
Discontinuation of trial treatment for a participant occurs when trial treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the participant or the 
investigator. Participants who discontinue trial treatment will be prematurely withdrawn from 
the trial. 
The investigator must discontinue trial treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being. 
Trial treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which trial participation might result in a safety risk to the participant 
If discontinuation of trial treatment occurs, the investigator should make a reasonable effort to 
understand the primary reason for the participant’s premature discontinuation of trial treatment 
and record this information.  
Whenever possible, participants discontinued early for any reason, should be requested to 
complete the assessments planned in EOT visit. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the trial for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the trial anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further trial related contacts 


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. All efforts should be made to complete the assessments prior to trial 
discontinuation. A final evaluation at the time of the participant’s trial discontinuation should 
be made as detailed in the assessment table. Trial treatment must be discontinued and no further 
assessments conducted, and the data that would have been collected at subsequent visits will be 
considered missing. Further attempts to contact the participant are not allowed unless safety 
findings require communicating or follow-up. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the trial evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for trial visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed. 
9.1.4 
Early trial termination by the sponsor 
The trial can be terminated by Novartis at any time. 
Reasons for early termination can be unexpected, significant, or unacceptable safety risk to 
participants enrolled in the trial. 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Considering that both alpelisib and fulvestrant are marketed drugs in Sweden and that 
participants will be able to pursue treatment as part of their standard of care, no specific 
procedures have been set up in case of early termination by the sponsor. The investigator or 
sponsor depending on local regulation will be responsible for informing IECs of the early 
termination of the trial. 
9.2 
Trial completion and post-trial treatment 
The end of study is defined as the last visit of the last participant, i.e. the End of Trial (EOT) 
visit of the last ongoing patient (Cycle 1, Day 28 or final visit for a participant who dropped-
out early).  
Participants will be followed-up until they reach the EOT visit and any repeat assessment 
associated with this visit have been documented and followed-up appropriately by the 
investigator, or until disease progression, death, withdrawal of consent, loss to follow-up, 
subject/guardian decision, whichever occurs first. Participants no longer willing to be follow-
up remotely will be offered to attend only on-site visits and will not be considered to have 
prematurely discontinued the trial. 


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The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.4 “SAE Reporting”. Documentation of 
attempts to contact the participant should be recorded in the source documentation. 
Considering that both alpelisib and fulvestrant are marketed drugs in Sweden and that 
participants will be able to pursue treatment as part of their standard of care after trial 
completion, no specific procedures have been set up for continuing care. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant after providing written informed consent for participation in the trial. Therefore, an 
AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Once the main trial ICF is signed, all AEs per the descriptions below will be captured as AEs. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the trial. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, 
PROs or other assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.4 “SAE Reporting”): 
1. The severity grade (CTCAE Grade 1-4) 
2. Its relationship to the trial treatment. If the event is due to lack of efficacy or progression of 
underlying illness (i.e. progression of the trial indication) the assessment of causality will 
usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a lack of 
efficacy or progression of underlying illness are not caused by the trial treatment, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 


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5. Action taken regarding with trial drugs. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome 
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 AEs 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. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. AEs (including laboratory abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the trial – EOT visit), and assessment must be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a SAE, except if the investigator 
considers that progression of malignancy is related to trial treatment. 
AEs separate from the progression of malignancy (i.e. deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the 
drug. 
Information about adverse drug reactions for the trial treatments can be found in their respective 
SmPCs. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 


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10.1.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines, 2004). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, elective or pre-planned treatment for a pre-existing 
condition that is unrelated to the indication under trial and has not worsened since 
signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH E2D Guidelines, 2004). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
trial indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred. 
10.1.3 
Adverse events of 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 


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communication by the investigator to the sponsor may be appropriate. Such events may require 
further investigation in order to characterize and understand them. 
The following AESIs are defined for this on the basis of results from the SOLAR-1: 
hyperglycemia, rash, and diarrhea. For additional detail, refer to Section 4.5.3 “Risk 
Management Strategies”. 
10.1.4 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until EOT visit must be reported to Novartis safety 
immediately, without undue delay, under no circumstances later than within 24 hours of 
learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. All follow-up 
information for the SAE including information on complications, progression of the initial SAE 
and recurrent episodes must be reported as follow-up to the original episode 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 must be 
reported separately as a new event. 
If the SAE is not previously documented in the Package Insert (new occurrence) and is thought 
to be related to the trial treatment, a Chief Medical Office and Patient Safety (CMO & PS) 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any trial with the same trial treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with EU Guidance 2011/C 
172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the EOT visit should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to trial treatment. 
10.1.5 
Pregnancy 
This trial is planned for men, post-menopausal women or pre-menopausal women with ovarian 
suppression. No pregnancies are expected for participants. However, in the rare cases when this 
occurs, to ensure participant safety, each pregnancy occurring while the participant is on trial 
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. Baby status should be followed up 
to one year after pregnancy due date. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the trial treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 


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Pregnancy outcomes should be collected for the female partners of any males who took trial 
treatment in this trial. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
10.1.6 
Reporting of trial treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a HCP, participant or consumer (EMA 
definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Trial treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
investigator’s awareness. 
Table 10-1 
Guidance for capturing the trial treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional trial 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional safety monitoring 
Not Applicable. 
11 
Data collection and database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements, investigator or site personnel will not be given access to the 
electronic data capture (EDC) system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff. 


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The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated contract research organization) 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 or site personnel 
are required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the MedDRA terminology. 
The telemedicine platform will be the source document for the ePROs. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
Additional information will be included in a separated operation manual. 
11.3 
Site monitoring 
Before trial initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the trial, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data.  
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture/data entry, the adherence to the protocol and to GCP, the progress of 
enrollment, and to ensure that trial treatment is being stored, dispensed, and accounted for 
according to specifications. Key trial personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. If applicable and approved by local law, 
remote monitoring including remote source data verification (where applicable) will be 
performed. Additional details will be included in the Monitoring Plan. 


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The investigator must maintain source documents for each participant in the trial, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original ICF signed by the participant (a 
signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis site monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the trial-specific site monitoring plan. No information in source documents about the identity 
of the participants will be disclosed. 


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12 
Data analysis and statistical methods 
Data analysis will be carried out when all patients have completed the trial. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants that received any trial treatment. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data collected during the trial will be listed and summarized 
descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class (SOC) and preferred term (PT). 
12.3 
Treatments 
Duration of trial treatment exposure, cumulative dose and dose intensity, the number of 
participants with dose changes/interruptions along with reasons for the dose change/interruption 
will be presented. 
Number of participants treated with SGLT2 antagonist or metformin, dose, duration of 
treatment and reason for treatment administration (prophylaxis or hyperglycemia) will be 
summarized descriptively. Number of participants treated with goserelin will be described. 
Concomitant medications taken concurrently with the trial treatment will be listed and 
summarized by Anatomical Therapeutic Chemical Classification System term, preferred term 
by means of frequency counts and percentages. Surgical and medical procedures will be coded 
using MedDRA and summarized by SOC and PT. These summaries will include therapy 
starting on or after the start of trial treatment (defined as Cycle 1, Day 1) or therapy starting 
prior to the start of trial treatment and continuing after the start of trial treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of trial treatment will be listed. 
12.4 
Analysis of the primary endpoint 
12.4.1 
Definition of primary endpoint 
The primary objective of the trial is the participant satisfaction with the DTC experience. 
Participant satisfaction will be assessed at the start of the trial, every 12 weeks, and at the end 
of the trial through the TFQ. 


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12.4.2 
Statistical model, hypothesis, and method of analysis 
The number of participants completing the TFQ and the number of missing or incomplete 
assessments will be summarized for each scheduled assessment time point. No formal statistical 
tests will be performed. No imputation procedures will be applied for missing items or missing 
assessments. Descriptive statistics will be used to summarize items of the questionnaire. 
12.5 
Analysis of secondary endpoints 
Full details of the methods to be used for the analysis of these endpoints will be given in the 
statistical analysis plan (SAP), which will be finalized before any analysis takes place. 
Summary of qualitative research on the overall DCT experience from the Investigators and 
Clinical Trial Team will be also added in the Clinical Study Report. 
12.5.1 
Patient retention on DCT approach 
Proportion of patients on remote monitoring at 3, 6, 12 months for participants still on treatment 
will be summarized descriptively. 
12.5.2 
Safe and suitable remote management of patients on DCT approach 
Total number of unscheduled in-clinic visits because of safety reasons, total number of 
unscheduled in-clinic visits and the reason, and number of unscheduled in-clinic visits per 
participant in the study will be summarized descriptively. Discontinuation rate related to AEs 
will be summarized descriptively. 
12.5.3 
Compliance with treatment and adherence to procedures 
Number of patients with missed doses, adjusted dose, interruptions and discontinuations and 
reason why will be summarized descriptively. 
Overall compliance will be summarized descriptively overall and by categories (≤ 80%, 80 > 
and < 100%, and ≥ 100%). Overall compliance will assess the degree of correspondence of the 
actual dosing history with the prescribed drug regimen. Detail of overall compliance calculation 
will be provided in the SAP. 
12.5.4 
Safety endpoints 
The safety endpoint will be type, frequency and severity (incidence proportion) of AESIs per 
CTCAE v4.03. In addition, a separate summary for death will be provided. 
Adverse events 
The number (and percentage) of participants with treatment emergent AEs (events started after 
the first dose of trial medication or events present prior to start of treatment but increased in 
severity based on preferred term) will be summarized in the following ways: 
• by primary SOC and PT 
• by primary SOC, PT and maximum severity 
• by PT 


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Separate summaries will be provided for trial medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation. 
A participant with multiple AEs within a primary SOC is only counted once towards the total 
of the primary SOC. 
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by SOC and or PT, severity (based on CTCAE grades), type of AE, and 
relationship to trial treatment. 
SAEs, non-serious AEs and AESIs during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and SAEs will be listed. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by participant and visit/time, and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI CTCAE 
version 4.03. The calculation of CTCAE grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account. CTCAE Grade 0 will be assigned for 
all non-missing values not graded as 1 or higher. Grade 5 will not be used. For laboratory tests 
where grades are not defined by CTCAE version 4.03, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE version 
4.03 grades if applicable and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE version 4.03: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 4.03 grades to compare baseline to the worst on-treatment 
value. 
For laboratory tests where grades are not defined by CTCAE version 4.03: 


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• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
12.5.5 
Participant reported outcomes: Global Health Status, Quality of Life, 
and Pain 
For each PRO (EORTC QLQ-C30, EQ-5D-5L, and BPI-SF), the number of participants 
completing each questionnaire and the number of missing or incomplete assessments will be 
summarized for each scheduled assessment time point. No formal statistical tests will be 
performed. 
Scoring of PRO data and methods for handling of missing items or missing assessments will be 
performed according to the scoring manual and user guide for each respective participant 
questionnaire. No imputation procedures will be applied for missing items or missing 
assessments. 
For each questionnaire, descriptive statistics will be used to summarize dimension values and 
overall score. Additionally change from baseline will be summarized. Participants with an 
evaluable baseline score and at least one evaluable post baseline score during the treatment 
period will be included in the change from baseline analyses. 
12.5.6 
Treatment effectiveness 
Analysis of PFS according to RECIST 1.1 will be described to assess effectiveness of treatment 
alpelisib plus fulvestrant. The median PFS along with 95% confidence intervals will be 
presented. 
12.6 
Analysis of exploratory endpoints 
Not Applicable. 
12.7 
Interim analyses 
Not Applicable. 
12.8 
Sample size calculation 
As this is a pilot trial to evaluate the use of DCT, there is no formal calculation of sample size. 
Approximately 20 participants will be included based on feasibility. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical trial was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and General Data 
Protection Regulation (EU) 2016/679 [GDPR]), with the guidance on the management of 
clinical trials during the COVID-19 (Coronavirus) pandemic and with the ethical principles laid 
down in the Declaration of Helsinki. 


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13.2 
Responsibilities of the investigator and IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IEC for the trial protocol, written ICF, consent form updates, participant recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
participants. Prior to trial start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the trial in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IECs, and regulatory authorities as required. If an inspection of 
the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 
Roles and responsibilities of local oncologists and district nurses will be defined in a contract 
with site. 
Participants will be closely monitored by the investigator via the telemedicine platform and the 
investigator will also have oversight of the local oncologist and district nurse. Local oncologist 
and district nurse will be in charge of standard of care assessments, but they could also be 
involved in unscheduled visits for adverse events monitoring, if requested by Investigator. 
Investigators will keep the responsibility and authority to make decision for all aspects related 
to the management of participants during the entire clinical trial duration. 
13.3 
Publication of trial protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after trial completion (defined as last participant last visit) 
and finalization of the trial report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality control and quality assurance 
Novartis maintains a robust Quality Management System that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, site monitoring or performing quality control 
of the clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operative procedures, and are performed according to written 
Novartis processes. 


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


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15 
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Symptom Assessment System with the Rotterdam Symptom Checklist and the Brief Pain 
Inventory. Support Care Cancer; 6:539-41. 
Rugo HS, Bianchi GV, Chia SKL, et al (2018) BYLieve: A phase II study of alpelisib (ALP) 
with fulvestrant (FUL) or letrozole (LET) for treatment of PIK3CA mutant, hormone receptor-
positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast 
cancer (aBC) progressing on/after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy. 
Journal of Clinical Oncology; 36(15_suppl):TPS1107-TPS1107. 
Rugo HS, Lerebours F, Ciruelos E, et al (2020) Alpelisib (ALP) + fulvestrant (FUL) in patients 
(pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth 
factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with 
cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study 
results. J Clin Oncol; 38(15_suppl):1006-1006. 
 
 


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Protocol No. CBYL719A03201 
 
16 
Appendices 
16.1 
Appendix 1: Permitted medication to be used with caution 
In general, the use of any concomitant medication deemed necessary for the care of the 
participant is permitted in this trial, except as specifically prohibited below. Combination 
administration of trial drugs could result in drug-drug interactions (DDI) that could potentially 
lead to reduced activity or enhanced toxicity of the concomitant medication and/or alpelisib. 
Please note that all lists in Section 6-2 are not comprehensive. Please refer to regular updated 
online sources and the label of a concomitant drug to decide whether a drug is permitted (with 
caution) or prohibited based on Section 6-2. In doubt, please contact the medical monitor with 
any questions.  
16.1.1 
Permitted medication to be used with caution 
This list of CYP substrates and list of inhibitors / inducers were compiled from the University 
of Washington’s Drug Interaction Database (Updated November 2020). This list is only meant 
to be used as a guide.  
Table 16-1 
List of CYP450 substrates to be used with caution 
Category 
Drug names 
CYP2C9 substrates 
Narrow Therapeutic index substrates of 
CYP2C9 
(S)-Warfarin 
Sensitive substrates of CYP2C9 
Benzbromarone, Celecoxib, Glimepiride, 
Glipizide, (R)/(S)-Ibuprofen, Lornoxicam, 
Meloxicam, Piroxicam, Tolbutamine, (S)-
Warfarin 
CYP2B6 substrates 
Narrow Therapeutic index substrates of CYP2B6 
Not Applicable 
Sensitive substrates of CYP2B6 
Bupropion, Efavirenz 
Selected CYP3A4 substrates 
CYP3A4 substrates which are known or 
potential auto-perpetrators 
Clarithromycin, Conivaptan, Encorafenib, 
Erythromycin, Diltiazem, Mifepriston, Ribociclib, 
Telthromycin, Troleandomycin, Verapamil 
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. Torsades de 
Pointes, QT prolongation). 
CYP3A4 substrates which are auto-perpetrators: Based on Novartis internal assessment. 
16.1.2 
Prohibited Medication 
Strong inducers of CYP3A4 
This list of CYP inducers was compiled from the University of Washington’s Drug Interaction Database 
(Updated November 2020). This list is only meant to be used as a guide.  


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Table 16-2 
List of prohibited strong inducers of CYP3A 
Category 
Drug Name 
Strong CYP3A Inducers  
Apalutamide, Avasimibe1, Carbamazepine, 
Enzalutamide, Ivosidenib, Lumacaftor, Mitotane, 
Phenobarbital, Phenytoin, Rifapentine, Rifampin 
(Rifampicin), St. John's wort (hypericum 
perforatum)1  
1 Herbal product 
Inhibitors of BCRP 
The table encompasses only drugs and molecular entities for which inhibition of BCRP has 
been investigated and/or formally shown in vivo in a clinical DDI study. Please note that this is 
not an exhaustive list and only meant to be used as a guide. When in doubt, refer to the 
prescribing information of the drug to assess whether a potential for BCRP inhibition is 
described.  
Table 16-3 
List of prohibited BCRP inhibitors 
Category 
Drug Name 
BCRP inhibitors - 
Evidence for DDI potential shown in vivo 
Atazanavir/ritonavir1,2, Elvitegravir/cobicistat1,2, 
Lopinavir/ritonavir1,2, Tipranavir/ritonavir1,2, 
Curcumin1,2, Cyclosporine1,2, Daclatasvir1,2, 
Eltrombopag1,2, Gefitinib2, Lapatinib1, 
Ledipasvir2, Pantoprazole1,2, Paritepravir2, 
Tipranavir2 
1 Lee et al 2015 
2 Novartis PK Sciences DDI List (January, 2018) 
 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-4 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline: 
· ALT or AST > 5 × ULN 
· ALP > 2 × ULN (in the absence of known bone 
pathology) 
· Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome) 
· ALT or AST > 3 × ULN and INR > 1.5 
· Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
· Any clinical event of jaundice (or equivalent 
term) 
· ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia 
· Any adverse event potentially indicative of a 
liver toxicity* 
If ALT or AST abnormal at baseline: 
· ALT or AST > 2 × baseline or > 300 U/L 
(whichever occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit of normal 


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Table 16-5 
Follow up requirements for liver laboratory triggers with liver 
symptoms  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
If normal at baseline: 
ALT > 3 × ULN 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
None 
· No change to trial 
treatment 
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours. 
· Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
ALT > 5 × ULN for 
more than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
None 
· Interrupt trial drug 
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours. 
· Follow-up for 
symptoms. 
· Initiate close 
monitoring and workup 
for competing 
etiologies. 
· Trial drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline. 
If elevated at 
baseline: 
ALT > 3 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than two 
weeks 
If normal at baseline: 
ALT > 8 × ULN 
Normal 
None 
ALT increase with bilirubin increase: 
If normal at baseline: 
ALT > 3 × ULN 
TBL > 2 × ULN (or 
INR > 1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
ALT > 3 × ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 


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Table 16-6 
Follow up requirements for liver laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
> 1.5 to 3.0 ULN 
· Maintain treatment 
· Repeat LFTs within 48 to 72 
hours 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline 
> 3 to 10 × ULN (in the 
absence of known Gilbert 
syndrome) 
· Interrupt treatment 
· Repeat LFT within 48 to 72 
hours 
· Hospitalize if clinically 
appropriate 
· Establish causality 
· Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in the 
appropriate CRF 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 × ULN 
· Discontinue the trial treatment 
immediately 
· Hospitalize the participant 
· Establish causality 
· Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab) in the 
appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity* 
· Consider trial treatment 
interruption or discontinuation 
· Hospitalization if clinically 
appropriate 
· Establish causality 
· Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in the 
appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event can include: Serology 
tests, imaging and pathology assessments, hepatologist’s consultancy; obtaining more detailed history of 
symptoms and prior or concurrent diseases, history of concomitant drug use, exclusion of underlying liver disease 
 
 

SAP_001.pdf: 
Clinical Development 
BYL719/ Alpelisib /Piqray® 
CBYL719A03201 / NCT04862143  
Open-label, multicenter, pilot-trial evaluating the safety and utility of 
a hybrid decentralized clinical trial (DCT) approach using a 
TELEmedicine platform in patients with HR-positive/HER2-negative 
advanced breast cancer with a PIK3CA mutation treated with 
alpelisib – fulvestrant  
Statistical Analysis Plan (SAP) 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis  
Template Version 4.0, Effective from 23-Apr-2021 
Document type: 
SAP Documentation 
Document status: 
Final 2.0 
Release date: 
11-Oct-2022
Number of pages: 
36 


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SAP 
 
Study No. CBYL719A03201 
 
 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
07-
Mar-
2022 
Prior 
to DB 
lock 
Creation of final version 
N/A - First version 
NA 
06-
Oct-
2022 
Prior 
to DB 
lock 
Trial closeout early due to 
low rate of enrollment; SAP 
has been updated to align 
with synoptic CSR.  
First amendment 
All 
 
 
 
 
 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives, endpoints and estimands ........................................................... 10 
1.2.1 
Primary estimand(s) .............................................................................. 11 
1.2.2 
Secondary estimand(s) .......................................................................... 11 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 14 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 14 
2.3.2 
Demographics and other baseline characteristics ................................. 14 
2.3.3 
Prior, concomitant and post therapies ................................................... 18 
2.3.4 
Protocol Deviations ............................................................................... 19 
2.4 
Analysis supporting primary objective(s) .............................................................. 19 
2.4.1 
Primary endpoint(s) ............................................................................... 19 


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2.4.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.4.3 
Handling of intercurrent events ............................................................. 20 
2.4.4 
Handling of missing values not related to intercurrent event ............... 20 
2.4.5 
Sensitivity analyses ............................................................................... 20 
2.4.6 
Supplementary analyses ........................................................................ 20 
2.5 
Analysis supporting secondary objectives ............................................................. 20 
2.5.1 
Secondary endpoint(s) ........................................................................... 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.5.3 
Handling of intercurrent events ............................................................. 23 
2.5.4 
Handling of missing values not related to intercurrent event ............... 23 
2.5.5 
Sensitivity analyses ............................................................................... 23 
2.5.6 
Supplementary analyses ........................................................................ 23 
2.6 
Safety analyses ....................................................................................................... 23 
2.6.1 
Adverse events (AEs) ............................................................................ 23 
2.6.2 
Deaths .................................................................................................... 25 
2.6.3 
Laboratory data ..................................................................................... 25 
2.6.4 
Other safety data ................................................................................... 26 
2.7 
Pharmacokinetic endpoints .................................................................................... 27 
2.8 
PD and PK/PD analyses......................................................................................... 27 
2.9 
Patient-reported outcomes ..................................................................................... 27 
2.9.1 
EORTC QLQ-C30 ................................................................................ 28 
2.9.2 
EQ-5D-5L ............................................................................................. 29 
2.9.3 
Brief Pain Inventory .............................................................................. 29 
2.9.4 
TFQ ....................................................................................................... 29 
2.10 
Biomarkers ............................................................................................................. 29 
2.11 
Other Exploratory analyses .................................................................................... 29 
2.12 
Interim analysis ...................................................................................................... 29 
3 
Sample size calculation ..................................................................................................... 30 
4 
Change to protocol specified analyses .............................................................................. 30 
5 
Appendix ........................................................................................................................... 30 
5.1 
Imputation rules ..................................................................................................... 30 
5.1.1 
Study drug ............................................................................................. 30 
5.1.2 
AE date imputation ............................................................................... 30 
5.1.3 
Concomitant medication date imputation ............................................. 30 
5.2 
AEs coding/grading ............................................................................................... 31 


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5.3 
Laboratory parameters derivations ........................................................................ 31 
5.4 
Statistical models ................................................................................................... 31 
5.4.1 
Analysis supporting primary objective(s) ............................................. 31 
5.4.2 
Analysis supporting secondary objective(s).......................................... 32 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 32 
6 
Reference ........................................................................................................................... 36 
 


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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 10 
Table 2-2 
Planned dose intensity ........................................................................... 17 
Table 2-3  
Sources for overall lesion response ....................................................... 21 
Table 2-4  
AESI groupings ..................................................................................... 25 
Table 2-5  
Time windows for patient reported outcomes ....................................... 28 
Table 5-1 
Protocol deviations that cause subjects to be excluded ......................... 32 
Table 5-2 
Code Text .............................................................................................. 35 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
 


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List of abbreviations 
AE 
AESI 
ALT 
ALP 
AST 
ATC 
BP 
CI 
CRF 
CRS 
CSP 
CSR 
CTCAE 
DAR 
DCO 
DCT 
DFI 
DI 
DMS 
Adverse Event 
Adverse Event of Special Interest 
Alanine Aminotransferease 
Alkaline Phosphatase 
Aspartate Aminotransferase 
Anatomical Therapeutic Chemical 
Blood Pressure 
Confidence Interval 
Case Report Form 
Case Retrieval Sheet 
Clinical Study Protocol 
Clinical Study Report 
Common Terminology Criteria for Adverse events 
Drug Administration Record 
Data Cut-off 
Decentralized Clinical Trial 
Disease Free Interval 
Dose Intensity 
Document Management System 
DRL 
ECOG 
ECG 
EOT 
ET 
FAS 
HR 
HER2 
HLGT 
HLT 
IA 
Drug Reference Listing 
Eastern Cooperative Oncology Group 
Electrocardiogram 
End Of Trial 
Endocrine Therapy 
Full Analysis Set 
Hormone Receptor 
Human Epidermal Growth Factor Receptor 2 
High Level Group Terms 
High Level Terms 
Interim Analyses 
ICF 
LHRH 
LVEF 
MedDRA 
MUGA 
Informed Consent Form 
Luteinizing Hormone-Releasing Hormone 
Left Ventricular Ejection Fraction 
Medical Dictionary for Drug Regulatory Affairs 
Multigated Acquisition Scan 
NCI 
NMQ 
OFS 
PD 
PDI 
PDS 
PFS 
PK 
National Cancer Institute 
Novartis MedDRA Queries 
Ovarian function suppression 
Pharmacodynamics 
Planned Dose Intensity 
Programming Datasets Specifications 
Progression Free Survival 
Pharmacokinetics 
PPS 
Per-Protocol Set 


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Study No. CBYL719A03201 
 
 
 
PR 
Progesterone Receptor 
QOL 
RAP 
Quality Of Life 
Reporting & Analysis Process 
RDI 
RECIST 
SAE 
SAP 
SAS 
Relative Dose Intensity 
Response Evaluation Criteria in Solid Tumors 
Serious Adverse Event 
Statistical Analysis Plan 
Statistical Analysis System 
SGLT2 
SOC 
SMQ 
TBIL 
TFLs 
sodium glucose co-transporter 2 
System Organ Class 
Standardized MedDRA Queries 
Total bilirubin 
Tables, Figures, Listings 
TFQ 
ULN 
WHO 
Trial Feedback Questionnaire 
Upper Limits Of Normal 
World Health Organization 


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Study No. CBYL719A03201 
 
 
 
 
1 
Introduction 
This document describes the detailed statistical methodology to be used for the Clinical Study 
Report (CSR) for the analysis of study CBYL719A03201, open-label, multicenter, pilot-trial 
evaluating the safety and utility of a hybrid decentralized clinical trial (DCT) approach using a 
TELEmedicine platform in patients with HR-positive/HER2-negative advanced breast cancer 
with a PIK3CA mutation treated with alpelisib – fulvestrant. 
The content of this SAP is based on CBYL719A03201 Protocol Amendment version 01, dated 
15Jun2021). All decisions regarding final analysis, as defined in the SAP document, have been 
made prior to database lock of the study data. 
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in Tables Figures and Listings (TFL) shells and Programming Datasets 
Specifications (PDS) documents, respectively. 
This study terminated early due to very low rate of enrollment, which made it no longer feasible 
to continue with the trial; which meant there was insufficient data to perform the planned 
statistical analyses so study data will be listed only. This SAP amendment was issued after the 
decision to terminate the study; therefore, the changes to planned analyses are reflected in this 
document. 
1.1 
Study design 
This is an open-label, single arm, multi-center, Phase II interventional pilot trial conducted to 
evaluate if a DCT using a telemedicine platform offers a satisfactory, safe and suitable 
management for HR-positive/HER2-negative patients with ABC harboring a PIK3CA mutation 
and treated with alpelisib plus fulvestrant. 
In this pilot trial, approximately 20 participants living in a geographically well-defined region 
in Sweden will be treated with alpelisib plus fulvestrant after progression on an endocrine-based 
therapy. Upon enrollment in the trial (i.e., completion of the informed consent form [ICF]), 
participants will attend on-site visits for screening and on Cycle 1, Day 1. During the Cycle 1, 
Day 1 visit, participants will be trained on using the telemedicine platform and other monitoring 
devices to be used during remote participation: a glucometer and a smartphone with the 
telemedicine application installed. During this visit, participants will initiate treatment with 
alpelisib plus fulvestrant. Pre-menopausal women will be treated with goserelin, a luteinizing 
hormone-releasing hormone (LHRH) agonist, concomitantly with alpelisib plus fulvestrant. 
Participants with risk factors for developing hyperglycemia and participants who had a first 
fasting glucose level above the normal range (onset of hyperglycemia) may be treated, at the 
investigator's discretion, with sodium glucose co-transporter 2 (SGLT2 inhibitors) with or 
without metformin if needed, as prophylactic treatment to prevent hyperglycemia.  
Following this visit, investigators will transition participants to remote participation enabled by 
the telemedicine platform with support of local healthcare providers under the investigator’s 
oversight (Refer Section 8 of clinical study protocol(CSP) “Visit schedule and assessments” for 


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Study No. CBYL719A03201 
 
 
 
additional details on visit schedule during remote participation). Treatment with alpelisib plus 
fulvestrant will continue until end of trial, disease progression, intolerable toxicity or 
participants/investigators’ decision. Participants will be followed remotely up to 12 cycles of 
treatment or until treatment discontinuation, death, withdrawal of consent, or loss to follow-up, 
whichever occurs first. Discontinuation of remote participation is not a reason for trial 
discontinuation. Participants who do not wish to continue with remote participation will have 
the option to attend on-site visits. For each participant, the trial will conclude with an on-site 
end of trial (EOT) visit. 
Throughout the trial, investigators will be asked to provide their inputs on DCT approach on a 
regular basis. 
The study design is summarized in Figure 1-1. 


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Study No. CBYL719A03201 
 
 
 
Figure 1-1 
Study design  
 
Screening 
28 days 
Trial Treatment 
C1, D1 
Visit 
Cycle 1 to Cycle 12 
EOT 
Visit 
On-Site 
Remote Participation 
Through telemedicine platform with support of a local oncologist and a district nurse 
On-Site 
 
 
+ goserelin in pre-menopausal women 
+/- SGLT2 inhibitors with or without metformin in participants at risk of 
hyperglycemia[a] and in participants who had a first fasting glucose level 
above the normal range (onset of hyperglycemia) (at the investigators 
discretion) 
 
[a] baseline BMI ≥30, baseline age ≥75 years, and baseline diabetic and pre-diabetic status have been found to be risk factors 
for hyperglycemia in patients treated with alpelisib. 
BMI= body mass index, C1, D1 = Cycle 1, Day 1; EOT= End of trial; SGLT2= sodium glucose co-transporter 2 
 
1.2 
Study objectives, endpoints and estimands  
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1 
Table 1-1 
Objectives and related endpoints 
 
Objectives 
Endpoints 
Analysis 
Primary Objective 
• 
To assess participant 
satisfaction with the 
DCT experience 
Endpoint for primary objective 
• 
Participant satisfaction, assessed at the 
start of the trial, every 12 weeks, and at 
the end of trial through the Trial Feedback 
Questionnaire (TFQ) 
Refer section 2.4.1 
 
 
Secondary Objectives 
• 
To explore patient 
retention on DCT 
approach 
 
Endpoints for secondary objectives 
• 
Proportion of participants on remote 
monitoring at 3, 6, 12 months for 
participants still on treatment. 
Statistical assumptions (descriptive): targeted 
proportion of patients remaining on remote 
monitoring after 6 months, 75% 
Note: unscheduled in-clinic visit does not exclude 
for DCT monitoring 
• Refer section 
2.5.1 
• 
To explore if the DCT 
approach ensures 
safe and suitable 
remote management 
of patients 
• 
Total number of unscheduled in-clinic 
visits because of safety reasons 
• 
Total number of unscheduled in-clinic 
visits and the reason 
• 
Number of unscheduled in-clinic visits per 
participant in the study 
• 
Refer section 
2.5.1 
alpelisib + fulvestrant 


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1.2.1 
Primary estimand(s) 
Primary estimands have not been described as trial is not planning any hypothesis testing.  
1.2.2 
Secondary estimand(s) 
Secondary estimands have not been described as trial is not planning any hypothesis testing. 
2 
Statistical methods 
2.1 
Data analysis general information 
The data will be analyzed by Novartis according to the data analysis section 12 of the study 
protocol which is available in Appendix 16.1.1 of the CSR.  Important information is given in 
the following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
• 
Discontinuation rate related to adverse 
events 
Note: Visits initially planned to be performed 
remotely but finally performed on site and 
unscheduled visits on site or at the local 
oncologist’s (regional hospital) will be considered 
as unscheduled in-clinic visits. Visits that require 
treating oncologists or district nurses assessments 
are considered unscheduled visits. 
• 
Patient compliance to 
treatment  
• 
Overall compliance 
• 
Refer section 
2.3.2.5 
• 
To assess AEs 
(Adverse Event) of 
special interest 
(AESIs) and AEs 
leading to in-clinic 
visits 
 
• 
Type, frequency and severity of AESIs 
(hyperglycemia, rash, and diarrhea) per 
Common Terminology Criteria for Adverse 
events (CTCAE) v4.03 (incidence 
proportion) 
• 
Number and proportion of AEs leading to 
in-clinic visits 
 
• 
Refer section 
2.6.1 
• 
To evaluate 
participant-reported 
global health status, 
quality of life (QOL) 
and pain 
 
• 
Change in scores of participant reported 
outcome (PRO) questionnaire (within 
same participant) from baseline to each 
time point of questionnaire administration 
(every 12 weeks) 
 
• 
Refer section 
2.9 
• 
To assess the 
effectiveness of 
alpelisib plus 
fulvestrant 
• 
PFS according to RECIST 1.1 
• 
Refer section 
2.5.1 


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Statistical analysis will be performed using Statistical Analysis System (SAS)® (SAS Institute, 
North Carolina), Version 9.4 or higher. 
Summary statistics for continuous variables will generally include the number of patients (n), 
mean, standard deviation, minimum, lower quartile, median, upper quartile, and maximum. 
Summary statistics will also be presented graphically wherever applicable. For discrete 
(categorical or binary) variables, the number and percentage of patients in each category will 
be presented. 95% CIs presented will be 2-sided unless otherwise specified. No formal 
statistical testing of hypothesis are planned to be performed. 
All statistical analyses will be performed under the direction of Novartis personnel. It is planned 
that the data from all centers that participate in this study will be used. Trial duration is planned 
to be 12 cycles of 28 days of treatment each. Cut-off date will be Last Patient Last Visit (LPLV) 
is scheduled as per trial. 
The statistical results will be displayed using tables, figures and listings (TFLs). Listings will 
include all data collected in the eCRF. When dates are imputed, a flag should be provided to 
show that this is imputed rather than an actual date. In listings, the imputed dates are reported 
in their original format before imputation. In general, patient listings will be sorted by patient 
number and assessment date (and time), if applicable. 
2.1.1 
General definitions  
2.1.1.1 
Study drug and study treatment:  
Study drug is defined as alpelisib. 
Study treatment is defined as alpelisib plus fulvestrant. 
2.1.1.2 
Date of first administration of study drug/treatment  
The date of first administration of study drug is defined as the first date when a nonzero dose 
of study drug is administered and recorded on the Dose Administration Record (DAR) 
eCRF/eDiary. The date of first administration of study drug will also be referred to as start of 
study drug. Similar definitions apply for the other components of study treatment. 
The date of first administration of study treatment is defined as the first date when a nonzero 
dose of any component of study treatment is administered and recorded on the DAR 
eCRF/eDiary. The date of first administration of study treatment will also be referred to as the 
start of study treatment. 
2.1.1.3 
Date of last administration of study drug/treatment 
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on the DAR eCRF. Similar definitions apply for the 
other components of study treatment. 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR eCRF. 


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2.1.1.4 
Study day 
Study day on first study drug intake date is 1. 
The study day will be calculated as: 
The date of the event (visit date, onset date of an event, assessment date etc.) – reference start 
date + 1 if event is on or after the reference start date; 
The date of the event (visit date, onset date of an event, assessment date etc.) – reference start 
date if event precedes the reference start date. 
The reference start date for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) is the start of study treatment. (Note: 
if an adverse event starts before the start of study treatment the study day displayed on the listing 
will be negative). 
The reference start date for all other, non-safety assessments (e.g., tumor assessment, death, 
disease progression, tumor response, and patient reported outcomes (PRO)) is the start of study 
treatment. In other words, all efficacy time -to-event variables (e.g., progression-free survival) 
will be calculated from start of study treatment. 
2.1.1.5 
Baseline 
For efficacy evaluations, the last available assessment on or before start date of study treatment 
will be used as the “baseline” value or “baseline” assessment. In the context of baseline 
definition, the efficacy evaluations also include ECOG performance status and patient-reported 
outcomes. For RECIST based endpoint PFS, within 28 days prior to start of trial treatment (Day 
−28 to Day −1 prior to Cycle 1, Day 1). A window of 28 days from the start of study treatment 
will be allowed, i.e., the investigators will be maintained and baseline considered valid if the 
baseline assessment is within 28 days of treatment start date. 
For safety evaluations (e.g., laboratory assessments and ECG), the last available assessment 
before or at date of start of study treatment will be used as the ‘baseline’ assessment. 
Assessments specified to be collected post-dose on the first date of treatment are not considered 
as baseline values. 
If patients have no value as defined above, the baseline results will be considered missing. 
2.1.1.6 
On-treatment assessment/event  
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. An on-treatment assessment/event is defined as any assessment/event in 
the following time interval:  
[date of first administration of study treatment, date of last administration of study treatment + 
30 days], i.e., including the lower and upper limits. (Note: However, the calculation of study 
treatment duration will use different rules as specified in Section 2.3.2.5).  
An AE started in the screening phase and ongoing in the on-treatment phase will not be 
considered as an on-treatment AE unless it has worsened.  


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If the last date of study treatment is missing, any assessment/event occurring after the start of 
study treatment will be considered as on-treatment. 
Data listings will include all assessments/events, flagging those which are not on-treatment. 
Note: The date of first administration of study treatment and the date of last administration of 
study treatment are defined in Sections 2.1.1.2 and 2.1.1.3, respectively. 
2.2 
Analysis sets  
Enrolled Set: The enrolled set consists of all patients who signed the inform consent. 
Full Analysis Set: The Full Analysis Set (FAS) consists of all enrolled set patients who received 
at least one dose of any component of study treatment. 
Safety Set: The Safety Set consists of all enrolled set patients who received at least one dose of 
any component of study treatment and have at least one post-baseline safety assessment.  
2.2.1 
Subgroup of interest 
Not applicable 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Enrollment by study sites and local oncology clinics will be summarized on enrolled set. The 
reasons for screen failure will also be summarized. 
2.3.1 
Patient disposition 
Patient disposition for all patients will be summarized based on enrolled set. 
• Number (%) of patients treated/untreated 
• Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
treatment’ page) 
• Number (%) of patients who discontinued study treatment (based on the ‘End of 
Treatment’ page) 
• Reasons for study treatment discontinuation (based on ‘End of Treatment’ page). 
• Number (%) of patients who enroll into 15 year follow up protocol 
End of Screening Phase Disposition with subject status for all patients will be summarized based 
on enrolled set. 
2.3.2 
Demographics and other baseline characteristics 
The FAS will be used for all baseline disease characteristics and demographic summaries and 
data listings. 


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2.3.2.1 
Demographics 
Demographic data will be listed in detail. Quantitative data (e.g., age) will be summarized by 
appropriate descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum). 
2.3.2.2 
ECOG status 
ECOG performance status will be summarized (n and %, missing if any). 
2.3.2.3 
Diagnosis and extent of cancer 
Diagnosis and extent of cancer for each patient will be listed. This listing will include the 
following: primary site of cancer, histological grade, stage at initial diagnosis, time since initial 
diagnosis, time from initial diagnosis to first recurrence/progression, stage at time of study entry, 
presence/absence of target and non-target lesions, number and type of metastatic sites involved, 
HER-2 / estrogen / progesterone receptor status, number of de novo patients. disease free 
interval (DFI) for non-de novo patients and prior endocrine therapy status (ET).  
Estrogen and progesterone receptor status summary will be combined into 3 categories (ER+ 
PR+, ER+ PR-, ER- PR+). 
 
2.3.2.4 
Medical History 
Medical history and ongoing conditions, including cancer-related conditions, will be listed. 
Medical history/current medical conditions are coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of the 
analyses. The MedDRA version used for reporting will be specified in the CSR and as a footnote 
in the applicable listings. 
2.3.2.5 
Study treatment 
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized. The number of patients with dose reductions/interruptions, 
and the reasons, will be summarized and listed. Details of the derivations and summaries are 
provided in the following sections. 
The safety set will be used for all summaries and listings of study treatment. 
Duration of study treatment exposure 
The duration of exposure to study treatment will be calculated as Duration of exposure to study 
treatment (days) = (last date of exposure to any study treatment component) – (date of first 
administration of study treatment) + 1. 
Duration of exposure to alpelisib (days) = (last date of exposure to alpelisib) – (date of first 
administration to alpelisib) + 1. 
Duration of exposure to fulvestrant (days) = (last date of exposure to fulvestrant) – (date of first 
administration to fulvestrant) + 1. 


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The last date of exposure is defined as follows for the study treatment components:  
For alpelisib: the last date of exposure is defined as the date of last administration of the 
corresponding medication; 
For fulvestrant, the last date of exposure is defined as following: 
If patient discontinues fulvestrant before C2D1 dose, then: 
• Last date of exposure = last date of administration + 13 days. 
If patient died or lost to follow-up within last date of administration + 13 days, 
• then last date of exposure is date of death or last contact date, respectively. 
If patient discontinues fulvestrant after C2D1 dose, then: 
• Last date of exposure = last date of administration + 27 days. 
If patient died or lost to follow-up within last date of administration + 27 days, 
• then last date of exposure is date of death or last contact date, respectively. 
The duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). The duration of study treatment exposure will be 
summarized. In addition, the duration of exposure to study treatment will be 
categorized into time intervals (. < 1 month, 1- 2 months, 2 to 3 months, 3 to 4 months,  4 to 6 
months, 6 to 8 months, 8 to 10 months and >= 10 months); frequency 
counts and percentages will be presented for the number of patients in each interval. 
Cumulative dose and average daily dose 
Cumulative dose for any component of study treatment is defined as the total dose of the 
medication given during the study treatment exposure. 
Average daily dose is defined as [Cumulative dose (mg) / Number of dosing days]; drug free 
day(s) are not counted as dosing days. 
Cumulative dose and average daily dose will be summarized using descriptive statistics for each 
component of study treatment. Patients with no exposure to the study treatment component will 
be excluded from the corresponding summary. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for alpelisib for patients with non-zero duration of exposure to alpelisib is 
defined as follows: 
DI (mg / day) = Cumulative dose (mg) / duration of exposure to alpelisib (day), 
Planned dose intensity (PDI) is defined as the assigned dose by unit of time planned to be given 
to patients as per protocol. The PDI for alpelisib is displayed in Table 2-2. Note that DI for 
alpelisib will also be calculated and will be reported in the units displayed in Table 2-2, whereas 
duration of exposure itself will be summarized in months. 


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Table 2-2 
Planned dose intensity 
 
Medication 
PDI (dose unit/unit of time) 
alpelisib 
300mg/day 
Alpelisib relative dose intensity (RDI) is defined as: RDI = DI (dosing unit / unit of time) / PDI 
(dosing unit / unit of time). 
Fulvestrant RDI is defined as: 
RDI = actual cumulative dose / planned cumulative dose, where planned cumulative dose is 
defined as 500* (# completed D1 in a 28-days cycle) and added by 500 mg if patients completed 
C1D15. 
DI for alpelisib and RDI for alpelisib and fulvestrant will be summarized separately for each of 
the study treatment component. 
Dose reductions, interruptions and delays 
The number and percentage of patients with dose reductions, interruptions or delays, and the 
reasons, will be summarized. 
Interruption: An interruption is defined as a 0 mg dose given on one or more days during the 
period where a patient is not on the “off” part of a treatment cycle, after which > 0mg dose 
resumes. For patients who had dose interruption checked but never resumed non-zero dose, the 
dose interruption will not be counted. For example, in the sequence of 300 mg – 0mg (dose 
break) -0mg (dose interruption) – 0 mg (dose permanently discontinuation) the 0mg (dose 
interruption) will not be counted as dose interruption. Interruptions will be summarized for each 
component of the study treatment. Delay: A special case of alpelisib interruption occurs at the 
start of a new cycle, after a planned rest period. It will be determined based on alpelisib dose 
administration record where a planned dose break is followed by a dose interruption. Such 
instances will be identified as a subset of the interruptions and will be summarized separately 
as dose delays. 
Reduction: A reduction is defined as a decrease from the previous non-zero dose to another 
non-zero dose less than protocol planned dose, even if this decrease has been directly preceded 
by an interruption. For example, in the sequence of alpelisib 300mg – 0mg – 150mg, the 150mg 
dose will be counted as a reduction. 
If due to dosing error, a patient took a dose during the dosing with a dose that is lower than the 
previous dose, this will not be considered as dose reduction. For example, a patient took 300 
mg from day 1-15, and mistakenly took 150 mg per day on day 15-28 which is supposed to be 
300 mg per day. The patient resumed 300 mg dosing on day 29. This will not be considered as 
dosing reduction. 
Dose reductions and interruptions will be tabulated separately. No dose escalations or dose 
modifications are allowed with fulvestrant. No dose escalation will be allowed for alpelisib as 
alpelisib is to be started at the maximum recommended daily dose according to the SmPC. Thus, 
Dose escalations are not allowed according to the protocol and will not be counted in these 
summaries. 


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Missing data: If dose is recorded but frequency is missing or entered as ‘none’, it is assumed 
that the study drug was taken as per-protocol. 
Discontinuation of study treatment components 
The reasons for discontinuation of alpelisib will be summarized, based on the information on 
the alpelisib DAR eCRF/eDiary for patients who have the “dose permanently discontinued” 
box checked. 
Partial discontinuation: A partial discontinuation is defined as the event when the last nonzero 
dose of alpelisib is more than 21 days before the last non-zero dose of fulvestrant when the 
permanent discontinuation checkbox is checked in the alpelisib DAR page. Partial 
discontinuation of alpelisib will be summarized. 
Prohibited Medication 
Refer clinical study protocol Section 16.1.2 for the list of Prohibited Medication. 
Treatment with the prohibited substances mentioned clinical study protocol Section 16.1.2 will 
be identified in the database as protocol deviations. 
Some patients may take Prohibited substances during the treatment period so these concomitant 
medications will be selected via programming and tabulated and listed in the Clinical Study 
Report. 
Number of patients who are receiving prohibited medication with percentage will be 
summarized. Clinical review of individual study data will be performed in order to identify 
those anti-neoplastic medications which are considered disallowed. 
2.3.3 
Prior, concomitant and post therapies 
Prior anti-neoplastic therapy 
Any prior anti-neoplastic medications, radiotherapy or surgery (biopsy and non-biopsy 
separately) will be listed for each patient.  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
Concomitant therapy 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, coinciding with the study 
assessment period (even if started before the study assessment period). 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to 
the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings. 


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Any anti-neoplastic therapy administered concomitantly with study treatment will be listed. . 
2.3.4 
Protocol Deviations 
The number and percentage of patients in the FAS and safety with any protocol deviation will 
be tabulated by deviation category (as specified in Data Management Plan of the study). 
All protocol deviations as well as protocol deviations leading to exclusion from FAS and SAF 
will be listed. 
2.4 
Analysis supporting primary objective(s) 
All efficacy analyses will be performed on the set of Full Analysis Set. Primary efficacy and 
safety analyses will be conducted at the end of study. 
2.4.1 
Primary endpoint(s) 
The primary objective of the trial is the participant satisfaction with the DCT experience. 
The Trial Feedback Questionnaire (TFQ) is a brief, validated patient questionnaire designed to 
capture patient trial experience independent of disease and treatment.  
Participants will be asked to complete the TFQ to provide feedback on their clinical trial 
experience. TFQ is divided in 3 parts: Part A – Participant experience before they started the 
trial; Part B – Participant experience during the trial; and Part C – Participant experienced at 
the end of the trial. 
Participant satisfaction will be assessed at the start of the trial, every 12 weeks or monthly in 
between visits when full questionnaire is not dispensed during conduct, and at the end of the 
trial through the TFQ. All of the questions: 
Question with five point Likert scale responses: Strongly disagree to Strongly agree; 
Question with three point Likert scale responses: Many difficulties to no difficulties; 
Question with three point Likert scale responses: Too little/too much and acceptable; 
And question with two point Likert scale responses: Yes and no range in score from 1 to 5.  
Question with five point Likert scale responses will be scored as 1(worst response), 2, 3, 4 and 
5 (best response). Question with three point Likert scale responses will be scored from as 
1(worst response), 3 and 5 (best response). Question with two point Likert scale responses will 
be scored as 1(worst response) and 5(best response). Question A3a and C4a will not have score 
as question asked in subjective manner. 
2.4.2 
Statistical hypothesis, model, and method of analysis  
No formal statistical tests will be performed. No imputation procedures will be applied for 
missing items or missing assessments.  
TFQ scores for each patient for each timepoint will be listed. 


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2.4.3 
Handling of intercurrent events  
Not applicable.  
 
2.4.4 
Handling of missing values not related to intercurrent event 
Not applicable. 
2.4.5 
Sensitivity analyses  
Not applicable. 
2.4.6 
Supplementary analyses 
Not applicable. 
2.5 
Analysis supporting secondary objectives  
2.5.1 
Secondary endpoint(s) 
The secondary efficacy objectives in this study are to 
- 
To explore patient retention on DCT approach 
- 
To explore if the DCT approach ensures safe and suitable remote management of 
patients 
- 
Patient compliance to treatment 
- 
To assess AEs of special interest (AESIs) and AEs leading to in-clinic visits 
- 
To evaluate participant-reported global health status, quality of life (QOL) and pain 
- 
To assess the effectiveness of alpelisib plus fulvestrant 
Patient retention on DCT approach 
Unscheduled in-clinic visits and the reason will be listed. 
Unscheduled in-clinic visits because of safety reasons will be listed. 
The enrolled set will be used for unscheduled in-clinic visits with safety reasons data listings. 
Discontinuation related to adverse events will be listed. 
All visit data by participant will be listed for enrolled set. 
Patient compliance to treatment 
Refer section 2.3.2.5. 
AEs of special interest (AESIs) and AEs leading to in-clinic visits 
Refer section 2.6.1. 
Participant-reported global health status, quality of life (QOL) and pain 
Refer section 2.9. 


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The effectiveness of alpelisib plus fulvestrant 
Progression free Survival: 
The efficacy endpoints based on the tumor assessments will be derived according to the 
RECIST guideline version 1.1 (see [Novartis guideline version 3.1 (Appendix 3) based on 
RECIST 1.1] for details). The tumor endpoint derivation is based on the sequence of overall 
lesion responses at each assessment/time point. However, the overall lesion response at a given 
assessment/time point may be provided from different sources as illustrated in Table 2-3 . 
Table 2-3  
Sources for overall lesion response 
Sources 
Description 
investigators and site personnel 
Imaging will be performed on-site at screening 
and at EOT. 
investigators and site personnel 
During the remote participation period, imaging 
will be performed at the local oncologist 
facilities. Once available, source imaging data 
will be made accessible to investigators and site 
personnel. 
The investigator reported overall lesion response at each assessment/time point will be used to 
derive the efficacy endpoint, PFS. 
Implementation of RECIST 
Response and progression evaluation will be performed according to the Novartis RECIST 
guideline which is based on the RECIST 1.1 guidelines (Eisenhauer et al 2009). The text below 
gives instructions and rules to provide details needed for programming. 
If CT or MRI scan available before signing of ICF but within 28 days of first dose, no need to 
repeat the procedures for baseline assessment. Any imaging assessments obtained after 
treatment initiation cannot be considered as baseline images. 
Overall lesion responses for patients with only non-measurable lesions at baseline  
Patients with at least one predominantly lytic bone lesion but not having measurable disease per 
RECIST 1.1 are allowed to enter the study. For patients with non-measurable lesions only at 
baseline, the overall lesion response will be based solely on non -target lesion response or an 
occurrence of a new lesion. Non-measurable lesions will be entered as non-target lesions. 
Therefore, the best overall response is determined from non-target lesion response and presence 
of new lesions (refer to RECIST Novartis guidelines). 
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression, unless there is unequivocal progression 
of existing non-target lesions or a new lesion. 
Disease progression 
Progressive disease should only be assigned if it is confirmed by an assessment method as per 
RECIST 1.1 guidelines (e.g., CT scan photos for skin lesions, etc.). If a new lesion is detected 
using an objective assessment method other than radiologic scan then it should also be entered 


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on the ‘New lesion’ RECIST eCRF with appropriate method. Discontinuation due to disease 
progression (Progressive disease) or death due to study indication in death CRF page, without 
corresponding supportive data in the RECIST eCRF (as defined above), will not be considered 
as progressive disease in the analysis of PFS. 
Change in imaging modality 
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use 
(e.g., keeping the same technique, like CT, but switching from with to without contrast use or 
vice versa, regardless of the justification for the change) or a major change in technique (e.g., 
from CT to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for the 
purposes of response assessment. A change in methodology will result by default in an UNK 
(unknown) overall lesion response based on the Novartis calculation as per Novartis calculated 
response. However, a response from the investigator that differs from the Novartis calculated 
UNK is acceptable if a definitive response assessment can be justified based on the available 
information. 
Potential discrepancies between the modality used and overall lesion response (e.g., change in 
modality but response is different from ‘Unknown’) will be queried during the data validation 
process. 
Determination of missing adequate assessments 
The term ‘missing adequate assessment’ is defined as assessments that are not done or 
assessments for which the overall lesion response equals ‘Unknown’. The ‘missing adequate 
assessment’ is also referred to as ‘missing assessment’. 
PFS censoring and event date options depend on the presence and the number of missing tumor 
assessments. An event occurring after two or more missing assessment is censored at the last 
adequate tumor assessment. 
PFS based on site radiology assessment is the efficacy variable in this study. PFS is defined as 
the time from the start date of study treatment to the date of the first documented disease 
progression or death due to any cause. If a patient has not progressed or died at the analysis 
cutoff date, PFS will be censored at the time of the last adequate tumor assessment before the 
cut-off date.  
Discontinuation due to disease progression (collected on the ‘End of treatment’ and ‘End of 
post treatment follow up’ disposition page) without supporting objective evidence (as defined 
in Section 2.5.1) satisfying progression criteria per RECIST will not be considered disease 
progression for PFS derivation. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
No formal statistical tests will be performed. No imputation procedures will be applied for 
missing items or missing assessments.  


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The PFS analysis will be performed on the FAS and will use the default censoring and event 
date. For the analysis, in this study, PFS will not be censored if a new antineoplastic therapy is 
started.  
PFS will be listed for each patient. 
Overall DCT experience 
Summary of qualitative research on the overall DCT experience from the Investigators and 
Clinical Trial Team will be also added in the Clinical Study Report. 
2.5.3 
Handling of intercurrent events  
Not Applicable 
2.5.4 
Handling of missing values not related to intercurrent event 
Not Applicable 
2.5.5 
Sensitivity analyses 
Not Applicable 
2.5.6 
Supplementary analyses 
Not Applicable 
2.6 
Safety analyses 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory/ECG values that fall outside of pre-determined ranges. Other safety data 
(e.g., vital signs and special tests) will be considered as appropriate. 
All safety outputs will use the safety set. The safety summary tables will include ‘on -treatment’ 
events/assessments, i.e., those collected on or after the first date of study treatment and collected 
no later than 30 days after the date of last study treatment administration. The AEs started before 
the first dose but worsening during the treatment period are also considered as ‘on - treatment’ 
events. All safety events/assessments will be listed and those collected outside of the on 
treatment window will be flagged. 
2.6.1 
Adverse events (AEs) 
General rules for AE Reporting: AE summaries will include all AEs starting on or after study 
Day 1 (i.e., on or after the day of the first intake of study treatment) and starting no later than 
30 days after the last administration of study treatment (see section 2.1.1.6). All AEs will be 
listed. AEs starting prior to study Day 1 and AEs starting later than 30 days after the last 
treatment date will be flagged in the listings. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, having at least one AE in each primary system organ class, and for each preferred term 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the AE category. 


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Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum grade. A patient with multiple grades for an AE will be summarized under the 
maximum 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 frequency of 
grade 3 and 4 AEs will be summarized separately. Any information collected (e.g., grades, 
relationship to study treatment, action taken etc.) will be summarized and listed as appropriate. 
AE summaries: 
The following adverse event summaries will be produced: 
• Summary of adverse events 
• Adverse events, irrespective of causality, by primary system organ class, preferred term 
and maximum grade 
• Adverse events with suspected relationship to study treatment by primary system organ 
class, preferred term and maximum grade 
• Grade 3 or 4 adverse events, irrespective of causality, by primary system organ class, 
preferred term and maximum grade 
• Grade 3 or 4 adverse events with suspected relationship to study treatment by primary 
system organ class, preferred term and maximum grade 
• Serious adverse events, irrespective of causality, by primary system organ class and 
preferred term and maximum grade 
• Adverse events leading to study drug discontinuation, irrespective of causality, by 
primary system organ class, preferred term and maximum grade 
• Adverse events leading to study drug reductions, irrespective of causality, by primary 
system organ class, preferred term and maximum grade 
• Adverse events leading to study drug interruptions, irrespective of causality, by primary 
system organ class, preferred term and maximum grade 
• All AEs, and SAEs will be listed. 
AEs of special interest will also be summarized. See Section 2.6.1.1 for the grouping details. 
2.6.1.1 
Adverse events of special interest / grouping of AEs 
AESI are defined as events (serious or non-serious) which are ones of scientific and medical 
concern specific to the alpelisib, 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. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group terms), 
HLTs (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 


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a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. For each specified AESI, the number and percentage of patients with at least 
one event of the AESI occurring during the on-treatment period will be summarized. 
Summaries of these AESIs will be provided, (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, etc.). 
All AESIs will be listed. 
A Case Retrieval Sheet (CRS) with the exact composition of the AE 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, and therefore the groupings are also subject to 
potential change. Table 2-4 provides the latest groupings at the time of the finalization of the 
SAP, from the CRS dated DDMmmYYYY. The most up-to-date version of the CRS will be 
used at the time of the analysis. 
The following AESIs are defined for this on the basis of results from the SOLAR-1: 
hyperglycemia, rash, and diarrhea. For additional detail, refer to Section 4.5.3 of CSP “Risk 
Management Strategies”. 
Table 2-4  
AESI groupings 
 
AESI grouping 
MedDRA category 
Hyperglycemia 
SMQ? SOC? HLT? and PT? 
Rash 
SMQ? SOC? HLT? and PT? 
Diarrhea 
SMQ 
2.6.2 
Deaths 
All deaths will be listed. 
2.6.3 
Laboratory data 
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. All laboratory assessments will be listed and those collected later than 30 days after 
the last treatment date will be flagged in the listings. 
Laboratory data will be classified (by biostatistics/statistical programming) into CTC grades 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0.3. The calculation of laboratory CTC grades will be based on the observed laboratory values 
only; clinical assessments will not be taken into account. CTCAE Grade 0 will be assigned for 
all non-missing values not graded as 1 or higher. Grade 5 will not be used. For laboratory tests- 
where grades are not defined by CTCAE version 4.03, results will be categorized as 
low/normal/high based on laboratory normal ranges. The criteria to assign CTC grades in this 
study are given in Appendix 1. 
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. 


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The following listings will be produced for the laboratory data: 
• Listing of patients with CTC grade 3 or 4 laboratory abnormalities; 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges. 
All lab data will be listed. 
2.6.4 
Other safety data 
2.6.4.1 
ECG and cardiac imaging data 
ECG 
A standard 12-lead ECG will be performed on-site at screening and thereafter only if clinically 
indicated. ECG data will be listed. 
The following parameters will be assessed: QT, QTcF, RR, PR, and QRS intervals in msec, 
heart rate (bpm), and the overall interpretation if clinically significant abnormalities are present. 
A newly occurring ECG abnormality is defined as an abnormal post-baseline ECG finding that 
is not present at Baseline. Baseline is defined as the last ECG measurement (taken on or before 
date of first dose of study treatment).  
Cardiac imaging data 
Cardiac assessments will only be performed if clinically indicated by the investigator or the 
local oncologist. Cardiac imaging (MUGA or ECHO) overall interpretation will be provided. 
Percentages will be based on all patients in the Safety set. 
A listing of patients with newly occurring clinically significant abnormality will be produced. 
2.6.4.2 
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 trial site if the visit is an onsite 
visit or at the practice of the local oncologist. Once available, source documents from the 
practice of the local oncologist will be made accessible to investigators and site personnel per 
current practice as allowed per country regulation. Additional details on transfer of source 
documents will be detailed in a separate operational manual. 
Significant findings that were present prior to the signing of ICF must be included in the 
Medical History page on the patient’s CRF. Significant new findings that begin or worsen after 
signing of ICF must be recorded on the AE page of the participant’s CRF. 
Listing of patients with physical examination data will be produced. 


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2.6.4.3 
Vital signs 
Vital signs assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height, weight, temperature, pulse rate, and 
systolic and diastolic blood pressure. 
The criteria for clinically notable abnormalities are defined as follows:  
Clinically notable elevated values 
• Systolic blood pressure (BP): ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline. 
• Temperature: ≥ 39.1°C 
• Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm 
Clinically notable below normal values 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Temperature: ≤ 35°C 
• Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm 
The following two listings will be produced by participant, and visit/time: 
• Patients with clinically notable vital sign abnormalities. 
• All vital sign assessments will be listed by vital sign parameter and if ranges are 
available. 
 
2.7 
Pharmacokinetic endpoints   
Not applicable.  
2.8 
PD and PK/PD analyses 
Not applicable.  
2.9 
Patient-reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) and the EuroQoL 5-level instrument (EQ-5D- 
5L, Version 4.0) will be used to evaluate patient-reported outcome measures of health-related 
quality-of-life, functioning, disease symptoms and treatment-related side effects. The BPI-SF 
will be used to assess patient’s subjective assessment of pain. 


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The PRO instruments except TFQ are planned to be administered during screening, cycle 4 day 
1, cycle 7 day 1, cycle 10 day 1 and the end of treatment. PRO assessments will continue to be 
collected during the efficacy follow-up after the end of treatment. 
The following electronic participant-reported outcomes (ePROs) EORTC QLQ-C30, EQ-5D- 
5L and BPI-SF will be used to evaluate participant-reported outcome measures of health-related 
quality of life, functioning, disease symptoms, treatment-related side effects, global health 
status, and cancer related pain. 
The following time based intervals will be used to group the PRO data over time. Day is defined 
as date of PRO assessment date – treatment start date + 1. 
Table 2-5  
Time windows for patient reported outcomes 
 
Time interval 
Baseline 
Screening and Cycle 1, Day 1, before trial treatment 
administration 
Cycle 4, 7 until 
cycle 10 Day 1 
During treatment period, questionnaires to be performed in 
the week preceding Day 1 of Cycle 4, Cycle 7, and Cycle 10. 
i.e., days (1, 113] for Day 1 of cycle 4 (2nd assessment) 
i.e., days (114, 197] for Day 1 of cycle 7 (3rd  assessment) 
i.e., days (198, 281] for Day 1 of cycle 10 (4th  assessment) 
End of treatment 
Assessment taken at the end of treatment visit 
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. If 2 assessments within a time window are equidistant 
from the target date, then the assessment obtained prior to target date will be used. If the closest 
assessment to the target date has two questionnaires filled out on the same date, then the worst 
score of these assessments will be used for each subscale score. 
The FAS will be used for all PRO listings. 
2.9.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single 
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson et al 1993). 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a 
high/healthy level of functioning; a high score for the global health status/QoL represents a high 
QoL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers 2001). 


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2.9.2 
EQ-5D-5L 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal. Whatever 
the version of the EQ-5D questionnaire, the EQ-5D essentially consists of 2 pages: the EQ-5D 
descriptive system and the EQ visual analogue scale (EQ VAS). The patient is asked to indicate- 
his/her health state by ticking the box next to the most appropriate statement in each of the five 
dimensions. The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale, where the endpoints are labeled ‘The best health you can imagine’ and ‘The worst health 
you can imagine. 
The EQ-5D descriptive system comprises of the 5 following dimensions: mobility, self- care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems. Scoring 
of raw data and methods for handling missing items or missing assessments will be handled 
according to scoring manuals for each respective patient questionnaire (Oemar and Janssen 
2013; Cleeland 2009). 
2.9.3 
Brief Pain Inventory 
The BPI-SF is a self-administered assessment tool validated to assess pain (Atkinson et al 2011; 
Philip et al 1998). The basic aim of the BPI is to provide the information on the intensity of 
pain, along with the degree to which the pain interferes with the everyday functioning of life. 
The BPI uses simple numeric rating scales from 0 to 10. Since pain can vary to a considerable 
measure over a day, the BPI asks the patients to rate their pain at the time of responding to the 
questionnaire. In addition, the questionnaire also asks the respondent to specify the pain at its 
worst, least and average over the previous week. 
No scoring algorithm have been developed for the BPI, but "worst pain" or the arithmetic mean 
of the four severity items can be used as measures of pain severity; the arithmetic mean of the 
seven interference items can be used as a measure of pain interference. 
Analysis of PRO 
EORTC QLQ-C30, EQ-5D-5L and Brief Pain Inventory data will be listed. 
2.9.4 
TFQ 
For TFQ analysis, please refer Section 2.4.2 
2.10 
Biomarkers 
Not applicable. 
2.11 
Other Exploratory analyses 
Not Applicable.  
2.12 
Interim analysis 
Not Applicable. 


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3 
Sample size calculation 
As this is a pilot trial to evaluate the use of DCT, there is no formal calculation of sample size. 
Approximately 20 participants will be included based on feasibility. 
4 
Change to protocol specified analyses 
Not Applicable. 
5 
Appendix 
5.1 
Imputation rules 
Throughout the study reasonable attempts will be made to limit the amount of missing data. 
However missing data will not be imputed, unless imputation is needed to perform specific 
analyses (e.g., for a dose administration record (DAR) with missing end date or end date after 
the cut-off date, the cut-off last contact date needs to be imputed as an end date to allow for 
calculation of treatment exposure duration and dose intensity). If it is required to impute an end 
date, the imputed date will be displayed and flagged in the appropriate listing, if produced. 
Imputation rules for missing dates (if applied) will be defined in the PDS before the database 
lock. 
5.1.1 
Study drug 
The default rule for missing/partial start date or end date of study drug imputation is the 
following: 
- 
Day missing will be replaced by 15; 
- 
Day & month missing will be replaced by 1 July; 
- 
No imputation if day, month and year are missing. 
Imputed dates will not be displayed in listings except when required. 
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings, and study day, and any corresponding durations will be presented based on the 
imputations specified in the following paragraphs of this section. 
5.1.2 
AE date imputation 
Missing or partial AE dates will not be imputed. 
5.1.3 
Concomitant medication date imputation 
5.1.3.1 
Prior therapies date imputation 
In order to define prior medications/therapies, missing or partial start and stop dates will be 
handled as described in Section 5.1.1. 


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5.1.3.2 
Post therapies date imputation 
In order to define post/concomitant medications/therapies, missing or partial start and stop dates 
will be handled as described in Section 5.1.1. 
5.1.3.3 
Other imputations 
Imputation of missing or partial dates for medical/disease history will be handled as described 
in Section 5.1.1. 
Partial date imputation is allowed for event (death)/censoring coming from ‘Death information’ 
eCRF. 
For rare cases when either day is missing or both month and day are missing for the date of 
death, the following imputation rules will be implemented: 
• If only day is missing, then date of death is imputed as max [(1 mmm-yyyy), min(last 
contact date +1, cutoff date)]. 
• If both day and month are missing, then date of death is imputed as max [(1 Jan-yyyy), 
min (last contact date +1, cutoff date)]. 
5.2 
AEs coding/grading 
Adverse events are coded using the latest version of 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 v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. 
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will not be 
used in this study; if an AE results in death it will be documented in the outcome (“fatal”). 
Information on deaths will also be collected on the ‘Death’ CRF. 
5.3 
Laboratory parameters derivations 
CTC grades for laboratory values in Novartis Oncology (based on CTCAE v4.03 – Month 
YEAR) 
Table for CTCAE v4.03 
5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
Not Applicable. 


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5.4.2 
Analysis supporting secondary objective(s) 
Not Applicable. 
 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of deviation 
Exclusion in analyses 
Severity 
Code 
IC01 
Participant is an adult ≥ 18 years old at the time of 
consent 
Include in all analyses 
49 
IC02 
Participant with ABC (loco-regionally recurrent or 
metastatic) not amenable to curative 
therapy. 
Include in all analyses 
49 
IC03 
Participant with a histologically and/or 
cytologically confirmed diagnosis of ER-positive 
and/or PR-positive breast cancer by local 
laboratory. 
Include in all analyses 
49 
 
IC04 
Participant with a confirmed HER2-negative ABC 
(see Protocol definition) 
Include in all analyses 
49 
IC05 
Participant with a pathology report confirming 
PIK3CA mutant status by a certified 
laboratory using a validated PIK3CA mutation 
assay (from either tissue or blood). 
Include in all analyses 
49 
IC06 
Participant had progression of disease during or 
after endocrine-based therapy 
Include in all analyses 
49 
IC07 
Participant has a Performance Status at screening 
and at Cycle 1, Day 1 visit lower than or 
equal to 1 (ECOG/WHO PS ≤ 1) 
Include in all analyses 
49 
IC08 
Participant has adequate bone marrow and organ 
function as defined in the following 
laboratory valued (as assessed by site laboratory 
for eligibility) - see protocol 
Include in all analyses 
49 
IC09 
Participant is a man or a pre- or post-menopausal 
woman (for Pre and Post-menopausal se Protocol 
definition) 
Include in all analyses 
49 
IC10 
Participant is willing to operate a smartphone 
including the telemedicine application and a 
medical device (glucometer) 
Exclude from all 
analyses 
8 
IC11 
Participant is willing to follow the requirements for 
remote participation 
Exclude from all 
analyses 
8 
IC12 
Participant has signed ICF before any trial related 
activities and according to local 
guidelines. 
Exclude from all 
analyses 
8 
E01 
Participant has received prior treatment with any 
PI3K, mTOR, or AKT inhibitor. 
Include in all analyses 
49 


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E02 
Participant with known hypersensitivity to alpelisib 
or fulvestrant, or to any of the excipients of 
alpelisib or fulvestrant. 
Include in all analyses 
49 
E03 
Participant has had major surgery within 14 days 
prior to trial treatment start and/or has not 
recovered from major side effects. 
Include in all analyses 
49 
E04 
Participant with inflammatory breast cancer at 
screening. 
Include in all analyses 
49 
E05 
Participant with an established diagnosis of 
diabetes mellitus type I or not controlled type II 
(based on fasting glucose [FG] and HbA1c, see 
inclusion criterion 8) 
Include in all analyses 
49 
E06 
Participant with impairment of gastrointestinal 
function or gastrointestinal disease that may 
significantly alter the absorption of the trial 
treatments (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection) based on 
investigator discretion. 
Include in all analyses 
49 
E07 
Participant has currently documented 
pneumonitis/interstitial lung disease (the chest 
Computerized Tomography (CT) scan performed 
at baseline for the purpose of tumor assessment 
should be reviewed to confirm that there are no 
relevant pulmonary complications present). 
Include in all analyses 
49 
E08 
Participant with Child Pugh score B or C. 
Include in all analyses 
49 
E09 
Participant with uncontrolled hypertension defined 
by a Systolic Blood Pressure ≥ 160 mmHg and/or 
Diastolic Blood Pressure ≥ 100 mmHg, with or 
without antihypertensive medication. Initiation or 
adjustment of antihypertensive medication(s) is 
allowed prior to screening. 
Include in all analyses 
49 
E10 
Participant with clinically significant, uncontrolled 
heart disease and/or recent cardiac events (see 
Protocol version 01 for definition) 
Include in all analyses 
49 
E11 
Participant with any other concurrent severe 
and/or uncontrolled medical condition that 
would, in the investigator’s judgment, 
contraindicate participant participation in the 
clinical 
trial (e.g., chronic active hepatitis, [testing not 
mandatory unless required by local 
regulations or requirements] confirmed 
pneumonitis etc.). 
Include in all analyses 
49 
E12 
Participant is currently receiving any of the 
following medications and cannot be 
discontinued 7 days prior to the start of the 
treatment: 
- Strong cytochrome P (CYP)3A4 inducers 
Include in all analyses 
49 


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- Inhibitors of breast cancer resistance protein 
(BCRP) 
E13 
Participant has a history of acute pancreatitis 
within 1 year of screening or past medical 
history of chronic pancreatitis. 
Include in all analyses 
49 
E14 
Participant with unresolved osteonecrosis of the 
jaw. 
Include in all analyses 
49 
E15 
Participant has a history of severe cutaneous 
reactions like Stevens-Johnson-Syndrome, 
Erythema Multiforme, or Toxic Epidermal 
Necrolysis, or Drug Reaction with Eosinophilia 
and Systemic Symptoms. 
Include in all analyses 
49 
E16 
Participant with evidence of disease progression 
during the pre-trial induction therapy and 
prior to first dose of alpelisib 
Include in all analyses 
49 
E17 
Participant has received radiotherapy ≤ 4 weeks 
or limited field radiation for palliation 
≤ 2 weeks prior to trial treatment initiation, and 
who has not recovered to grade 1 or better 
from related side effects of such therapy (with the 
exception of alopecia). 
Include in all analyses 
49 
E18 
Participant is currently receiving or has received 
systemic corticosteroids ≤ 2 weeks prior 
to starting trial treatment, or who have not fully 
recovered from side effects of such 
treatment. (see Protocol for definition) 
Include in all analyses 
49 
E19 
Participant participated in a prior investigational 
study within 30 days prior to the start of 
trial treatment or within 5 half-lives of the trial 
treatment, whichever is longer. 
Include in all analyses 
49 
E20 
Participant has not recovered from all toxicities 
related to prior anticancer therapies to NCI 
CTCAE version 4.03 Grade ≤ 1. Exception to this 
criterion: participants with any grade of 
alopecia are allowed to enter the trial. 
Include in all analyses 
49 
E21 
Participant has a concurrent malignancy or 
malignancy within 3 years of start of trial 
treatment, with the exception of adequately 
treated, basal or squamous cell carcinoma, 
nonmelanomatous 
skin cancer, or curatively resected cervical cancer 
Include in all analyses 
49 
E22 
Participant has central nervous system (CNS) 
involvement which was not previously treated 
and not fulfilling the following 3 criteria to be 
eligible for the trial: 
- Completed prior therapy (including radiation 
and/or surgery) for CNS metastases 
≥ 28 days prior to the start of trial entry and 
- CNS tumor is clinically stable at the time of 
screening and 
Include in all analyses 
49 


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- Participant is not receiving steroids and/or 
enzyme inducing anti-epileptic medications 
for brain metastases. 
E23 
Participant has a known history of Human 
Immunodeficiency Virus infection (testing not 
mandatory unless required by local regulations or 
requirements). 
Include in all analyses 
49 
E24 
Participant is not able to understand and to 
comply with trial instructions and requirements, 
including oral administration of trial treatment 
Exclude from all 
analyses 
8 
E25 
Participant is a nursing (lactating) or pregnant 
woman as confirmed by a positive serum 
(hCG) test prior to initiating trial treatment 
Include in all analyses 
49 
E26 
Participant is a woman of child-bearing potential 
defined as all women physiologically 
capable of becoming pregnant, unless they are 
using highly effective methods of contraception 
during trial treatment and at least for 2 years after 
the last dose of any trial treatment. Highly 
effective contraception methods include: see 
Protocol definition 
Include in all analyses 
49 
E27 
Participant is a sexually active male unwilling to 
use a condom during intercourse while 
taking trial treatment, and for 2 years after the last 
dose of trial treatment. A condom is 
required for all sexually active male participants to 
prevent them from fathering a child 
AND to prevent delivery of trial treatment via 
seminal fluid to their partner. In addition, 
male participants must not donate sperm during 
the trial and up to the time period specified 
above 
Include in all analyses 
49 
E28 
Participants with active infections, including a 
COVID-19-related diagnosis 
Include in all analyses 
49 
S1 
Study medication not administered 
Exclude from safety 
analyses 
5 
O1 
Study drug related toxicity triggering a dose 
modification, as per protocol, and participant 
receives the incorrect dose 
Include in all analyses 
49 
O2 
Study drug related toxicity triggering a dose 
interruption, as per protocol and participant not 
discontinued from treatment 
Include in all analyses 
49 
O3 
Participant concomitantly administered with a 
strong inducer of CYP3A or inhibitors of BCRP, as 
per protocol 
Include in all analyses 
49 
O4 
Missed questionnaires or e-diary, as per protocol  
Include in all analyses 
49 
Table 5-2 
Code Text 
Code 
Code text 
5 
Exclude from safety analyses 


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8 
Exclude from all analyses 
49 
Include in all analyses 
 
6 
Reference 
Aaronson NK, Ahmedzai S, Bergman B, et al (1993) The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst; 85(5):365-76. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in 
solidtumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47. 
Fayers PM (2001). Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur J Cancer; 37(11):1331-4. 
ICH E9(R1) Harmonized Guideline: addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials. Final version on 20 November 
2019.