Clinical trial NCT02278120
Conditions: Advanced Metastatic Breast Cancer
Keywords: LEE011 ribociclib HR-positive HER2-negative Advanced breast cancer Letrozole Anastrozole Tamoxifen Goserelin CDK CDK4 CDK6 CDK4/6 Phase III ER-positive PR-positive Premenopausal
Sponsor: Novartis Pharmaceuticals
Start date: 2014-11-20; Completion date: 2023-04-20
Enrollment: 672 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine whether treatment with tamoxifen or a non-steroidal aromatase inhibitors (NSAI) + goserelin + LEE011 prolonged progression-free survival (PFS) compared to treatment with tamoxifen or a NSAI + goserelin + placebo in premenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.

Detailed description:
This was a randomized, Phase III, double-blind, global study comparing the treatment efficacy and safety of ribociclib + goserelin + tamoxifen or a NSAI (letrozole or anastrozole) versus placebo + goserelin + tamoxifen or a NSAI in premenopausal women with HR+, HER2- advanced breast cancer.

Eligible participants were randomized in a 1:1 ratio to either the ribociclib arm or the placebo arm. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation for any other reason.

Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up).

All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.

Following the final OS analysis (performed when approximately 189 deaths were recorded) and with protocol amendment 6 (dated 18-Jul-2019), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib + goserelin + NSAI. Cross-over was optional and was conducted at the investigator's discretion and upon participant consent.

Arms: arm 1: Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days) arm 2: Placebo daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days).

Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin.
Interventions: intervention 1: Ribociclib intervention 2: Tamoxifen intervention 3: Letrozole intervention 4: Anastrozole intervention 5: Goserelin intervention 6: Placebo
Intervention descriptions: intervention 1: Ribociclib (600 mg, in three 200 mg hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle. intervention 2: Tamoxifen (20 mg, tablets) was administered orally on a continuous daily schedule (days 1-28 of each 28-day cycle) intervention 3: Letrozole (2.5 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle) intervention 4: Anastrozole (1 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle) intervention 5: Goserelin (3.6 mg, subcutaneous implant) was administered on day 1 of every 28-day cycle intervention 6: Placebo (hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle.

Protocol documents:
Prot_002.pdf: 
Clinical Development
LEE011 (ribociclib)
Protocol CLEE011E2301 (MONALEESA-7) / NCT02278120
A Phase III randomized, double-blind, placebo-controlled 
study of LEE011 or placebo in combination with tamoxifen 
and goserelin or a non-steroidal aromatase inhibitor (NSAI) 
and goserelin for the treatment of premenopausal women 
with hormone receptor positive, HER2-negative, advanced 
breast cancer
Author(s):
 
Document type:
Amended Protocol Version
EUDRACT number
2014-001931-36
Version number
07 (clean)
Development phase
III
Document status:
Final
Release date:
24-Jan-2020
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 02-Dec-2013


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol summary:.............................................................................................................13
Amendment 7 (08-Jan-2020).............................................................................................21
Amendment 6 (18-Jul-2019) .............................................................................................23
Amendment 5 (06-Aug-2018)...........................................................................................26
Amendment 4 (24-Feb-2017)............................................................................................29
Summary of previous amendment(s).................................................................................31
1
Background........................................................................................................................42
1.1
Overview of epidemiology, disease pathogenesis and current treatment..............42
1.1.1
Epidemiology........................................................................................42
1.1.2
Treatment options for hormone receptor positive (HR+), HER2-
negative premenopausal advanced breast cancer..................................42
1.1.3
Role of the CDK4/6 pathway in breast cancer......................................45
1.2
Introduction to investigational treatment(s) and other study treatment(s).............46
1.2.1
Overview of LEE011 ............................................................................46
1.3
Overview of tamoxifen..........................................................................................53
1.4
Overview of non-steroidal aromatase inhibitors (NSAIs): letrozole and 
anastrozole.............................................................................................................54
1.4.1
Overview of letrozole............................................................................54
1.4.2
Overview of anastrozole .......................................................................57
1.5
Overview of goserelin............................................................................................58
1.6
Potential for drug-drug interactions.......................................................................58
1.6.1
Potential for a drug-drug interaction between LEE011 and 
tamoxifen...............................................................................................58
1.6.2
Potential for drug-drug interaction between LEE011 and NSAIs 
(letrozole, anastrozole)..........................................................................59
1.6.3
Low potential for drug-drug interactions with goserelin ......................60
2
Rationale............................................................................................................................60
2.1
Study rationale and purpose...................................................................................60
2.2
Rationale for the study design ...............................................................................61
2.3
Rationale for dose and regimen selection..............................................................61
2.4
Rationale for choice of combination drugs............................................................62


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Objectives and endpoints...................................................................................................63
4
Study design ......................................................................................................................67
4.1
Description of study design ...................................................................................67
4.1.1
Screening phase.....................................................................................69
4.1.2
Treatment phase ....................................................................................69
4.1.3
Safety follow-up....................................................................................69
4.1.4
Efficacy follow-up ................................................................................69
4.1.5
Survival follow-up ................................................................................70
4.2
Timing of interim analyses and design adaptations...............................................70
4.3
Definition of end of the study................................................................................70
4.4
Early study termination..........................................................................................71
5
Population..........................................................................................................................71
5.1
Patient population..................................................................................................71
5.2
Inclusion criteria ....................................................................................................71
5.3
Exclusion criteria...................................................................................................73
6
Treatment...........................................................................................................................76
6.1
Study treatment......................................................................................................76
6.1.1
Dosing regimen.....................................................................................77
6.1.2
Ancillary treatments..............................................................................79
6.1.3
Rescue medication ................................................................................79
6.1.4
Guidelines for continuation of treatment ..............................................79
6.1.5
Treatment duration................................................................................80
6.2
Dose escalation guidelines.....................................................................................80
6.3
Dose modifications................................................................................................80
6.3.1
Dose modification and dose delay ........................................................80
6.3.2
Follow-up for toxicities.........................................................................88
6.3.3
Anticipated risks and safety concerns of the study drug.......................89
6.4
Concomitant medications ......................................................................................89
6.4.1
Permitted concomitant therapy .............................................................89
6.4.2
Concomitant therapy requiring caution.................................................90
6.4.3
Prohibited concomitant therapy ............................................................91
6.4.4
Drugs with QT prolongation.................................................................91
6.4.5
Concomitant medications associated with menopausal status..............92
6.5
Patient numbering, treatment assignment or randomization .................................92
6.5.1
Patient numbering .................................................................................92
6.5.2
Treatment assignment or randomization...............................................92


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6.5.3
Treatment blinding................................................................................93
6.6
Study drug preparation and dispensation...............................................................94
6.6.1
Study drug packaging and labeling.......................................................94
6.6.2
Drug supply and storage........................................................................95
6.6.3
Study drug compliance and accountability ...........................................95
6.6.4
Disposal and destruction .......................................................................95
7
Visit schedule and assessments .........................................................................................96
7.1
Study flow and visit schedule................................................................................96
7.1.1
Molecular pre-screening......................................................................108
7.1.2
Screening.............................................................................................108
7.1.3
Run-in period ......................................................................................109
7.1.4
Treatment period.................................................................................109
7.1.5
End of treatment visit including study completion and study 
treatment discontinuation....................................................................110
7.1.6
Follow-up period.................................................................................111
7.1.7
End of post-treatment follow-up visit .................................................112
7.1.8
Withdrawal of consent ........................................................................113
7.2
Assessment types.................................................................................................113
7.2.1
Efficacy assessments...........................................................................113
7.2.2
Safety and tolerability assessments.....................................................116
123
129
133
7.2.6
Patient reported outcomes...................................................................134
8
Safety monitoring and reporting......................................................................................137
8.1
Adverse events.....................................................................................................137
8.1.1
Definitions and reporting ....................................................................137
8.1.2
Laboratory test abnormalities..............................................................138
8.2
Serious adverse events.........................................................................................139
8.2.1
Definitions...........................................................................................139
8.2.2
Reporting.............................................................................................139
8.3
Emergency unblinding of treatment assignment .................................................140
8.4
Pregnancies..........................................................................................................140
8.5
Warnings and precautions....................................................................................141
8.6
Data monitoring committee.................................................................................141
8.7
Steering committee..............................................................................................141


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Data collection and management.....................................................................................141
9.1
Data confidentiality .............................................................................................141
9.2
Site monitoring ....................................................................................................142
9.3
Data collection.....................................................................................................142
9.3.1
ECG data collection ............................................................................143
143
144
9.3.4
IRT data collection..............................................................................144
9.3.5
Central laboratory................................................................................144
9.3.6
Central radiology.................................................................................144
9.4
Database management and quality control..........................................................145
10 Statistical methods and data analysis ..............................................................................145
10.1
Analysis sets ........................................................................................................146
10.1.1
Full analysis set...................................................................................146
10.1.2
Safety set .............................................................................................146
10.1.3
Per-protocol set ...................................................................................146
146
10.1.5
Crossover analysis set .........................................................................146
10.2
Patient demographics/other baseline characteristics ...........................................146
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................146
10.4
Primary objective.................................................................................................147
10.4.1
Variable...............................................................................................147
10.4.2
Statistical hypothesis, model, and method of analysis........................147
10.4.3
Handling of missing values/censoring/discontinuations.....................149
10.4.4
Supportive analyses.............................................................................149
10.5
Secondary objectives ...........................................................................................150
10.5.1
Key secondary objective(s).................................................................150
10.5.2
Other secondary efficacy objectives ...................................................151
10.5.3
Safety objectives .................................................................................152
10.5.4
Patient-reported outcomes...................................................................155
156
156
158
160
160
10.7
Interim analysis....................................................................................................161


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10.7.1
Progression free survival.....................................................................161
10.7.2
Key secondary endpoint: overall survival...........................................161
10.8
Sample size calculation........................................................................................162
10.9
Power for analysis of key secondary variables....................................................163
10.9.1
Power for analysis of overall survival.................................................163
163
11 Ethical considerations and administrative procedures ....................................................165
11.1
Regulatory and ethical compliance......................................................................165
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................165
11.3
Informed consent procedures...............................................................................166
11.4
Discontinuation of the study................................................................................166
11.5
Publication of study protocol and results.............................................................166
11.6
Study documentation, record keeping and retention of documents.....................167
11.7
Confidentiality of study documents and patient records .....................................167
11.8
Audits and inspections.........................................................................................168
11.9
Financial disclosures............................................................................................168
12 Protocol adherence ..........................................................................................................168
12.1
Amendments to the protocol................................................................................168
13 References (available upon request)................................................................................169
14 Appendices ......................................................................................................................176
14.1
Appendix 1 - Concomitant medications ..............................................................176
14.2
Appendix 2 - Patient reported outcomes .............................................................181
14.3
Appendix 3 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....189
14.4
Appendix 4 - Bone Marrow Reserve in Adults ...................................................218


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List of figures
Figure 1-1
LEE011 in combination with letrozole in an ER+ primary breast 
cancer model .........................................................................................48
Figure 4-1
Study design..........................................................................................68
Figure 6-1
Suggested study drug administration for scheduled visit days .............79
Figure 14-1
EORTC QLQ - C30 ............................................................................181
Figure 14-2
EORTC QLQ-BR23............................................................................183
Figure 14-3
EQ-5D-5L ...........................................................................................185
187
List of tables
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal 
BC patients............................................................................................44
Table 1-2
Serious adverse events with a suspected causal relationship with 
LEE011 single agent .............................................................................51
Table 1-3
Preliminary pharmacokinetic data for LEE011 with and without 
letrozole.................................................................................................55
Table 1-4
Preliminary pharmacokinetic data for letrozole with and without 
LEE011 .................................................................................................56
Table 3-1
Objectives and related endpoints ..........................................................64
Table 6-1
Dose and treatment schedule.................................................................77
Table 6-2
Dose modification guideline .................................................................81
Table 6-3
LEE011/placebo dose adjustment and management 
recommendations for hematological adverse reactions (CTC AE 
v4.03) ....................................................................................................82
Table 6-4
LEE011/placebo dose adjustment and management 
recommendations for hepatic toxicities (CTC AE v4.03).....................83
Table 6-5
LEE011/placebo dose adjustment and management 
recommendations for QTcF prolongation (CTC AE v4.03).................86
Table 6-6
LEE011 dose adjustment and management recommendation for 
ILD/pneumonitis (CTCAE v 4.03) .......................................................87
Table 6-7
LEE011/placebo dose adjustment and management 
recommendation for all other adverse reactions (CTC AE v4.03)........88
Table 6-8
Packaging and labeling .........................................................................94
Table 6-9
Supply and storage of study treatments ................................................95
Table 7-1a
Visit evaluation schedule – Patients that, after protocol amendment 
6, continue with their originally randomized study treatment ..............98


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Table 7-1b
Visit evaluation schedule – Cross over treatment cycles for patients 
who cross over from placebo to LEE011 after protocol amendment 
6...........................................................................................................105
Table 7-2
Imaging collection plan.......................................................................115
Table 7-3
ECOG performance status...................................................................117
Table 7-4
Local clinical laboratory parameters collection plan ..........................118
Table 7-5
Central ECG collection plan ...............................................................121
125
125
127
128
128
129
130
130
Table 7-14
Patient reported outcomes collection plan ..........................................136
137
Table 10-1
Estimated timelines for interim and final analyses .............................162
164
164
165
Table 14-1
List of prohibited medications during study drug treatment...............177
Table 14-2
List of medications to be used with caution during study drug 
treatment..............................................................................................179


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List of abbreviations
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse Event
AI
Aromatase Inhibitor
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT
ATC
Anatomical therapeutic chemical classification system
AUC
Area under the curve
b.i.d.
bis in diem/twice a day
BC
Breast cancer
BCRP
Breast cancer resistance protein
BIRC
Blinded independent review committee
BOR
Best overall response
BSEP
Bile export salt pump
CBC
Complete blood count
CBR
Clinical Benefit Rate
CCND1
Cyclin D1
CDK
Cyclin Dependent Kinase
CI
Confidence interval
CISH
Cytokine-inducible SH2-containing protein
Cmax
Peak concentration
Cmin
Minimum concentration
CNS
Central nervous system 
CR
Complete response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DC
Discontinued
DDI
Drug drug interaction
DILI
Drug-induced liver injury
DLT
Dose Limiting Toxicity
DMC
Data monitoring committee 
DOR
Duration of Response
E2F
E2F transcription factor
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EORTC
European Organization for Research and Treatment of Cancer
EOS
EOT
End of Study
End of Treatment
ER
Estrogen Receptor


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FAS
FDG
Full Analysis Set
Fluorodeoxyglucose
FFPE
Formalin-Fixed, Paraffin-Embedded
FISH
Flouorescence in situ hybridization
FMO3
Flavin containing monooxygenase 3
FSH
Follicle stimulating hormone
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal 
GnRH
Gonadotropin-releasing hormone
hCG
Human chorionic gonadotropin
Hct
Hematocrit
HER2
Human Epidermal Growth Factor Receptor 2
HR
Hormone Receptor
i.v.
intravenous(ly)
IB
ICH
Investigator Brochure
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
ILD
Interstitial lung disease
INR
International normalization ratio
IRB
Institutional Review Board
IRT
ITT
Interactive Response Technology
Intent to Treat
IU
International Unit
IUD
Intra uterine device
LFT
Liver function test
LHRH
Luteinizing-hormone-releasing hormone
LKM
Liver-kidney microsome antibodies
LLOQ
Lower Limit of Quantification
LVEF
Left ventricular ejection fraction
MATE1
Multidrug and toxin exclusion protein -1
MDR1
Multidrug resistance 1
MRI
Magnetic resonance imaging 
MTD
Maximum tolerated dose
MUGA
Multi gated acquisition scan
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
Next generation sequencing 
NSAI
Non-steroidal aromatase inhibitor
NTI
OCT2
Narrow therapeutic window
Organic cation transporter 2
o.d.
omnia die/once a day
OFS
Ovarian follicular suppression
ORR
Overall Response Rate


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OS
Overall survival
p16
Product of the CDKN2A gene; a cyclin-dependent kinase inhibitor
p.o.
per os/by mouth/orally
PD
Progressive disease
PFS
Progression free survival
P-gp
P-glycoprotein
PgR
Progesterone receptor
PhRMA
Pharmaceutical Research and Manufacturers of America
PI3K
Phosphatidylinositol 3-kinase
PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
PK
Pharmacokinetics
PPS
Per protocol set
PR
Partial response
pRb
Retinoblastoma protein
PRO
Patient reported outcomes
PS
Performance status
PSL
Program standard language
PT
Prothrombin
PTEN
Phosphatase and tensin homolog
q.d.
Quaque die/everyday 
QLQ
Quality of Life Questionnaire
QoL
Quality of Life
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia)
Rb
Retinoblastoma
RBC
Red blood cells
REB
Research Ethics Board
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SAP
SC
Statistical Analysis Plan
Steering committee 
SD
Stable disease
SERM
Selective ER Modulators
SISH
In situ hybridization test
SLA
Soluble liver antigen antibodies
SMA
Smooth muscle antibodies soluble 
SOP
Standard Operating Procedure
TBIL
Total bilirubin
TEN
Toxic epidermal necrolysis
Tmax
The time at which the maximum observed concentration (Cmax) occurs
TdP
Torsades de Pointe
TTR
Time to response
ULN
Upper limit of normal 
WBC
White blood cell count


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological Sample
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Personal Data
Patient information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes patient 
identifier information, study information and biological samples.
Subject Number (Subject No.)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of Consent
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


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Protocol summary:
Study code
CLEE011E2301
Title
A Phase III randomized, double-blind, placebo-controlled study of LEE011or 
placebo in combination with tamoxifen and goserelin or a non-steroidal 
aromatase inhibitor (NSAI) and goserelin for the treatment of premenopausal 
women with hormone receptor positive, HER2-negative, advanced breast cancer.
Brief title
Study assessing the efficacy and safety of LEE011+ tamoxifen + goserelin or 
LEE011 + a NSAI + goserelin in premenopausal women with HR+, HER2-
negative advanced breast cancer.
Sponsor and
Clinical Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Treatment of hormone receptor (HR) positive, HER2-negative breast cancer still 
represents an unmet medical need as it typically affects younger women who 
become resistant to standard hormonal treatment. The rationale for assessing 
the efficacy of LEE011in combination with hormonal agents in a randomized 
Phase III study is based upon the role of the CDK4/6 pathway in HR+ breast 
cancer and the potential synergy when combined with hormonal agents such as 
tamoxifen or NSAIs.
The purpose of this study is to compare the progression-free survival (PFS) 
between tamoxifen or a NSAI + goserelin + LEE011and tamoxifen or a NSAI + 
goserelin + placebo in premenopausal women with HR+, HER2-negative 
advanced breast cancer.
Primary Objective
To determine whether treatment with tamoxifen or a NSAI + goserelin + LEE011 
prolongs PFS compared to treatment with tamoxifen or a NSAI + goserelin + 
placebo in premenopausal women with HR+, HER2-negative advanced breast 
cancer.
Secondary Objectives
Key Secondary:
To determine whether treatment with tamoxifen or a NSAI + goserelin + 
LEE011prolongs overall survival (OS) compared to treatment with tamoxifen or a 
NSAI + goserelin + placebo in premenopausal women with HR+, HER2-negative 
advanced breast cancer.
Other Secondary:
●
To evaluate the safety and tolerability of LEE011 in combination with either 
tamoxifen + goserelin or a NSAI + goserelin
●
To evaluate the two treatment arms with respect to response rate (RR) and 
clinical benefit rate (CBR)
●
To describe time to response (TTR) and duration of response (DOR) in each 
treatment arm
●
To evaluate the two treatment arms with respect to time to deterioration of 
Eastern Cooperative Group (ECOG) performance status (PS)
●
To evaluate patient reported outcomes for health-related quality of life in the 
two treatment arms
Study design
This is a randomized, phase III, double-blind, global trial comparing the 
combination of tamoxifen or a NSAI + goserelin + LEE011 to tamoxifen or a NSAI 
+ goserelin + placebo in premenopausal women with HR+, HER2-negative 
advanced breast cancer. The study will consist of a 28 day screening phase, 
treatment phase and post-treatment phase which includes safety, efficacy, and 
survival follow up.


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Population
The study will include premenopausal women with HR+ advanced breast cancer. 
The investigator or designee must ensure that only patients who meet all of the 
following inclusion and none of the exclusion criteria are offered treatment in the 
study.
Inclusion criteria
Refer to Section 5.2 for details on inclusion criteria.
●
Patient is an adult, female ≥ 18 years old and < 60 years old at the time of 
informed consent and has signed informed consent before any trial related 
activities are conducted according to local guidelines.
●
Confirmed negative serum pregnancy test (β-hCG) before starting study 
treatment or patient has had a hysterectomy
●
Patient is pre-menopausal or peri-menopausal at the time of study entry.
Premenopausal status is defined as either:
●
Patient had last menstrual period within the last 12 months,
OR
●
If on tamoxifen or toremifene within 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.
●
Patients who have undergone bilateral oophorectomy are not eligible.
Perimenopausal status is defined as neither premenopausal nor postmenopausal 
(see exclusion criteria).
●
Patient has advanced (locoregionally recurrent or metastatic) breast cancer 
not amenable to curative therapy (e.g. surgery and/or radiotherapy).
●
Patients who received (neo) adjuvant therapy for breast cancer are eligible.
●
If the patient has never received any prior endocrine therapy OR if ≥ 12 
months have elapsed since the patient’s last dose of adjuvant therapy, then 
the patient is eligible to receive tamoxifen + goserelin OR a NSAI + goserelin 
for advanced breast cancer based on the investigators choice.
●
If tamoxifen or fulvestrant was the last prior (neo) adjuvant therapy and 
the last dose was given < 12 months prior to randomization, then the patient 
is eligible to receive a NSAI (letrozole or anastrozole) + goserelin for 
advanced breast cancer.
●
If letrozole, anastrozole, or exemestane was the last prior (neo) adjuvant 
therapy and the last dose was given < 12 months prior to randomization, then 
the patient is eligible to receive tamoxifen + goserelin for advanced breast 
cancer.
●
Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or 
anastrozole) with or without goserelin or goserelin ≤ 28 days for advanced breast 
cancer prior to randomization are eligible. Patients must continue treatment with 
the same hormonal agent + goserelin during the study. No treatment interruption 
is required for these patients prior to randomization.
Note: Patients who are receiving goserelin for reasons other than advanced 
breast cancer treatment are eligible (e.g endometriosis). Patients who received ≤ 
28 days goserelin for advanced breast cancer are eligible.
●
Patients who have received up to 1 line of chemotherapy for advanced breast 
cancer and have been discontinued at least 28 days before randomization are 
eligible.
Note: If a cytotoxic chemotherapy regimen was discontinued for reasons other 
than disease progression and lasted less than 21 days, this regimen does not 
count as a prior line of chemotherapy.
●
Patient has a histologically and/or cytologically confirmed diagnosis of 
estrogen-receptor positive and/or progesterone receptor positive breast cancer 
by local laboratory (based on most recently analyzed biopsy).


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●
Patient has HER2-negative breast cancer (based on most recently analyzed 
biopsy) defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 
2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is
required by local laboratory testing.
●
Patient must have either:
●
Measurable disease, i.e., at least one measurable lesion as per RECIST 
1.1 criteria.
OR
●
If no measurable disease is present, then at least one predominantly 
lytic bone lesion must be present (patients with no measurable disease and 
only one predominantly lytic bone lesion that has been previously irradiated 
are eligible if there is documented evidence of disease progression of the 
bone lesion after irradiation).
●
Patient has an ECOG PS 0 or 1.
●
Patient has adequate bone marrow and organ function as defined by the 
following laboratory values (as assessed by central laboratory):
●
Absolute neutrophil count ≥ 1.5 × 109/L
●
Platelets ≥ 100 × 109/L
●
Hemoglobin ≥ 9.0 g/dL
●
Potassium, sodium, calcium (corrected for serum albumin), and 
magnesium within normal limits of the central laboratory
●
INR ≤1.5
●
Serum creatinine < 1.5 mg/dL
●
In absence of liver metastases, alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient 
has liver metastases, ALT and AST should be < 5 × ULN
●
Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct 
bilirubin <1.5 x ULN of the central laboratory in patients with well documented 
Gilbert’s Syndrome
●
Patient must be able to swallow study therapy
●
Patient must be able to communicate with the investigator and comply with 
the requirements of the study procedures
●
Patient must be willing to remain at the clinical site as required by the protocol
Exclusion criteria
Refer to Section 5.3 for details on exclusion criteria
●
Patient who has received a prior CDK4/6 inhibitor.
●
Patient has a known hypersensitivity to any of the excipients of LEE011, 
tamoxifen, NSAI (letrozole or anastrozole), or goserelin.
●
Patient is post-menopausal. 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 FSH and 
estradiol in the postmenopausal range per local normal range.
Note: For women with therapy-induced amenorrhea, serial measurements of 
FSH and/or estradiol are needed to ensure menopausal status (NCCN 
Guidelines Version 3.2014)
●
Patients who currently have inflammatory breast cancer at screening.


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●
Patients who received any prior hormonal anti-cancer therapy for advanced 
breast cancer except for ≤ 14 days of tamoxifen or a NSAI or goserelin ≤ 28 days 
for advanced breast cancer prior to randomization.
●
Patient who has not had resolution of all acute toxic effects of prior anti-
cancer therapy to NCI CTCAE version 4.03 Grade ≤1 (except alopecia or other 
toxicities not considered a safety risk for the patient at investigator's discretion).
●
Patient has a concurrent malignancy or malignancy within 3 years of 
randomization, with the exception of adequately treated basal cell carcinoma, 
squamous cell skin carcinoma, non-melanomatous skin cancer or curatively 
resected cervical cancer.
●
Patient with CNS metastases.
Note: CNS involvement must be ruled out by assessments if a patient has any 
signs or symptoms indicating potential CNS metastases.
●
Patient has impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection).
●
Patient has a known history of HIV infection (testing not mandatory).
●
Patient has any other concurrent severe and/or uncontrolled medical 
condition that would, in the investigator’s judgment, contraindicate patient 
participation in the clinical study (e.g., chronic pancreatitis, chronic active 
hepatitis, etc.).
●
Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality including any of the following:
●
History of angina pectoris, symptomatic pericarditis, or myocardial 
infarction or coronary artery bypass graft (CABG) within 6 months prior to 
study entry.
●
Documented cardiomyopathy.
●
Left Ventricular Ejection Fraction (LVEF) < 50% as determined by 
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
●
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade AV block (e.g., bifascicular 
block, Mobitz type II and third degree AV block)
●
Long QT syndrome or family history of idiopathic sudden death or 
congenital long QT syndrome, or any of the following:
●
Risk factors for Torsades de Pointe (TdP) including uncorrected 
hypokalemia or hypomagnesemia, history of cardiac failure, or history of 
clinically significant/symptomatic bradycardia
resting heart rate < 50 at rest, by the triplicate ECGresting heart rate >90 at 
rest, by the triplicate ECG
●
Systolic blood pressure >160 or <90 mmHg.
●
On screening, inability to determine the QTcF interval on the ECG (ie: 
unreadable or not interpretable) or QTcF >450 msec (using Fridericia’s 
correction). All determined by the average of the triplicate screening ECG, per 
central review.
●
Patient is currently receiving any of the following substances and cannot be 
discontinued 7 days prior to the start of the treatment:
●
Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, 
grapefruit hybrids, pomelos, star-fruit, and Seville oranges.
●
Medications with a known risk to prolong the QT interval or induce 
Torsades de Pointes that cannot be discontinued or replaced by safe 
alternative medication (e.g. within 5 half-lives or 7 days prior to starting study 
drug).


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●
Medications that have a narrow therapeutic window and are 
predominantly metabolized through CYP3A4/5.
●
Additionally, for patients receiving tamoxifen: known strong inducers or 
inhibitors of CYP2D6.
●
Herbal preparations/medication and dietary supplements (except for 
vitamins).
●
Patient has had major surgery within 14 days prior to starting study drug or 
has not recovered from major side effects of surgery.
●
Patient is currently receiving warfarin or other Coumadin derived anti-
coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low 
molecular weight heparin (LMWH), or fondaparinux is allowed.
●
Patient is currently receiving or has received systemic corticosteroids ≤ 2 
weeks prior to starting study drug, or who have not fully recovered from side 
effects of such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical 
applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways 
diseases), eye drops or local injections (e.g., intra-articular).
●
Patient is concurrently using other antineoplastic agents (except for patients 
who are receiving ≤ 14 days of tamoxifen or a NSAI or goserelin ≤ 28 days for 
advanced breast cancer prior to randomization).
●
Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to randomization, and who has not recovered to grade 
1 or better from related side effects of such therapy (with the exception of 
alopecia) and/or if ≥ 25% of the bone marrow was irradiated.
●
Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, 
confirmed by a positive hCG laboratory test.
●
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing of study treatment and for 21 days after stopping 
study medication. Highly effective contraception methods include:
●
Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
●
Total hysterectomy (surgical removal of the uterus and cervix) or tubal 
ligation (getting your “tubes tied”) at least six weeks before taking study 
treatment.
●
Male sterilization (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole 
partner for that subject.
●
Combination of the following:
a.
Placement of an intrauterine device (IUD) or intrauterine 
system (IUS)
b.
Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ 
vaginal suppository
●
Participating in a prior investigational study within 30 days prior to enrollment 
or within 5-half-lives of the investigational product, whichever is longer.
●
Not able to understand and to comply with study instructions and 
requirements.
●
Patient with symptomatic visceral disease or any disease burden that makes 
the patient ineligible for endocrine therapy per the investigator’s best judgment


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Investigational and 
reference therapy
LEE011 or LEE011-matching placebo will be given orally once a day on days 1-
21 of each 28 day cycle. Days 22-28 will be a “rest” period from LEE011 or 
LEE011-matching placebo. Tamoxifen or a NSAI will be given orally once a day 
on a continuous daily schedule (e.g., days 1-28 of each 28-day cycle). Goserelin 
will be given as an injectable subcutaneous implant on day 1 of every 28 day 
cycle. There will be no “rest” period in the tamoxifen or NSAI schedule.
Study 
treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or 
Regimen
LEE011/Placebo
Capsules for oral use
600 mg
Days 1-21 of each 
28 day cycle
Tamoxifen*
Tablets for oral use
20 mg
Days 1-28 of each 
28 day cycle
Letrozole*
Tablets for oral use
2.5 mg
Days 1-28 of each 
28 day cycle
Anastrozole*
Tablets for oral use
1 mg
Days 1-28 of each 
28 day cycle
Goserelin
Subcutaneous implant
3.6 mg
Day 1 of each 28 
day cycle
*Patients will be eligible to receive either tamoxifen or a NSAI (letrozole or 
anastrozole) based on prior (neo) adjuvant therapy received.
The study drugs will be administered as a flat-fixed dose, and not by body weight 
or body surface area. All oral study treatment drugs must be administered 
together at approximately the same time each day and can be given with or 
without food.
Efficacy assessments
●
CT/ MRI every 8 weeks for the first 18 months, then every 12 weeks 
thereafter until 36 months, then change to as clinically indicated until disease 
progression, death, withdrawal of consent, loss to follow-up, or subject/guardian 
decision.
●
Brain CT or MRI as clinically indicated.
●
Whole body bone scan at screening if not collected previously within 42 days 
(6 weeks) prior to randomization; as clinically indicated thereafter.
●
Bone x-ray, CT or MRI (if bone lesion at screening) every 8 weeks for the first 
18 months and then every 12 weeks thereafter until 36 months, then change to
as clinically indicated
●
Skin color photography (if skin lesions at screening) every 8 weeks during the 
first 18 months and then every 12 weeks thereafter until 36 months, then change 
to as clinically indicated
●
CT/ MRI for any disease outside of the chest, abdomen, pelvis (if lesion 
identified at baseline) every 8 weeks for the first 18 months and then every 12 
weeks thereafter until 36 months, then change to as clinically indicated
●
Survival status every 12 weeks (or earlier if required) regardless of treatment 
discontinuation reason.
Safety assessments
●
Physical examinations
●
ECOG performance status
●
Height, weight, and vital signs
●
12 lead ECGs
●
ECHO, MUGA scan
●
Laboratory assessments including hematology, biochemistry, lipid panel, 
coagulation (via INR),
 pregnancy and urinalysis


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Other assessments
Patient-reported outcomes: Patient questionnaires will be collected to assess 
health-related quality-of-life, health status, functioning, disease symptoms, side 
effects
●
European Organization for Research and Treatment of Cancer’s core quality 
of life questionnaire and breast cancer specific questionnaire (e.g., EORTC-QLQ-
C30 and QLQ-BR23)
●
EuroQoL 5-level instrument (EQ-5D-5L)
●
 
 
 
 
 


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Data analysis
The primary objective for this study is to determine whether treatment with 
tamoxifen or a NSAI + goserelin + LEE011 prolongs PFS compared to treatment 
with tamoxifen or a NSAI + goserelin + placebo in premenopausal women with 
HR+, HER2-negative advanced breast cancer. The primary efficacy endpoint, 
PFS, will be determined based on local tumor assessment following RECIST 1.1 
guidelines. The primary efficacy analysis will be the comparison of the distribution 
of PFS between the two treatment groups using a stratified (randomization strata 
per IRT) log-rank test at one-sided 2.5% level of significance.
The primary PFS analysis will be performed after approximately 329 PFS events 
have been documented per local assessment. Distribution of PFS will be 
estimated using the Kaplan-Meier method. The median PFS along with 95% 
confidence intervals will be presented for each of the two treatment groups. The 
stratified Cox regression will be used to estimate the hazard ratio of PFS, along 
with 95% confidence interval. The treatment effect in terms of PFS within the 
subgroup of patients receiving tamoxifen and goserelin with LEE011/placebo, 
and within the subgroup receiving NSAI and goserelin with LEE011/placebo, will 
be estimated using separate Cox regression models; estimated hazard ratios 
with corresponding 95% CIs will be presented for each subgroup.
The Full Analysis Set (FAS) will comprise all randomized patients. Following the 
intent to treat (ITT) principle, patients will be analyzed according to the treatment 
and strata they have been assigned to at the time of randomization. The FAS will 
be the primary population for all efficacy analyses. The safety set will consist of 
all patients who received at least one dose of the study treatment (tamoxifen and 
goserelin or NSAI and goserelin and LEE011/placebo. Patients will be analyzed 
according to treatment actually received..
The key secondary objective in this study is to compare the two treatment groups 
with respect to OS. OS will be compared between the two treatment groups, 
provided the primary endpoint PFS is statistically significant favoring the test 
treatment arm (tamoxifen or a NSAI + goserelin + LEE011). A hierarchical testing 
procedure will be adopted in this study and the OS analyses will be performed 
only if the primary efficacy endpoint PFS is statistically significant. A maximum of 
three analyses are planned for OS: (1) at the time of the primary analysis for 
PFS, at which point a total of 123 (49%) deaths are expected); (2) after 
approximately 189 (75%) deaths have been documented; and (3) a final analysis 
for OS when 252 deaths are expected (expected approximately 40 months from 
date of first patient to be randomized).
At the time of primary PFS analysis, both PFS and interim OS analyses will be 
performed by the Sponsor's clinical team. Investigators and patients will remain 
blinded to study treatment and all patients will continue to be followed for OS until 
the final OS analysis (or earlier if OS reaches statistical significance at any of the 
interim analyses).
The assessment of safety will be based mainly on the frequency of adverse 
events and on the number of laboratory values that fall outside of pre-determined 
ranges. Other safety assessments (e.g., electrocardiogram, vital signs) will be 
summarized by treatment group.
Key words
HR-positive, HER2-negative, advanced breast cancer, LEE011, tamoxifen or 
NSAI, goserelin, CDK4/6, Phase III, ER-positive, PR-positive, premenopausal


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Amendment 7 (08-Jan-2020)
Study CLEE011E2301 was initiated in November 2014 and completed enrollment on 01-Aug-
2016 with a total number of 672 randomized patients. The study met its primary endpoint of 
progression-free survival (PFS) at the time of the primary analysis in October 2017. The study 
met its key secondary endpoint of overall survival (OS) at the time of the planned second OS 
interim analysis in February 2019. As of 08-Jan-2020, there are still 114 patients ongoing on 
study treatment, including 79 patients on the ribociclib arm and 35 patients on the placebo arm,
of which 8 have crossed-over following Amendment 6. 
The main purpose of this amendment is to include information on:
i.
Interstitial Lung Disease (ILD)/pneumonitis—ILD/pneumonitis has been observed with 
CDK4/6 inhibitor treatment (Please refer to IB ed.14 for more information) Table 6-6, 
LEE011 dose adjustment and management recommendation for ILD/pneumonitis, has 
been added to the protocol section and listed in ICF as a risk. 
ii.
Toxic Epidermal Necrolysis (TEN)—TEN has been reported in the post-marketing 
setting in a well-documented literature case report.  No case was observed in the clinical trials 
(please refer to IB ed.14 for more information).  The Program Standard Language (PSL) updates 
the Protocol Section 6.3.1.8 guidance for all other adverse reactions, including a specific
guidance to discontinue ribociclib if TEN is diagnosed and Informed Consent language updates
with relevant information on TEN. Other changes that were made during this update are as 
follows:

Clarify cross over opportunity in the study design 

Clarify tamoxifen washout requirement

Updated both Table 14-1 ‘List of prohibited medications during study treatment’ and 
Table 14-2 ‘List of medications to be used with caution during study treatment’

Other administrative changes throughout the document as indicated in the track changes 
version of the current program standard language
Changes to the protocol: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes made to the protocol due to this amendment are incorporated in the following 
sections:

List of Abbreviations was updated to include DC – Discontinued, ILD – Interstitial 
Lung Disease, PSL – Program Standard Language, TEN- toxic epithelial necrolysis
and to remove ROP – Roll Over Protocol

Section 4.1 was updated to remove a paragraph stating crossovers would not be 
permissible, and was replaced with a paragraph stating that OS endpoint was met and 
after Amendment 6 the study would now allow patients to cross over from placebo to 
LEE011 after being unblinded 

Figure 4-1: footnote was added with high level explanation of Protocol Amendment 6 
Study Design change with unblinding and crossover information 


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
Section 6.1 was updated to include an explanation on the rationale for the washout 
period between Tamoxifen and LEE011

Table 6-4: changed biweekly to every two weeks for clarification

Section 6.3.1.4 was updated to include reference to new table

Section 6.3.1.7 was added to explain additional follow up for ILD/pneumonitis

Table 6-6 was created for dose adjustment guidance and management 
recommendations for Interstitial Lung Disease (ILD)/pneumonitis

Section 6.3.1.8: added clarification on Toxic Epidermal Necrolysis (TEN) guidance

Section 6.4.1: added clarification to consult the list of prohibited medications for 
guidance

Section 6.4.1.4: added clarification around cumulative courses of radiation therapy

Section 6.4.2: added clarification to specify that LEE011 has the potential to increase 
exposure to substrates of the specific transporters

Section 6.4.4 added a statement to refer to the LEE011 Investigators Brochure and 
other drug package inserts for information on possible interactions with other drugs  

Section 7.1 added a statement to refer to Section 6.1 for more details around the 
washout period between Tamoxifen and LEE011

Section 7.1.5 removed information in reference to a potential roll over protocol

Section 10.7.2 added a statement that the study had already met both its primary 
endpoint and its key secondary endpoint, therefore any analysis post Amendment 7 
will be descriptive

Section 14 Appendices:

Appendix 1, Table 14-1: concomitant medication table for prohibited 
medications updated 

Appendix 1, Table 14-2: list of medications to be used with caution table 
updated
Review requirements by IRB/IEC and Health Authorities
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.
Some changes herein may affect the Informed Consent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 6 (18-Jul-2019)
Study CLEE011E2301 was initiated in November 2014 and completed enrollment on 01-Aug-
2016 with a total number of 672 randomized patients. The study met its primary endpoint of 
progression-free survival (PFS) at the time of the primary analysis in October 2017. The study 
met its key secondary endpoint of overall survival (OS) at the time of the planned second OS 
interim analysis in February 2019. Given these results, study participants will be unblinded in 
preparation for study closure. In addition, patients who are still receiving study treatment in the 
placebo arm, will be allowed to cross over to the ribociclib arm, based on the Investigator’s 
judgement and an individualized benefit risk decision. 
As of 03-July-2019, there are still 135 patients ongoing on study treatment, including 89 patients 
on ribociclib and 46 patients on placebo. 
The purpose of this amendment is to:
i.
Unblind patients and investigators in order to allow for knowledge of patient’s current 
treatment allocation 
ii.
Allow for patients receiving placebo the opportunity to cross over to treatment with 
LEE011 per Investigator discretion
iii.
Provide guidance for patients receiving placebo + tamoxifen, who as per Investigator 
discretion will cross over to LEE011, to switch to an NSAI, if they are to cross over to 
treatment with LEE011. These patients will complete a wash out period of 5 half-lives.
iv.
Clarify end of study (EOS) and include information on post-study drug access 
v.
Specify that central safety assessments can cease and all laboratory and ECG 
assessments should be performed locally and clarify the frequency of assessments
vi.
Specify that patient reported outcome (PRO) measures should no longer be collected
viii.
Update the laboratory assessments to remove phosphorous and, per the IB, add serum 
pregnancy testing at EOT
Following this protocol amendment and the unblinding of study participants, the word “placebo” 
refers to the original treatment allocation in the study. Physical placebo capsules no longer need 
to be administered but the wording has been kept in places in the protocol to avoid confusion.
Changes to the protocol: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes made to the protocol due to this amendment are incorporated in the following 
sections:


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
Section 4.3 and 6.1: Definition of End of Study and Study Treatment sections were 
updated to note that the study will be unblinded and patients will have the opportunity to 
cross over from placebo to LEE011

Section 6.3.1.1 Tamoxifen section was updated to clarify that patients who cross over 
from placebo to LEE011 and are currently taking tamoxifen, must switch to an NSAI and 
have a wash-out period

Section 6.4.3 was updated to clarify prohibited concomitant medication therapies

Section 6.5.2: Treatment assignment or randomization was updated to clarify that the 
study will be unblinded and patients will have the opportunity to cross over from placebo 
to LEE011

Section 6.5.3 Treatment blinding was updated to clarify that the study will be unblinded

Section 7.1 Study Flow and Assessments were updated for all patients and additional 
clarification and instruction was given for cross over patients

Table 7-1a was updated to reflect revised assessments

Table 7-1b was added to clarify assessments for cross over patients

Section 7.1.5 was updated to include information about the roll over protocol 

Section 7.2.2.5 Lab Evaluations: was updated to clarify all labs will be performed locally 
not centrally and phosphorous was removed

Section 7.2.2.5.5 was updated to clarify that pregnancy testing during treatment can be 
performed as a urine or serum test, based on Investigator discretion or local requirements

Section 7.2.2.7 Cardiac Assessments was updated to clarify that all ECGs will be 
performed locally not centrally and the schedule of assessments was updated for all 
patients
 
 

Section 7.2.6 updated to confirm no additional patient reported outcome assessments will 
be collected

Section 8.3 Emergency Unblinding was updated to reflect this section is not applicable 
now that the study is centrally unblinded

Section 9.3 Updated data collection parameters regarding labs, ECG

Section 10.1.5 Added in information on the cross over analysis set

Section 10.3 Updated to include treatment exposure summaries for cross over patients

Section 10.4.4 Updated the supportive analysis to clarify further analysis

Section 10.5.1 Confirm that since the key secondary objective was met, no further formal 
analyses of OS are planned 

Section 10.5.3 Incorporate safety summaries for the crossover analysis set

Section 14 Appendices


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Appendix 1: concomitant medication table for prohibited medications updated
Review requirements by IRB/IEC and Health Authorities
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.
Some changes herein may affect the Informed Consent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Amendment 5 (06-Aug-2018)
Study CLEE011E2301 was initiated in November 2014 and completed enrollment on 01-Aug-
2016 with a total number of 672 randomized patients. The study met its primary endpoint of 
progression-free survival (PFS) at the time of the primary analysis in October 2017. The study 
will continue to assess overall survival and to collect safety data. 
The purpose of this amendment is to:
i.
Update the dose adjustment and management recommendations for QTcF 
prolongation. Analyses of preclinical and clinical data with ribociclib have 
demonstrated that ribociclib prolongs the QT interval in a concentration-dependent 
manner. Moreover, based on the ribociclib exposure-ΔQTcF relationship and the 
clinical experience in studies CLEE011A2301 (MONALEESA-2) and 
CLEE011E2301 (MONALEESA-7), ribociclib dose reduction is an effective strategy 
for managing ribociclib therapy in patients experiencing QTcF prolongation. 
Therefore, in order to reduce the risk of subsequent QTcF prolongation in patients 
experiencing a QTcF between 481-500 msec, ribociclib dosing should be reduced by 1 
dose level with the first occurrence of QTcF ≥ 481 msec. As a result, this amendment 
includes an update to the dosage management guidance for patients who experience 
QTc prolongation.
ii.
Update the prohibited concomitant medications based on compilation of drug-drug 
interaction and co-medication considerations
iii.
As the study has met its primary endpoint, after all patients have gone through 36 
months of follow-up from randomization, tumor and other efficacy assessments will 
be performed as clinically indicated. In order to capture patients PRO data close to the 
tumor assessment dates, PRO assessment schedule will also follow the efficacy 
assessment schedule.
iv.
Clarify the timing of collection of patient reported outcomes (PRO) to provide 
flexibility for sites to collect PRO’s at any time during the patient visit but prior to 
visiting the investigator
v.
Update the withdrawal of consent language to align with the new Global Data 
Protection Requirements
Changes to the protocol: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes made to the protocol due to this amendment are incorporated in the following 
sections:

Section 4.1.4, Section 7.1.6.2, Section 7.2.1.1, Table 7-1, Table 7-2, Section 9.3.6 updated 
the visit schedule for imaging assessments

Section 6.1.1.1: General dosing guidelines- updated guidance related to antiemetic 
medication, CYP3A4 inhibitors and herbal or dietary supplements. 


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Section 6.3.1.5: Additional follow-up for hepatic toxicities updated to include information 
on the LEE011X2109 study as well as updated text to mandate discontinuation, when liver 
test elevation is not due to cholestasis. 

Section 6.3.1.7.1: Adjustment of starting dose in special populations updated to include 
information on the LEE011A2116 study

Table 6-5: LEE/placebo dose adjustment and management recommendations for QTcF 
prolongation- Updated the recommended management for QT prolongation events 

Section 6.4.1: Permitted concomitant therapy- clarified the use of chronic concomitant 
medication

Section 6.4.1.3: Hematopoietic growth factors: clarified language on use of WBC growth 
factors 

Section 6.4.1.5: Use of antiemetic medications- added a new section to explain use of 
antiemetic medications according to NCCN guidelines 

Section 6.4.2: Concomitant therapy requiring caution- updated information on 
concomitant therapy requiring caution

Section 6.4.3: Prohibited concomitant therapy- updated list of prohibited concomitant 
therapy

Section 6.4.4: Drugs with QT prolongation- further clarified the co-administration of 
drugs with known risk of torsades de pointes (TdP) 

Section 7.1.8: Withdrawal of consent wording revised to align with new Global Data 
Protection Requirements

Table 7-1 and Table 7-9: updated the visit schedule for PRO assessments

Section 7.2.1.1: Imaging tumor assessments- note added to clarify stopping the 
transmission of images to CRO

Section 7.2.6: Patient reported outcomes- updated text to explain the timing of PRO 
administration during patient visit

Section 14 Appendices

Appendix 1: Concomitant medications: list of prohibited concomitant medications 
updated based on the oncology clinical pharmacology guidance, drug-drug interaction 
and co-medication considerations (v07, release date: Jan2018) 

Table 14-1 : List of prohibited medications during study drug treatment

Table 14-2: List of medications to be used with caution during study drug 
treatment
Review requirements by IRB/IEC and Health Authorities
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Some changes herein may affect the Informed Consent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Amendment 4 (24-Feb-2017)
Study CLEE011E2301 was initiated in November 2014 and enrollment is complete. The last 
patient was randomized on 01-Aug-2016 and 672 patients were randomized in total.
The purpose of this amendment is to:
(i)
Eliminate the efficacy interim analysis:
Elimination of the interim analysis will allow additional PFS events and longer follow-up for 
more robust treatment effect and PFS estimates, while not unduly delaying the readout of the 
study. Based on current events projection, it is expected that the cutoff date for the final PFS 
analysis (based on 329 PFS events) would occur approximately 3 months later than the cutoff 
for the currently planned interim analysis (based on 263 PFS events). An increase of 25% in the 
number of PFS events, together with an additional 3 months follow-up for all patients, is 
therefore warranted.
(ii) Update the clinical safety and efficacy data for LEE011 in line with newly reported 
results of CLEE011A2301.
(iii) Additional changes
(i)
The definition of the Safety set in the statistical analysis was updated to remove the 
requirement of a post-baseline safety assessment for inclusion in the Safety set. The 
updated definition, i.e. including all treated patients, reflects the current standard 
Novartis definition and a widely used definition in the industry.
 
 
 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Summary section of the protocol has been updated to maintain consistency with the main 
body of the protocol

Section 1.1.3 updated current preclinical and clinical data supporting CDK4/6 pathway in 
breast cancer

Sections 1.2.1.2 deleted study status of CLEE011A2301 as updated information has been 
provided in a later section.

Section 1.4.1.1 added clinical safety and efficacy of LEE011 with newly reported results 
of CLEE011A2301

Section 4.1 removed reference to IDMC review of efficacy data and interim analysis of 
PFS

Section 4.2 removed efficacy interim analysis for primary PFS endpoint


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Section 4.3 removed reference to interim PFS analysis and updated reference of final PFS 
analysis to primary PFS analysis

Section 7.2.1.1 corrected reference to Novartis guideline version 3.2

Sections 8.2.2 and 8.4 replaced “Novartis Drug Safety and Epidemiology (DS&E)” with 
“Novartis Chief Medical Office and Patient Safety (CMO&PS)”

Section 8.6 removed reference to IDMC review of efficacy data from the interim analysis; 
 

Section 10 removed reference to interim PFS analysis

Section 10.1.2 updated definition of Safety set

Section 10.4.2 removed reference to interim PFS analysis and indicated timing of primary 
efficacy analysis at approximately 329 PFS events

Section 10.4.4 clarified that the analysis of PFS as assessed by BIRC, implemented in 
protocol amendment 3, uses a sample-based/audit approach; 
 

Section 10.5.1 updated the timing of OS analyses as a result of removing the PFS interim 
analysis

Section 10.7.1 removed PFS interim analysis

Section 10.7.2 updated number and timing of OS interim analyses as a result of removing 
the PFS interim analysis

Section 10.8 removed the group sequential design aspects of the sample size calculation 
due to removal of PFS interim analyses (the sample size calculation itself, to the level of 
precision reported, is unchanged)

Section 10.9.1 changed from 4-look to 3-look design for OS as a direct result of removing 
PFS interim analysis (the sample size calculation itself, to the level of precision reported, 
is unchanged)

Section 10.9.2.1 corrected typographical errors in the half-width of 90% CI for the 
treatment difference; updated table numbers and references due to deletion of a table 
earlier in the section

Section 11.5 updated Novartis guidelines for publication of study protocols and results

Section 13 updated protocol references
Review requirements by IRB/IEC and Health Authorities
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Summary of previous amendment(s)
Amendment 3 (24-Jun-2016)
Study CLEE011E2301 was initiated in November 2014 and enrollment is currently ongoing. 
As of June 13, 2016, 611 patients have been randomized in the study.
The purpose of this amendment is to:
(i) Eliminate the planned futility analysis:
Since the start of Study CLEE011E2301, additional clinical data have been generated with 
LEE011 and other CDK 4/6 inhibitors that provide additional assurance of the activity of this 
compound and class in patients with breast cancer. In addition, Study CLEE011E2301 will be 
fully enrolled prior to the time of the originally planned futility analysis, negating the need for 
the originally planned interim futility analysis.
(ii) Change the approach for Blinded Independent Review Committee (BIRC) assessment of 
PFS from a full read to an audit (sample) based approach:
For studies with local PFS as the primary endpoint, central PFS has generally been used as a 
secondary analysis in support of the treatment effect observed in the primary efficacy analysis. 
Although 100% central review of scans has been performed in many trials, there is a growing 
body of evidence that an audit based approach for central evaluation is sufficient (Zhang et al 
2012, FDA ODAC 2012). Therefore, the BIRC assessment of PFS is being changed from a full 
read to an audit based approach. Consequently, BIRC based PFS will no longer be a secondary 
endpoint but will be considered supportive of the primary.
 
(iv)
The protocol appendix 3 has been updated to reflect the new Novartis guidance on the 
implementation of RECIST 1.1
(v)
Additional changes
(i)
The clinical pharmacokinetic section has been updated to reflect new data 
available
(ii) Palliative radiotherapy, previously only allowed for bone pain relief, is permitted 
provided it is not delivered to a target lesion
(iii) A sensitivity analysis has been added for ORR based on patients with measurable 
disease at baseline.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Summary section of the protocol has been updated to maintain consistency with the main 
body of the protocol


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Section 1.2.1.5 addition of language regarding new pharmacokinetics data on LEE011

Section 3, Table 3-1 removal of secondary objective to evaluate centrally assessed PFS, 

Section 4.1 update of centrally assessed PFS from a secondary endpoint to supportive 
evidence of the primary endpoint

Section 4.1, 4.2, and 4.3 removal of futility analysis

Table 6-5, to further clarify triplicate ECG measurements

Section 6.4.1.4, to remove the requirement of palliative radiation solely for bone pain 
relief.
 
 

Section 7.2.1.1 addition of language relating to audit-based central PFS assessment

Section 7.2.2.7.2 corrected reference to Table 6-6

Section 8.6 removal of reference to futility analysis

Section 9.3.6 addition of language describing audit-based BIRC assessment of PFS

Sections 10, 10.4.2, 10.5.1, 10.7.1, 10.7.2, 10.8 removal of futility interim analysis and 
update of corresponding operating characteristics and sample size descriptions

Section 10.4.4 addition of text describing supportive analysis of PFS based on audit-based 
BIRC assessment

Section 10.5 and 10.5.2.1 removal of BIRC-assessed PFS from secondary objectives; 
addition of a sensitivity analysis in Section 10.5.2.1 for ORR based on patients with 
measurable disease at baseline

Section 10.8 addition of sample size calculation for audit size of sample-based BIRC 
assessment of PFS

Section 13: addition of new protocol references.
Review requirements by IRB/IEC and Health Authorities
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Amendment 2
Study CLEE011E2301 was initiated in November 2014 and enrollment is currently ongoing. 
As of February 08, 2016, 372 patients have been randomized in the study.
The purpose of this amendment is to:
(i) Update and clarify the safety monitoring of patients to be consistent across LEE011 
clinical trials, and better characterize the QTc and liver side effects including:
(i) Management of QTcF prolongation: Potential risk of QT prolongation has been 
observed in patients treated with LEE011. Updates to inclusion and exclusion criteria, 
ECG monitoring and dose modification guidelines for QTcF prolongation have been 
made.
(ii) Management of hepatic toxicities: Recent data suggests a potential risk of hepatic 
toxicity (drug induced liver injury [DILI] indicated by an increase of transaminases, in 
isolation or together with bilirubin increase) in patients treated with LEE011. Updates 
to monitoring and dose adjustment guidelines for hepatobiliary toxicities including 
ALT, AST, and total bilirubin have been added and separated from the dose 
modification guidance for other adverse events. 
 
 
 
 
 
 
(iii)Management of dose modification based on local laboratory results: Clarification has 
been provided that, in case of safety emergency, local laboratory results can be used to 
evaluate the need for potential study treatment dose modifications
(ii) Additional changes
(i) List of prohibited concomitant medications has been updated based on recently 
released Novartis internal Oncology Clinical Pharmacology drug-drug interaction 
guidance (from 2015) and based on new data and recommendations from the latest 
version of LEE011 Investigator’s Brochure.
(ii) New information is provided on the safety pharmacology and toxicology
(iii)Updated clinical trial information with the most recent data
 
 
(v) Remove the requirement for a central radiology assessment by medical oncologist: 
Medical oncologist review has been replaced by a standard blinded independent 
review committee (BIRC) assessment
 
 


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Summary section of the protocol has been updated to maintain consistency within the 
main body of the protocol

Section 1.1.3 Addition of most recent information on available therapeutic options

Section 1.2 Addition of language to refer to most recent version of the LEE011 
investigator brochure

Section 1.4 Addition of language to refer to most recent version of the LEE011 
investigator brochure

Section 2.3 has been updated to incorporate most updated trial information
 

Section 5.2 Inclusion Criteria has been updated:

#2) Clarify that pregnancy test not needed in case of hysterectomy

#5) Remove prior neo adjuvant therapy washout requirements

#7) Phosphorus assessment has been removed from screening visit

#12) Bilirubin assessment lab ranges clarified

#13- #15) Added per program standard language

Section 5.3 Exclusion Criteria have been updated:

#12) and #13) to clarify the exclusion criteria for patients with clinically significant, 
uncontrolled heart disease and/or cardiac repolarization abnormality and for patients 
currently receiving prohibited medications. Also updated heart rate parameters.

#20) Clarified contraception requirements

#23) Added exclusion 23 to state that patients with disease burden which makes them 
poor candidates for endocrine therapy are excluded

Section 6.1 has been updated with timing recommendation on dosing schedule and meal 
conditions

Section 6.3.1.4:

To clarify the use of local laboratory results for dose modifications

To add clarity on dose modification guidelines


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Section 6.3.1.5 and Section 6.3.1.6: Table 6-3, Table 6-4 and Table 6-5

Dose modifications have been updated to clarify actions to be taken for 
 
 QTcF prolongation and all other toxicities, as well as providing new 
guidelines for hepatic toxicities.

“Placebo” has been added in the table wording and baseline value has been modified 
to baseline grade based on CTCAE

Section 6.4.1: wording around the use of corticosteroids has been updated

Section 6.4.3: wording around the use of prohibited concomitant medications has been 
clarified

Section 6.6.4 has been added to clarify the use of medications with a known risk of QT 
prolongation

Section 7, Table 7-1:

Modification to the timeframe for the ECGO/MUGA now includes a +/- 7 day 
window

Clarify that the ECOG assessment will not be repeated at Cycle 1 Day 1 when done in 
the timeframe -7 to -1 at the screening visit

Clarify that the FSH, 
 and serum pregnancy test can be done within 28 days 
before randomization.
 

Section 7.1.2 clarification on ICF process for patients who rescreen

Section 7.1.5.1 update to the study treatment discontinuation language in the case of AEs

Section 7.2.2.5:

Clarification on the use of local laboratory results

Section 7.2.2.7.1 and Table 7-5:

Electrocardiogram (ECG) was updated to include triplicate readings for each time 
point

Clarity was added on the unscheduled ECG management


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301

Table 7-13
 
 

Updated baseline tumor tissue collection language from strongly recommended to 
mandatory

Section 7.2.4.1.1: Updated baseline tumor sample language from strongly recommended 
to mandatory
 

Section 8: implementation of new Serious Adverse Event (SAE) reporting instructions

Section 9.3.6: medical oncologist review has been replaced by a standard blinded 
independent review committee (BIRC) review assessment

Section 13: new protocol references have been added

Section 14.1 Appendix 1- Concomitant medications

Table 14-1 and Table 14-2 have been updated with the latest information available.
Review requirements by IRB/IEC and Health Authorities
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.
Some changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Amendment 1
The purpose of this amendment is to:
(i) Further enhance and clarify safety monitoring of patients, including:
(i) Management of QTc prolongation: More specific recommendations for cases of QTc
prolongation have been included : addition of ECG assessments at the first day of each 
cycle, check and follow-up of electrolyte abnormalities until normalization, review of 
concomitant medications, and compliance with correct dose have been included with 
each grade. Additionally, if patient’s have any QTcF values ≥ 481 ms at any time before 
Cycle 7 Day 1, then continued ECG monitoring is indicated for all subsequent cycles.
(ii) Management of hepatic toxicities: Specific dose modification guidance for cases of 
hepatic toxicity has been included: dose adjustments as well as additional follow up for 
bilirubin and/or transaminases increase have been detailed and separated from the dose 
modification guidance for other adverse events.
(iii) Management of grade 3 neutropenia: Clarification that re-initiation of LEE011/placebo 
after grade 3 neutropenia may occur at the same dose level if the neutropenia resolves 
in ≤ 7 days to better manage consistency regarding dose reductions.
(ii) Update the protocol requirements for consistency with the most recent preclinical 
information:
(i)
In the initial rat ADME study cited in previous IB version, thyroid had the highest 
exposure in albino animals only. As a precaution, thyroid function was monitored in all 
clinical study protocols. A most recent study (DMPK 1300792) using p.o. dosing in 
partially pigmented animals with a longer observation period showed the highest 
distribution to the melanin-containing structures and not to the thyroid gland. In addition, 
no clinically significant thyroid adverse events have been reported in clinical trials so 
far. Based on this information, the risk to thyroid gland is removed from the reference 
safety information for the compound and thyroid laboratory monitoring in clinical 
protocols are no longer mandated.
(ii) In the 15-week rat toxicity study, kidney has been identified as an additional organ of 
toxicity for LEE011. In order to better characterize this potential side effect, as well as 
improve the management of the safety of the patients, monthly urinalysis has been added 
as well as blood urea nitrogen assessment with each chemistry panel.
(iii) Revise the treatment allocation in case of prior use of fulvestrant:
In the original protocol, patients who had a last dose of (neo)adjuvant fulvestrant (last dose 
given <12 months prior to randomization) were eligible to receive tamoxifen +goserelin on 
study. However, because fulvestrant is an estrogen receptor antagonist with a mechanism of 
action more similar to tamoxifen than to NSAIs, patients having received (neo)adjuvant 
fulvestrant (last dose was given < 12 months prior to randomization) will instead be eligible to 
receive a NSAI + goserelin on study instead of tamoxifen +goserelin.
(iv) Additional changes:
The assessment of PFS as per blinded independent review committee (BIRC) was changed from 
a supportive analysis of the primary endpoint to a secondary endpoint.


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Amended Protocol Version 07 (clean)
Protocol No. CLEE011E2301
Updated language has been included in the protocol covering “Discontinuation of Clinical Trial 
Protocol Elements” in order to maintain consistency with Novartis protocol template language.
Additionally, Amendment 1 includes minor editorial changes, typographical error corrections, 
and additional clarifications to address investigators’ questions as described in the list of 
changes below. Lastly, minor changes to the evaluation schedule have been made to allow the 
screening period to be more efficiently managed.
Changes to the protocol:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Summary section of the protocol has been updated to maintain consistency within the main
body of the protocol.

Section 1.2.1: Addition of language to refer to most recent version of the LEE011 
Investigator Brochure.

Section 3 Table 3-1: Addition of secondary objective which includes the evaluation of the 
two treatment arms with respect to centrally assessed PFS.

Section 4.1: Revision with regard to prior use of fulvestrant – Patients with prior use of 
fulvestrant will be eligible to receive a NSAI + goserelin on study as opposed to tamoxifen. 
Section 4.1: Clarification added to mention that crossover between NSAIs (letrozole to 
anastrozole or vice versa) is not permitted.

Section 4.2: Removal of “There is no intent to stop the study due to futility at this efficacy 
interim analysis.”

Section 4.3: Clarification regarding the definition of end of study.

Section 4.4: word “prematurely withdrawn patient” replaced by “discontinued or withdrawn 
patient.”

Section 5.1: Addition of clarification on study population and introduction of a statement 
that potential patients should be eligible to receive endocrine therapy in order to enroll in 
this study.

Section 5.2 Inclusion Criteria:

#2). Removal of “within 72 hrs” regarding the collection of a negative serum 
pregnancy test. A negative serum pregnancy test will be collected during the 
screening period (-14 to -1 days) in this amendment.

#3). Clarification of the definition of menopausal status: FSH and/or estradiol should 
be assessed per local normal range.

#5). Clarification of prior fulvestrant use as mentioned in Section 4.1

#6). Clarification of prior goserelin use: patients who are receiving goserelin for 
reasons other than for advanced breast cancer treatment are eligible (e.g 
endometriosis). Patients who received ≤ 28 days goserelin for advanced breast cancer 
are eligible.


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Amended Protocol Version 07 (clean)
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
#7). Addition of the note further describing 1 line of chemotherapy.

#12). Revision of the eligibility regarding serum creatinine.

Section 5.3 Exclusion Criteria:

#3). Clarification of the definition of menopausal status: FSH and/or estradiol should 
be assessed per local normal range.

#5). Clarification of prior goserelin use

#8). Further clarification regarding the exclusion of CNS metastases. CNS 
involvement must be ruled out by assessments if a patient has any signs or symptoms 
indicating potential CNS metastases.

#12). Addition of cardiac disease or history of dysfunction: Congenital long QT 
syndrome or a family history of long QT syndrome, and Bradycardia (heart rate <50 
at rest), by ECG or pulse. In addition, the word “per central review” was added.

#13). Clarification regarding tamoxifen and the known strong inducers or inhibitors of 
CYP2D6. Additionally, dietary supplements were added as an exclusion criterion.

#17). Clarification of prior goserelin use.

#20). Additional language added to specify patients must be using highly effective 
methods of contraception 21 days after stopping study medication.

#21 and #22). Two additional exclusion criterions were added to comply with 
Novartis standard protocol language.

Section 6.1.1: Addition of the word “placebo.”

Section 6.1.1.1: Clarification of the timing and dosing of patients allowed after Cycle 3 Day 
16. Addition of no herbal supplements and that multivitamins are permitted was also added.

Figure 6-1: Revised per site guidance

Section 6.1.4: Modified for better clarity

Section 6.1.5: Modified for better clarity

Section 6.3.1: Modified for better clarity

Section 6.3.1.4: Modified to ensure patients receive 7 consecutive rest days of 
LEE011/placebo to avoid any inadvertent overdose.

Section 6, Table 6-3: More detailed guidance regarding management of grade 3 neutropenia 
based on duration of adverse event prior to resolution: If resolved in ≤7 days, then maintain 
dose level. If resolved in > 7 days, then reduce LEE011/placebo dose to the next lower dose 
level.

Section 6, Table 6-4: Addition of dose adjustment and management recommendations for 
hepatic toxicities. Additional follow-up guidance was also added under Section 6.3.1.4.1.


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
Section 6, In Table 6-5: More specific guidance for electrolyte abnormalities with QTcF 
prolongations grade 1-4 was added: “If outside of the normal range, interrupt 
LEE011/placebo administration, correct with supplements or appropriate therapy, and 
repeat electrolytes until documented normalization of the electrolytes.”

Section 6.3.1.4.1, renumbered as 6.3.1.4.3. Word “planned” changed to “ongoing” 
regarding the status of the human ADME study.

Section 6.4: Modified for better clarity

Section 6.4.4: Additional clarification added regarding concomitant medication 
associated with menopausal status.

Section 6.5.3, added the words “for safety reasons” and “safety reasons for” in order to align 
protocol and IRT language regarding the specific reasons for emergency patient unblinding.

Section 7, to include Table 7-1, Table 7-2:

Minor modifications to screening windows

Further clarification of Cycle 1 Day 1 assessments

Removal of Thyroid T3 and TSH

Addition of monthly urinalysis collection

Further clarification of Local FSH and/or Estradiol for eligibility

Addition of “Fluid/Tissue Collection” in the Tumor Assessments, as clinically 
indicated.

Revision of window regarding whole body bone scan: change from within 28 days to 
within 42 days of randomization

Further clarification on ECG assessments

Removal of ECHO/MUGA after screening, and addition of ECHO/MUGA collection 
at End of Treatment (EOT).

Clarification of Serum Pregnancy test and Urine Pregnancy Test

Clarification regarding study treatment discontinuation

Clarification regarding tumor assessment schedule following randomization

Section 7.1.2: Minor modifications to reflect screening windows, removal of thyroid testing

Section 7.1.5: Modified for better clarity on the definition of study treatment discontinuation.

Section 7.1.6: Modified for better clarity regarding follow-up period.

Section 7.1.8 has been added to better clarify patient withdrawal of consent and process to 
follow by investigators.

Section 7.2.1: Modified for better clarity; revision of whole body bone scan screening 
window

Section 7.2.2.6, Table 7-5, Table updated to reflect the new ECG frequency and additional 
recommendations given with regards to ECG assessment in case of abnormalities and 
cardiologist consultation.

Section 7.2.4: Modified for better clarity

Table 7-14, 7-15: Screening window modified to reflect Table 7-1.


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
Section 9.3.5 modified to clarify which local lab results to collect in the CRF

Section 10.4.4, 10.5, 10.5.1, 10.5.2, 10.7.1, 10.7.2, Table 10-1: Revisions reflect the 
addition of secondary objective which includes the evaluation of the two treatment arms 
with respect to centrally assessed PFS and clarifications/corrections of typographical errors.

Section 11.3: Removal of language indicating an additional consent form.

Section 14 Appendix 1, Table 14-1, Table 14-2: Update to concomitant medications.
Review requirements by IRB/IEC and Health Authorities
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.
Some changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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1
Background
1.1
Overview of epidemiology, disease pathogenesis and current 
treatment
1.1.1
Epidemiology
Breast cancer is the most common cancer in women worldwide. It is estimated that more than 
1.7 million new cases of breast cancer occurred among women worldwide in 2012 
(GLOBOCAN 2012). In 2014, an estimated 232,670 new cases will be diagnosed in women in 
the United States; of those, 133,310 will be in women < 65 years old. More than 40,000 deaths 
will occur in the United States in 2014 from breast cancer with 16,970 of those women being 
less than 65 years old. Fewer than 5% of breast cancers occur in women < 40 years old 
(American Cancer Society 2014), but it is still the leading cause of cancer death among women 
20 to 59 years old (Siegel 2014). Death rates for breast cancer have steadily decreased in women 
since 1989, with larger decreases in younger women; from 2006 to 2010, rates decreased 3.0% 
per year in women under 50 years and 1.8% per year in women 50 and older. The decrease in
breast cancer death rates represents improvements in early detection and treatment, and possibly 
decreased incidence (American Cancer Society 2014).
Breast cancer incidence varies between women of different ethnicities and in different 
geographic locations around the world. According to GLOBOCAN generated data from 2008, 
the Age Standardized Incidence Rates of breast cancer in women < 40 years old are highest in 
Europe, North America, Argentina, Japan, Brazil and China with 13.2, 9.8, 9.0, 7.4, 6.3, and 
4.4 cases per 100,000 women per year, respectively. Some of the differences in rates may be 
due to local screening guidelines for women who are less than 40 years old (Assi 2013).
Invasive breast cancer is classified by the presence of estrogen receptor (ER), progesterone 
receptor (PgR), and human epidermal growth factor receptor 2 (HER2) antigen for prognostic 
and treatment purposes. Seventy percent of invasive breast cancers in women > 45 years express 
ER and/or PgR and are termed hormone receptor positive (HR+). Compared with women aged > 
45, those ≤ 45 years are slightly less likely to be ER-positive; ER-positivity may decrease to 
approximately 55% in women aged 20-39 years (Li 2003). Younger women are also more likely 
to have higher tumor grades, larger tumor sizes, and positive axillary lymph nodes. 
Approximately 20% of invasive breast cancers express HER2 and are termed HER2-positive 
(irrespective of ER and PgR expression). There are no differences in HER2 or PgR status 
between younger and older women with breast cancer (Huang 2005).
In 1983, the median survival time for premenopausal women with metastatic breast cancer was 
35 months, with only 28% still alive at 5 years (Falkson 1995). Nineteen to twenty-five years 
later (2002 to 2008), the 6 year survival rate for women diagnosed with metastatic breast cancer 
was 24% in the United States (American Cancer Society 2013).
1.1.2
Treatment options for hormone receptor positive (HR+), HER2-
negative premenopausal advanced breast cancer
Endocrine therapy remains the therapeutic backbone for the treatment of HR+, HER2 negative 
breast cancer. Based on current treatment guidelines (NCCN breast cancer guidelines version 


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3.2014), tamoxifen is a standard treatment option in premenopausal women with HR+, HER2-
negative, advanced BC, in addition to ovarian function suppression (OFS) or anti-hormonal 
therapy with NSAIs and OFS (NCCN breast cancer guidelines version 3.2014).
Tamoxifen is approved for the treatment of metastatic breast cancer in premenopausal women. 
It works by blocking the ER in the breast cancer cells, thereby preventing estrogen from binding.
In women < 40 years of age with HR+ breast cancer, 5 years of adjuvant tamoxifen, with or 
without ovarian suppression, is considered the standard endocrine treatment and remains the 
first choice for endocrine therapy in the metastatic setting as well (Christinat 2013). The 
therapeutic benefits of tamoxifen are determined by the menopausal status and they are limited 
by the development of resistance. A prospective study of nearly 400 women demonstrated that 
menopausal status is a key factor that determined whether the disease would respond well to 
tamoxifen (Ravdin 1992). Premenopausal women with ER+ tumors had an overall response 
rate of only 24%, as compared with an 86% response rate among postmenopausal women whose 
tumors were strongly positive for estrogen and progesterone receptors. Despite the efficacy of 
endocrine therapy for HR+ advanced BC, approximately 30% of women with metastatic disease 
will have primary resistance to endocrine therapy, which is commonly defined as recurrence 
within the first 2 years on adjuvant endocrine therapy or as progressive disease within 6 months 
of treatment initiation for advanced disease. Furthermore, many patients with initial response 
to endocrine therapy will acquire secondary resistance, commonly defined as disease 
progression more than 6 months after endocrine therapy initiation (Pritchard 2013, Bachelot 
2012, Bedard 2008). Almost 50% of ER-positive metastatic breast cancer patients do not 
respond to tamoxifen in the first-line setting, thereby demonstrating intrinsic resistance. Even 
if patients respond to tamoxifen initially, they all eventually develop acquired resistance and 
their disease progresses.
Tamoxifen may be given either alone or in combination with an ovarian function suppression
(OFS) agent, such as goserelin, an approved agent for the palliative treatment of pre- and 
perimenopausal advanced breast cancer. Goserelin and tamoxifen may function through 
different pathways (those of estrogen withdrawal and estrogen receptor blockade, respectively), 
which might target different cell populations (Davidson 2000). The addition of luteinizing 
hormone-releasing hormone (LHRH) agonists such as goserelin to tamoxifen in premenopausal 
women will suppress the tamoxifen-induced stimulation of the pituitary-ovarian function and 
act in a similar way to an oophorectomy (Zoladex® Prescribing Information). Data assessing
the combination of endocrine therapy in premenopausal women are limited. A meta-analysis (n 
= 506) of 4 randomized studies (Boccardo 1994, Jonat 1995, Klijn 2000) showed the 
combination of a LHRH agonist plus tamoxifen is superior to the LHRH agonist alone in 
premenopausal women with advanced breast cancer. The results of this study showed an 
improved hazard ratio (HR) favoring the combination in terms of response (HR, 0.67; 95% 
confidence interval [CI], 0.46-0.96) and survival (HR, 0.78; 95% CI, 0.63-0.96) after 6.8 years 
of median follow- up. Goserelin was the LHRH agonist used in 3 of the 4 studies (Klijn 2001).
Most premenopausal women with ER+ advanced breast cancer have received tamoxifen as 
adjuvant therapy; once breast cancer has relapsed new endocrine treatment options are required. 
According to current treatment guidelines (NCCN breast cancer guidelines version 3.2014), 
these patients can also receive ovarian ablation/suppression treatment and receive anti-
hormonal treatment such as aromatase inhibitors (AIs) similar to what postmenopausal women 


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typically receive. AIs block the peripheral conversion of androgens to estrogens and reduce 
estrogen levels in tissue and plasma. Third generation non-steroidal AIs (NSAIs) are highly 
selective for the enzyme aromatase and are fairly well tolerated. Both anastrozole (Arimidex®) 
and letrozole (Femara®) are third generation NSAIs that reversibly bind aromatase. Exemestane 
(Aromasin®) is a third generation steroidal AI that irreversibly binds aromatase.
Based on the clinical benefit shown in postmenopausal patients, AIs in combination with 
ovarian function suppression (OFS) have been investigated in premenopausal patients with 
breast cancer in neoadjuvant, adjuvant and advanced settings. Results from the randomized 
phase III trials SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and 
EXemestane Trial) showed that adjuvant treatment with exemestane+OFS as compared with 
tamoxifen+OFS, significantly reduced recurrence in premenopausal women with HR+ early 
breast cancer. Results from both trials (N=5,738) showed statistically significant differences in 
disease free survival (DFS) at 5 years (91.1% in exemestane + OFS vs 87.3% in tamoxifen + 
OFS) and rate of freedom from breast cancer at 5 years (92.8% in exemestane+OFS vs 88.8% 
in tamoxifen+OFS) (Pagani 2014). Studies exploring the combination of third generation AIs 
and goserelin in metastatic premenopausal BC patients are shown below in Table 1-1. 
(Montagna 2013)
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal BC 
patients
Study
N
AI+goserelin (G)
ORR 
(CR+PR) (%)
CB 
(CR+PR+SD) 
(%)
TTP 
(months)
First line 
endocrine 
therapy
(Forward 2004)
16
Anastrozole+G
6.2
75
N/R
No
(Cheung 2010)
36
13
Anastrozole+G
Exemestane+G*
36
N/R
67
38
12
N/R
Yes
No
(Carlson 2010)
35
Anastrozole+G
37
72
8.3
Yes
(Park 2010)
35
Letrozole+G
46
77
9.5
Yes
(Yao 2011)
52
Letrozole+G
21
71
10
Yes/No
(Roche 2009)
33
Anastrozole+G
55
64
13
Yes
(Nishimura 2012)
37
Anastrozole+G
19
62
7.2
Yes/No
ORR=Objective response rate, CR=Complete response, PR=Partial response, CB=Clinical benefit, SD=Stable 
disease, PD=Progressive disease, TTP=Time to progression, N/R=Not reported
*In study by Cheung et al, patients received treatment with exemestane after they received treatment with 
anastrozole.
Although data are limited (Montagna 2013), clinical benefit of the combination of AIs and OFS 
in premenopausal women with advanced ER+ breast cancer has been shown in small phase II 
studies with letrozole and anastrozole. In one study (Cheung 2010), patients received 
exemestane, but only after they had received anastrozole, so the effect of single-agent 
exemestane has not been well characterized. Lastly, novel therapeutic approaches targeting 
promising pathways should be explored to further improve efficacy in premenopausal women 
with advanced HR+ breast cancer.


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1.1.3
Role of the CDK4/6 pathway in breast cancer
Cell cycle progression is directly regulated by cyclin-dependent serine-threonine protein 
kinases (CDKs). Extracellular growth and adhesion signals increase the level and function of 
cyclin D proteins within the cell. In turn, the cyclin D proteins associate with and activate CDK4 
and CDK6 (Musgrove et al 2011). CDK4 and CDK6 phosphorylation leads to inactivation of 
the retinoblastoma protein (pRb) and thus releases E2F which in turn leads to the transcription 
initiation of proteins involved in cell cycle propagation and cell proliferation. The luminal A 
and B subtypes of breast cancer (85% of which are ER+/HER2-negative) have high rates of 
cyclin D/CDK activation; in the luminal A and B subtypes, cyclin D1 (CCND1) amplifications 
were observed in 29% and 58%, and CDK4 amplifications were observed in 14% and 25% 
respectively (Holm et al 2012; The Cancer Genome Atlas Network 2012). Luminal A subtype 
tumors also have loss of CDKN2A, which encodes p16Ink4a, a CDK inhibitor (Beroukhim et 
al 2010). The luminal subtypes also maintain expression of Rb, which is essential for benefit 
from treatment with a CDK4/6 inhibitor (Thangavel et al 2011).
Dysregulation of cell cycle checkpoints is common in cancer. Modulating the cell cycle has 
always been an attractive therapeutic target in cancer, and previously published data have 
suggested that CDK4/6 inhibition may play a key role in the treatment of subsets of breast 
cancers. Patients with HR+ breast cancer exhibiting a gene expression signature of Rb loss had 
shorter recurrence-free survival following adjuvant tamoxifen (Bosco et al 2007). A tumor gene 
expression signature of E2F activation was associated with higher residual tumor cell 
proliferation following pre-surgical AI therapy. Therefore, activation of the CDK4/CDK6/E2F 
axis promotes endocrine resistance, and treatment with a CDK4/6 inhibitor or knockdown of 
CDK4 expression abrogates endocrine-resistant cell proliferation.
In conclusion, loss of cell cycle control is a hallmark of cancer, and aberrations in the 
cyclin/CDK/Rb pathway are common in breast cancer. Consequently, inhibition of this pathway 
at the level of CDK4/6 leads to reactivation of Rb and binding of E2F, thus leading to cell cycle 
arrest. Therefore, targeting the inhibition of this pathway is considered an attractive therapeutic 
strategy.
Additionally, preclinical and clinical data demonstrate that CDK4/6 inhibitors are active in 
advanced HR+ breast cancer. Palbociclib (PD 0332991) is a selective inhibitor of CDK4/6 that 
inhibits proliferation and induces apoptosis in preclinical models of endocrine-resistant breast 
cancer (Miller et al 2011, Thangavel et al 2011). Preclinical data with palbociclib demonstrated 
synergy with tamoxifen in ER+ breast cancer cell lines; moreover, palbociclib enhanced 
sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade (Finn et al 
2009).
Palbociclib in combination with fulvestrant for the treatment of patients with HR+ Her 2 -
advanced breast cancer who relapsed or progressed during prior endocrine therapy, resulted in 
prolonged progression free survival (median PFS was 9.5 months for palbociclib plus 
fulvestrant versus 4.6 months for the fulvestrant – placebo (HR 0.46; 95% CI: 0.36 - 0.59; 
P:<0.001)). In this study, women were eligible regardless of their menopausal status and up to 
1 line of prior chemotherapy in the context of advanced disease was allowed and the relative 
difference in progression-free survival between palbociclib and placebo was similar in 


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premenopausal or perimenopausal patients and postmenopausal patients (HR 0.50 and 0.45 
respectively) (Cristofanilli M 2015).
Selective inhibitors of CDK4/6, such as palbociclib and ribociclib, inhibit proliferation and 
induce apoptosis in preclinical models of endocrine-resistant breast cancer (Miller et al 2011; 
Thangavel et al 2011; [ribociclib Investigators Brochure]). Both palbociclib and ribociclib 
demonstrated synergy with endocrine treatments in preclinical studies and efficacy in clinical 
studies in patients with HR-positive, HER2-negative advanced BC (Finn et al 2009; [ribociclib 
Investigators Brochure]). Addition of palbociclib to letrozole improved median progression-
free survival (PFS) from 10.2 months to 20.2 months (hazard ratio 0.49, 95% CI: 0.32-0.75, 
p=0.0004) in a randomized, open-label, multicenter phase II study (Finn et al 2015) and from 
14.5 to 24.8 months (hazard ratio 0.58, 95% CI: 0.46-0.72, p=0.0001) in a phase III study in 
systemic non-adjuvant treatment-naïve postmenopausal women with ER-positive, HER2-
negative advanced BC (Finn et al 2016). In addition, in a phase III study in 521 patients with 
advanced HR-positive, HER2-negative BC that had relapsed or progressed during prior ET, 
addition of palbociclib to fulvestrant improved median PFS from 3.8 months to 9.2 months 
(hazard ratio 0.42; 95% CI: 0.32-0.56; p<0.001) (Turner et al 2015). Efficacy and safety of the 
combination of ribociclib and letrozole as first line treatment was evaluated in 668 
postmenopausal women with HR-positive, HER2-negative advanced BC in a phase III study 
[CLEE011A2301]. Ribociclib significantly improved PFS (hazard ratio 0.56, 95% CI: 0.43-
0.72, p = 0.00000329) (Hortobagyi et al 2016). Refer to the most recent [ribociclib Investigators 
Brochure] for more details.
Considering demonstrated efficacy of CDK4/6 inhibitors in the HR-positive, HER2-negative 
advanced BC, co-targeting the CDK4/6-Rb-E2F pathway with CDK4/6 inhibitors may be a 
viable strategy to enhance endocrine responsiveness and prevent or delay the development of 
acquired resistance.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
This study includes LEE011, tamoxifen, goserelin, anastrozole and letrozole as treatments.
1.2.1
Overview of LEE011
LEE011 is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that 
potently induces G1 arrest with sub-micromolar IC50’s in a variety of pRb-positive cancer cells. 
Please refer to the most recent [ribociclib Investigators Brochure] for more information.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Nonclinical pharmacology
In Jeko-1 MCL cells that overexpress cyclin D1 as a result of the t(11;14) chromosomal 
translocation, LEE011 inhibits the phosphorylation of pRb at CDK4/6-specific sites with an 
average IC50 of 60 nM. In nude rats bearing Jeko-1 subcutaneous xenografts, LEE011 
demonstrates dose-dependent target inhibition in the tumors. LEE011 doses that induce >75% 
inhibition of pRb phosphorylation in this model are associated with complete tumor regression.


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LEE011 also inhibits the growth of many other tumor cell types in vitro and in vivo, including 
liposarcoma, melanoma, rhabdoid cancer, and carcinomas of the esophagus, breast, lung and 
pancreas. Regardless of the various genetic aberrations that may be present in the cancer cells, 
the anti-tumor activity of LEE011 requires the presence of functional pRb. Refer to [LEE011 
Investigators Brochure] for more details.
Preclinical data with LEE011 in a primary model of ER+ breast cancer demonstrated synergy 
when given in combination with letrozole, showing complete and sustained inhibition of tumor 
growth (Figure 1-1).
1.2.1.1.2 Safety pharmacology and toxicology
In vivo cardiac safety studies demonstrated a signal for QT prolongation with the potential to 
induce incidences of premature ventricular contractions (PVCs) at higher exposure levels.
The effects of LEE011 on the bone marrow (hypocellularity), lymphoid system (lymphoid 
depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) and 
testes (atrophy) are considered to be related to the pharmacological inhibition of cell replication 
in these tissues due to CDK4/6 inhibition.
An increased number of ovarian corpora lutea was observed in a single female dog in the 4-
week toxicity study at the highest dose tested (20 mg/kg/day) and this effect could also be 
related to the pharmacology of LEE011 (arrest of estrous cycle).
The liver, bile system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder 
calculi and inspissated bile) and the kidney (concurrent degeneration and regeneration of 
tubular epithelial cells) were identified as additional target organs of toxicity which are not 
likely related to the primary pharmacology of LEE011.
Inflammatory changes in the lungs of dogs were considered secondary to aspiration of test 
article and are indicative of the irritant potential of the formulated test-article in the respiratory 
tract. Correlating hematological and/or biochemistry changes were seen for the effects 
described in the bone marrow, lymphoid system and liver.
Generally all changes demonstrated either reversibility or a clear tendency towards reversibility. 
In the rat, there was no evidence of teratogenicity however LEE011 was embryofetotoxic. Data 
from a rabbit embryofetal development study, shows that LEE011 is teratogenic in the rabbit in 
the absence of maternal toxicity.


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Figure 1-1
LEE011 in combination with letrozole in an ER+ primary breast cancer 
model
Mean tumor volumes in mice treated at clinically relevant doses for 56 days with LEE011 (75 mg/kg qd) 
alone; letrozole (2.5 mg/kg qd) alone; LEE011 (75 mg/kg qd) plus letrozole (2.5 mg/kg qd); or vehicle. 
The combination arm shows complete inhibition of tumor growth that was sustained for more than 30 
days of post-treatment observation.
1.2.1.1.3 Nonclinical pharmacokinetics and metabolism
The pharmacokinetics (PK) of LEE011 was investigated in mouse, rat, dog and monkey. 
LEE011 showed high clearance (CL) in the mouse, rat, dog and monkey. The volume of 
distribution was large across species and the terminal elimination half-life (T1/2) was moderate 
in rodents and monkey (~2 to 5 h) and longer in dog (18 h). Bioavailability was low to moderate 
in rat (37%) and cynomolgus monkey (17%); moderate in mouse (65%) and dog (64%). 
Following oral administration, time to reach maximal plasma concentrations (Tmax) occurred 
between 2 to 4 h across species. Gender dependent toxicokinetics were observed in rats with 
higher exposure to LEE011 in males as compared to females and higher exposure to the 
metabolite, LEQ803. Plasma protein binding was moderate in all species (unbound fraction (fu) 
in human: 30%).
In a rat ADME (absorption, distribution, metabolism and excretion) study, extensive 
distribution of [3H] LEE011 and its metabolites was observed. In pigmented rats, radioactivity 
was specifically found in melanin-containing structures; the highest exposure to total 
radiolabeled components was observed in eye ciliary body, eye choroid, meninges, tactile hair 
and hair follicles. Radioactivity was not detected in the brain. LEQ803 (N-demethylation) was 
a prominent metabolite found in mouse, rat, dog, monkey and human hepatocytes. This 
metabolite retains some pharmacologic activity and interacts with human Ether-a-go-go Related 
Gene (hERG) channels in vitro.
Results from the ADME (male rats) study showed that 3H-components were predominantly 
excreted with bile (61.4% of dose). Minor urinary excretion was observed (5.9% of dose after 
p.o.). The majority of the administered dose (87.3%) was excreted within 24 h via urine, feces 
(enteric secretion) and bile.


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In vitro, LEE011 was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 
CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. LEE011 may inhibit
CYP3A4 under therapeutic conditions. No induction of CYP1A2, CYP2B6 or CYP3A4 was 
observed. The in vitro inhibitory potency of LEE011 observed for the transporters OATP1B1 
(organic anion transporting polypeptide 1B1), BCRP (breast cancer resistance protein), OCT1 
(organic cation transporter 1), OCT2, MATE1 (multidrug and toxin extrusion protein 1), 
MATE2K and BSEP (bile salt export pump) may translate into clinically relevant inhibition at 
therapeutic doses. Elimination of LEE011 is dominated by oxidative metabolism mainly via 
CYP3A4 with a minor contribution by flavin-containing monooxygenase 3 (FMO3). The 
elimination of LEE011 may be affected by co-administered drugs that inhibit or induce 
CYP3A4. Although LEE011 is a substrate of the P-glycoprotein (P-gp) efflux transporter, this 
process is likely not clinically relevant due to the high passive permeability of LEE011.
1.2.1.2
Clinical experience of LEE011
LEE011 is currently being investigated in patients as a single agent in 3 phase I studies, in 2 
phase II studies and in combination in 15 studies: 12 phase Ib/II studies and 3 randomized phase 
III studies. Four studies were closed for enrollment: a randomized phase II study; a phase I dose 
finding study; a phase I study in malignant rhabdoid tumors and neuroblastomas; and a phase 
Ib/II study in BRAF mutant melanoma. LEE011 is also being investigated in 4 clinical 
pharmacology studies: 3 clinical pharmacology studies in healthy subjects have been completed. 
Details on ongoing studies can be found in the [LEE011 Investigator Brochure, Section 5.1 and 
Section 5.2].
In single agent trials, a total of 199 patients have been treated: 157 in study [CLEE011X2101]
as of 15-Jun-2015(in a Caucasian population, including 85 in the dose escalation), 17 in 
[CLEE011X1101] as of 28-Jan-2015 (in Japanese patients, all in the dose escalation) and 32 in 
[CLEE011X2102] as of 9-Apr-2015 (in patients under the age of 21 years, all in the dose 
escalation). Please refer to the [ribociclib Investigator Brochure] for more details.
The combination of LEE011 (600 mg) with letrozole (2.5 mg once daily) is being evaluated in 
an ongoing studies [CLEE011A2201], [CLEE011A2115C] and [CLEE011A2301].
1.2.1.3
Clinical safety of LEE011
As of 15-Jun-2015, 157 patients have been treated with single agent LEE011 in the first-in-
human (FIH) phase I study; 85 patients have been treated in the initial dose escalation part for 
the 3 week on/1 week off regimen and 47 patients in the dose expansion part of the study; 18 
patients were enrolled for the continuous dosing regimen with LEE011 and, 7 patients were 
enrolled in the liquid formulation cohort.
Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
LEE011 orally, once daily (qd) for 21 days followed by a 1-week rest (28-day cycle). Doses 
ranging from 50 mg to 1200 mg were evaluated on this schedule. Treatment has been 
discontinued in 120 (90%) patients; the primary reasons for treatment discontinuation were: 
disease progression (106 [80%] patients); AEs (7 [5%] patients); death (2 [1.5%] patients); 
withdrawal of consent (3 [2%] patient); and loss to follow up (1 [1%] patient).


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The most frequently reported AEs (≥10%), regardless of grade, causality and LEE011 dose 
were: nausea (52.3%); fatigue (40.9%); diarrhea (37.1%); vomiting (35.6%); neutropenia 
(34.1%); anemia (32.6%); decreased appetite (23.5%), thrombocytopenia (23.5%); white blood 
cell count decrease (22.7%); leukopenia (22%); constipation (21.2%); dyspnea (20.5%); 
asthenia (19.7%); cough (18.2%); hyperglycemia (17.4%); headache, hypoalbuminemia 
(16.7% each); ECG QT prolonged (15.9%); abdominal pain, back pain, lymphocyte count 
decrease, pyrexia (15.2% each); AST increase, blood creatinine increased, dizziness, 
lymphopenia (14.4% each), peripheral edema (13.6%), neutrophil count decreased (12.9%); 
ALT increase; pain in extremity (12.1% each) and hypocalcemia (11.4%).
For either continuous or intermittent dosing, the onset of neutropenia (most frequently Grade 
2) typically occurs by Day 15, reaching a nadir in the third or fourth week with recovery during 
the week of drug holiday for the three weeks on/one week off schedule. Some patients require 
additional time for recovery (7 to 14 days). QT changes become evident in the first cycle by 
Day 8 and later (once steady state is reached), are associated with the maximum drug levels 
between 1 to 8 h post-dose, and remain stable or improve in subsequent cycles.
As of 15-Jun-2015, asymptomatic Grade 2 QTcF prolongation was observed with increasing 
frequency when increasing the dose, starting at 600 mg: ten patients (13.5%) in the 600 mg 
cohort, three patients (21%) in the 750 mg cohort, four patients (31%) in the 900 mg cohort, 
and two patients (67%) in the 1200 mg cohort. Four patients (5.4%) at 600 mg and two patients 
(15%) at 900 mg had asymptomatic QTcF prolongation that resulted in a QTcF interval of 500 
ms or more. As compared to baseline value, QTcF prolongation was at least 30 msec in 2 
patients (50%) at 250mg, 2 (40%) at 350 mg and 400 mg, 59 (79.7%) at 600 mg, 11 (78.6%) at 
750 mg, 11 (85%) at 900 mg and 2 (67%) at 1200 mg; and at least 60 msec in 23%, 0%, 39% 
and 67% of patients at 600 mg, 750 mg, 900 mg and 1200 mg, respectively. One grade 1 
atrioventricular block of first degree was reported as related to LEE011 given at the dose of 140 
mg. No other cardiac abnormalities were observed as related adverse events in any patient.
There have been no deaths related to study drug reported on study [CLEE011X2101]. The 
following serious adverse events shown in Table 1-2 have been reported with a suspected causal 
relationship in study [CLEE011X2101] as of 6-Aug-2015. For a complete list of AEs, all grades 
and Grade 3/4 that are suspected to be related to LEE011 refer to the [ribociclib Investigator 
Brochure].


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Table 1-2
Serious adverse events with a suspected causal relationship with 
LEE011 single agent
Serious suspected adverse events which have occurred with LEE011 (single agent)
System Organ Class Preferred Term
Preferred Term
Blood and lymphatic system disorders
Anaemia, Febrile neutropenia,
Neutropenia,Thrombocytopenia
Gastrointestinal disorders
Diarrhoea, Nausea, Pancreatitis
General disorders and administration site conditions
Generalized oedema
Infections and infestations
Herpes simplex
Investigations
Blood creatinine increased, Electrocardiogram QT 
prolonged
Refer to [LEE011 Investigators Brochure] for more details.
1.2.1.4
Clinical efficacy of LEE011
Preliminary anti-tumor activity of LEE011 from an ongoing Phase I trial [CLEE011X2101]
was assessed across all dose levels (50 mg – 1200 mg). Out of 114 evaluable subjects, 3 partial 
responses were observed at the 600 mg dose level; one each in BRAF/NRAS wild type with 
CCND1 amplified melanoma, and head and neck acinar carcinoma with CDKN2A loss (both 
on the 3 weeks on/1 week off regimen), and ER+/HER2, PIK3CA mutant, CCND1 amplified 
breast cancer (on the continuous daily dosing regimen) [LEE011 Investigator Brochure].Stable 
disease (SD) was the best overall response in 41 (37%) patients. Stable disease ≥4 cycles and 
≥6 cycles was observed in 26 (24%) and 17 (15%) patients, respectively. Six patients with SD 
≥4 cycles received treatment for >1 year, of these 2 patients, were on study for >2 years (Jeffrey 
R Infante ASCO 2014 abstract 2528).
Refer to the [LEE011 Investigators Brochure] for the most recent details.
1.2.1.5
Clinical pharmacokinetics of LEE011
The pharmacokinetics of LEE011 have been evaluated following single and repeat daily doses 
in the ongoing single agent, phase I study in patients with advanced solid tumors or lymphomas 
[CLEE011X2101]. Following oral administration of LEE011, peak plasma concentrations 
(Cmax) are achieved at approximately 1-4 hours post-dose. LEE011 plasma exposure (Cmax 
and AUC0-24h) demonstrates slightly over-proportional increases across the dose range tested 
(50 to 1200 mg). Steady-state is generally reached by Day 8 and the mean effective T1/2 based 
on accumulation ratio (i.e., T1/2, acc) ranged from 12.3 to 42.9 hours across the dose range 
tested.
The mean accumulation ratio (Racc) calculated from AUC0-24h at steady-state and AUC0-24h 
after a single dose across the studied doses ranged from 1.35 to 3.11. At the recommended dose 
for future development (600 mg), steady-state plasma Cmax (n=56) ranges from 606-6170 
ng/mL (geometric mean = 1790 ng/mL or 4.1 µM), median Tmax (n=72) is 2.1 h, and AUC0-
24h (n=53) ranges from 6770-90600 ng*h/mL (geometric mean = 23600 h*ng/mL). At this 
dose, inter-patient variability in Cmax and AUC is 62% and 66%, respectively, as assessed by 
geometric mean percent coefficient of variation (% CV). At the 600 mg dose level, LEQ803, 
an active metabolite of ribociclib, accounted for approximately 8% (geometric mean) of 
ribociclib AUC0-24h after single and multiple doses.


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In the human ADME study [CLEE011A2102], a single oral dose of 600 mg [14C]LEE011 was 
administered to 6 healthy male subjects. The majority of the administered dose was excreted in 
feces (69.1%), with a minor amount excreted in urine (22.6%). Absorption was estimated to be 
approximately 58.8%. Ribociclib accounted for approximately 23% of the total radioactivity in 
plasma, based on AUCinf. Metabolites M1 (glucuronidation of M15), M4 (LEQ803, N-
demethylation) and M13 (CCI284, N-hydroxylation) were the most abundant metabolites in 
plasma, representing an estimated 7.78%, 8.60% and 9.39% of total [14C]AUC0-48h, and 
17.9%, 19.8% and 21.6% of ribociclib AUC0-48h, based on metabolite profiles.
In a food effect study [CLEE011A2111] in 24 healthy subjects, a single dose of LEE011 (600 
mg) was administered as drug-in-capsule (DiC) with a high-fat, high-calorie meal and under 
fasted conditions. Compared to the fasted state, oral administration of a single 600 mg dose of 
LEE011 DiC with a high-fat, high calorie meal decreased the rate of absorption resulting in a 
23% decrease in Cmax (geometric mean ratio: 0.775; 90% confidence interval [CI]: 0.700, 
0.858) and a median difference in Tmax of 2 hours. However, there was no effect on the extent 
of absorption as the overall exposure (AUCinf) was unaffected under fed conditions (geometric 
mean ratio: 0.994; 90% CI: 0.925, 1.070). A similar trend was observed for LEQ803, an active 
metabolite of LEE011, with a decrease in Cmax (32%), a delay in median Tmax, and no 
substantial effect on overall exposure. Results from this study indicate the DiC can be taken 
without regard to meals.
A DDI study with ritonavir (a strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 
inducer) was conducted in 48 healthy subjects [CLEE011A2101]. Compared to LEE011 alone, 
ritonavir (100 mg bid for 14 days) increased LEE011 Cmax and AUCinf by 1.7-fold and 3.2-
fold, respectively, following a single oral dose of 400 mg LEE011. Cmax and AUClast for 
LEQ803 decreased by 96% and 98%, respectively. These results demonstrated that concurrent 
use of strong CYP3A4 inhibitors may markedly increase LEE011 exposure and are prohibited.
Compared to LEE011 alone, rifampicin (600 mg daily for 14 days) decreased LEE011 Cmax 
and AUCinf by 81% and 89%, respectively, following a single oral dose of 600 mg LEE011. 
LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. These results 
demonstrated that concurrent use of strong CYP3A4 inhibitors or strong CYP3A4 inducers may 
markedly decrease LEE011 exposure and are prohibited. A DDI cocktail study with midazolam 
(a sensitive CYP3A4 substrate) and caffeine (a sensitive CYP1A2 substrate) conducted in 25 
healthy subjects [CLEE011A2106] indicated that LEE011 (400 mg) is a moderate inhibitor of 
CYP3A4, but did not have a substantial effect on CYP1A2 substrates in humans. PK data 
indicated that compared to midazolam and caffeine alone, multiple doses of LEE011 (400 mg 
qd for 8 days) increased midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. 
The effect of multiple doses of LEE011 on caffeine was minimal, with Cmax decreased by
approximately 10% and AUCinf increased slightly by 20%. Based on these data, LEE011 (400 
mg) is a moderate CYP3A4 inhibitor (≥ 2- fold but < 5-fold increase in AUC). Concurrent use 
of sensitive CYP3A4 substrates with a narrow therapeutic index is prohibited. LEE011 (400 
mg) did not have a substantial effect on CYP1A2 in humans; therefore concurrent use of 
CYP1A2 substrates is not expected to lead to clinically significant DDIs.
Refer to the [LEE011 Investigators Brochure] for more details.


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1.3
Overview of tamoxifen
Tamoxifen has been used for over 30 years to treat both pre- and postmenopausal women with 
HR+ breast cancer. Its antitumor effects are thought to be due to its anti-estrogenic activity, 
mediated by competitive inhibition of estrogen binding to ER (Osborne 1996). Adjuvant 
therapy with tamoxifen for 5 years resulted in a 34% reduction in the annual breast cancer death 
rate, with an absolute reduction in mortality of 9.2% at 15 years (Early Breast Cancer Trialists’ 
Collaborative Group 2005).
The recommended dose for treatment of breast cancer is 20 mg daily (Tamoxifen Prescribing 
Information). Tamoxifen is generally well tolerated and side effects are mainly attributable to 
estrogen deprivation. However, in some tissues, tamoxifen acts as an estrogen agonist, and these 
estrogenic effects may be beneficial or detrimental, depending on the target organ. For example, 
tamoxifen has favorable effects on bone health, lipid metabolism and the cardiovascular system, 
but long-term tamoxifen use is also associated with serious, potentially life-threatening adverse 
events, including invasive endometrial cancer and thromboembolic disease (Perez 2007).
Following oral administration of a single dose of tamoxifen (20 mg), Tmax was achieved 
approximately 5 hours post-dose and concentrations declined with a terminal elimination T1/2
of approximately 5-7 days. Steady-state is achieved for tamoxifen in approximately 4 weeks, 
while for its metabolite, N-desmethyltamoxifen, steady-state is achieved in approximately 8 
weeks (Tamoxifen Prescribing Information). Tamoxifen metabolism is complex and extensive 
after oral administration. Tamoxifen is a substrate of CYP3A4/5, CYP2D6, and CYP2C9 and 
an inhibitor of P-glycoprotein (P-gp) (Tamoxifen Prescribing Information). Tamoxifen is 
predominantly metabolized by CYP3A4/5 to N-desmethyltamoxifen. A minor route of 
metabolism occurs via CYP2D6 to form the pharmacologically active metabolite, 4-
hydroxytamoxifen. These metabolites are further metabolized to several secondary metabolites, 
one of which is the pharmacologically active metabolite, 4-hydroxy-desmethyltamoxifen 
(endoxifen), formed mainly via CYP2D6 from N-desmethyltamoxifen. The two 
pharmacologically active metabolites, 4-hydroxytamoxifen and endoxifen, are 30- to 100-fold 
more potent than tamoxifen in terms of ER binding affinity and effects on breast cancer cell 
proliferation and gene expression (Johnson 2004). In breast cancer patients, endoxifen plasma 
concentrations are 5- to 10-fold higher than 4-hydroxytamoxifen (Lien 1990; Stearns 2003), 
suggesting that endoxifen may contribute significantly to the overall response to tamoxifen 
therapy. However, it is also likely that the combined pharmacologic activity of tamoxifen and 
its active metabolites contribute to the clinical efficacy of tamoxifen (Johnson 2004).
Formation of the pharmacologically active metabolites (4-hydroxytamoxifen and endoxifen) 
occurs predominantly through CYP2D6 (Stearns 2003). Reduced CYP2D6 activity, either 
through genetic polymorphisms of the enzyme or through concomitant administration of drugs 
that 
are 
CYP2D6 
inhibitors, 
could 
lead 
to 
reduced 
exposure 
to 
endoxifen 
(Hoskins 2009; Stearns 2003). In addition, inhibition or induction of CYP3A4 may affect the 
metabolism of tamoxifen. Based on the prescribing information of tamoxifen, no dose 
adjustment is required for CYP2D6 poor metabolizers or for individuals taking medications that 
are strong inhibitors or inducers of CYP3A4. CYP2D6 poor metabolizer status has been 
associated with poorer invasive disease-free survival in tamoxifen treated patients in a number 
of studies, though not in others (Province 2014). The value of CYP2D6 genotyping in tamoxifen 
therapy is therefore still under investigation.


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For information on tamoxifen and management of potential tamoxifen related adverse events 
refer to the Tamoxifen SmPC or Prescribing Information.
1.4
Overview of non-steroidal aromatase inhibitors (NSAIs): letrozole 
and anastrozole
1.4.1
Overview of letrozole
Letrozole (Femara®) is a nonsteroidal competitive inhibitor of the aromatase enzyme system 
with demonstrated efficacy in the treatment of postmenopausal patients with HR+ breast cancer. 
Letrozole acts by inhibiting in a highly selective fashion the conversion of adrenal androgens 
to estrogens, which is the primary source of estrogens in postmenopausal women. Letrozole is 
a highly selective inhibitor of aromatase that induces a 75% to 95% decrease of estrogen levels 
after two weeks of treatment using daily doses of 0.1 to 5 mg, with no significant clinical and 
laboratory toxicities or changes in levels of other hormones of the endocrine system as shown 
in early phase I (Lipton 1995; Trunet 1996). It is indicated for the adjuvant treatment of
postmenopausal women with HR+ early breast cancer as well as the extended adjuvant 
treatment of patients who have received 5 years of tamoxifen therapy. It is also indicated for 
the treatment of advanced HR+ breast cancer, both in the first-line setting as well as in patients 
who have disease progression following anti-estrogen therapy. Letrozole was compared with 
tamoxifen in a phase III trial in the first line setting in ER+/HER2+ breast cancer. Letrozole 
was superior to tamoxifen for time to progression (median, 9.4 v. 6.0 months) and median OS 
trended superior for Letrozole (median, 34 versus 30 months) but this difference was not 
statistically significant (Mouridsen 2001).
Letrozole is administered orally once daily at a dose of 2.5 mg and is rapidly and completely 
absorbed from the gastrointestinal tract. Concomitant intake of food has no effect on the extent 
of Letrozole absorption and only a minor effect on the rate of absorption, which is considered 
to be of no clinical relevance. The terminal elimination half-life of letrozole is 2 days and 
steady-state plasma concentration with daily dosing at the standard dose is reached in 2-3 weeks. 
Letrozole is metabolized via CYP3A4 to a pharmacologically-inactive carbinol metabolite 
(4,4’-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this 
metabolite is the major pathway of letrozole clearance. In addition, CYP2A6 forms the carbinol 
metabolite as well as its ketone analog (Femara® Prescribing Information Novartis).
The most frequently reported adverse events that were significantly different from placebo for 
letrozole in the adjuvant and extended adjuvant setting include hot flashes, arthralgia/arthritis 
and myalgia. In the first line setting, the most frequently reported adverse events include 
musculoskeletal pain (bone/back pain and arthralgia), hot flashes, nausea and dyspnea and 
incidences of adverse events were similar for tamoxifen in this setting. In general, the observed 
adverse reactions are mild to moderate in nature (Femara® Prescribing Information Novartis).
Letrozole, when given as neoadjuvant treatment to women with unresectable hormone receptor 
positive early breast cancer, was associated with significantly higher response rate than 
tamoxifen (60% versus 48%, P=0.004) and a higher percentage of patients underwent breast 
conservative surgery (48% versus 36%, P=0.036) (Ellis 2001).


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For information on letrozole and management of letrozole related adverse events refer to the 
Femara® SmPC or Prescribing Information.
1.4.1.1
Clinical data with the combination of LEE011 and letrozole
Study [CLEE011X2107] is an ongoing multicenter phase Ib/II dose escalation/expansion study 
of LEE011 and BYL719 in combination with letrozole in adult patients with advanced ER+ 
breast cancer. Patients must be postmenopausal with metastatic or locally advanced ER+, 
HER2-negative breast cancer. Dose escalation is to occur in cohorts of 3-6 patients within one 
of the three treatment arms:

Letrozole (2.5 mg daily) plus LEE011 (Arm 1)

Letrozole (2.5 mg daily) plus BYL719 (Arm 2)

Letrozole (2.5 mg daily) plus LEE011 and BYL719 (Arm 3)
In the dose escalation phase, patients may have received any number of prior lines of hormonal 
treatment and less than or equal to one prior line of chemotherapy in the metastatic or locally 
advanced setting. Selection criteria include: absolute neutrophil count (ANC) > 1 x 109 g/dL, 
platelets > 100 x109/L, hemoglobin > 9 mg/dL, total bilirubin and creatinine < 1.5x ULN, and 
AST/ALT < 3 x the upper limit of normal (or ≤ 5x in the presence of liver metastases).
As of 2-Mar-2015, 98 patients have been enrolled to one of the following dose combinations:(1) 
LEE011 (600 mg) + letrozole (2.5 mg), n=41; (2) alpelisib (300 mg) + letrozole (2.5 mg),n=21; 
and (3) LEE011 + alpelisib + letrozole (2.5 mg), n=36. The median age of patients treated with 
LEE011 + letrozole was 58 (range: 38–76) years, all the patients were female, and the 
distribution of ECOG performance status of 0/1 at baseline was 24/17 patients, respectively. 
Among the 41 patients treated with LEE011 + letrozole, 23 were discontinued from the study 
(22 due to progressive disease, 1 due to adverse events) and 18 patients were still ongoing. The 
most frequent AE, regardless of grade, causality, was neutropenia (70.7%) and a total of two 
patients experienced dose limiting toxicities (DLTs) (Grade 4 neutropenia).
As of 15-May-2014, preliminary PK data for letrozole (2.5 mg qd) in the presence of LEE011 
(600 mg, qd, 3 weeks on/1 week off) on Day 1 and on Day 21 are summarized below. Mean
Cmax and AUC0-24h for LEE011 on Day 1 and at steady-state (Day 21) in the presence 
of letrozole are comparable to those observed for single agent LEE011 [CLEE011X2101] as 
shown in Table 1-3.
Mean Cmax and AUC0-24h for letrozole on Day 1 and at steady-state (Day 21) in the
presence of LEE011 are compared to the historical single agent data for letrozole as shown 
in Table 1-4.
Table 1-3
Preliminary pharmacokinetic data for LEE011 with and without 
letrozole
LEE011
(600 mg)
Single Dose or Day 1a
Repeat Dosesa
Cmax (ng/mL)
AUC0-24h 
(h*ng/mL)
Cmax (ng/mL)
AUC0-24h 
(h*ng/mL)
With letrozole 
(2.5 mg)b
1180 ± 664(1030)
[n=13]
11900 ± 4550
(11000)
[n=12]
2080 ± 800 (1930)
[n=10]
27600 ± 12300 
(2500) [n=8]


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LEE011
(600 mg)
Single Dose or Day 1a
Repeat Dosesa
Cmax (ng/mL)
AUC0-24h 
(h*ng/mL)
Cmax (ng/mL)
AUC0-24h 
(h*ng/mL)
Without 
letrozolec
1200 ± 718 (1030) 
[n=62]
11800 ± 7120
(10100)
[n=60]
2100 ± 1290 1790)
[n=47]
29200 ± 19300 
(24500)
[n=43]
a Values are mean ± SD (geometric mean) [n]
b Preliminary data (data cut-off: 15-May-2014) on Day 1 and Day 21 from combination study with letrozole 
(CLEE011X2107)
c Preliminary data (data cut-off: 28-Mar-2014) on Day 1 and Day 18 or 21 from single agent study with LEE011 
(CLEE011X2101)
Table 1-4
Preliminary pharmacokinetic data for letrozole with and without 
LEE011
Letrozole
(2.5 mg)
Single Dose or Day 1
Repeat doses
Cmax (ng/mL)
AUC0-24h 
(h*ng/mL)
Cmax (ng/mL)
AUC0-24h (h*ng/mL)
With LEE011 
(600 mg)a
22.4 ± 5.66 (21.8) 
[n=13]
352 ± 71.1(346) 
[n=12]
95.3 ± 45.1(88) 
[n=10]
1720 ± 581 (1640) [n=9]
Without 
LEE011b
39.3 ± 9.47 [n=20]c
37.3 ± 10.9 [n=20]c
30.5 ± 11.2 [n=27]d
43.2 ± 16.1 [n=12]e
32.4 ± 5.50 [n=10]e
559 ± 191 [n=12]e
465 ± 88 [n=12]e
133 ± 69.5 [n=24]d
186 ± 59.1 [n=12]e
152 ± 52.8 [n=10]e
2547 ± 1388 [n=24]d
3709 ± 1182 [n=12]e
3297 ± 1268 [n=10]e
2677 ± 1073 [n=14]f
a Values are mean ± SD (geometric mean) [n] for preliminary data (data cut-off: 15-May-2014) on Day 1 and 
Day 21 from study (CLEE011X2107)
b Values are mean ± SD for letrozole published data with some values back-calculated from molar 
concentrations
c Filipe et al. 2008; single dose in healthy volunteers (two different formulations)
d Pfister et al. 2001; single vs multiple dose in breast cancer patients (8 weeks)
e Tanii et al. 2011; population PK after 2 or 4 weeks administration in Japanese postmenopausal women
f Dowsett et al. 1999; multiple dose in postmenopausal women with breast cancer (6 weeks)
The safety and efficacy profile of ribociclib in combination with letrozole was investigated in 
a randomized clinical trial of ribociclib and letrozole versus placebo and letrozole 
[CLEE011A2301] in 668 treatment-naive postmenopausal women with HR-positive, HER2-
negative, advanced BC. Most common treatment-emergent AEs reported in the ribociclib arm 
in this study occurring in >30% of patients were neutropenia (74.3%), nausea (51.5%), 
infections (50.3%), fatigue (36.5%), diarrhea (35.0%), alopecia (33.2%) and leukopenia 
(32.9%). The most common grade 3 or 4 AEs reported in ≥5 % of patients in the ribociclib arm 
were neutropenia (59.3%), leukopenia (21.6%), hypertension (9.9%), increased alanine 
aminotransferase (9.3%), lymphopenia (6.9%) and increased aspartate aminotransferase (5.7%). 
Febrile neutropenia occurred in 1.5% of the patients in the ribociclib arm. Four patients (1.2%) 
met the biochemical and clinical criteria for Hy’s Law with 3 reported as treatment-related and 
all 4 returning to normal values after treatment discontinuation. Eleven patients (3.3%) 
presented on treatment QTcF prolongation >480 msec. Serious AEs were reported in 21.3% of 
patients in the ribociclib arm with 7.5% of serious AEs deemed by investigators as treatment-
related. There were 3 fatal events in the ribociclib arm (disease progression, sudden death, 
unknown cause) with 1 AE (sudden death) reported as treatment-related in a patient that had 
grade 3 hypokalemia and grade 2 QTcF prolongation (483 msec). Neutropenia, QT interval 
prolongation and hepatobiliary toxicity are considered to be important identified risks for 


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ribociclib which appear to be manageable and reversible with adequate monitoring, interruption 
and/or reduction of ribociclib dosing.
Ribociclib improved PFS (hazard ratio 0.56, 95% CI: 0.43-0.72, p=0.00000329). The 
investigator-reported overall response rate was 40.7% (95% CI: 35.4%-46.0%) in the ribociclib 
arm and 27.5% (95% CI: 22.8%-32.3%) in the placebo arm (p=0.000155) in the full analysis 
set; and 52.7% (95% CI: 46.6%, 58.9%) and 37.1% (95% CI: 31.1%, 43.2%) (p=0.00028) in 
patients with measurable disease at baseline (Hortobagyi et al 2016).
Refer to the most recent [ribociclib Investigators Brochure] for additional details of the safety 
and efficacy profile of ribociclib in combination with letrozole.
1.4.2
Overview of anastrozole
Anastrozole (Arimidex®) is a selective non-steroidal aromatase inhibitor. It significantly lowers 
serum estradiol concentrations and has no detectable effect on formation of adrenal 
corticosteroids or aldosterone.
Anastrozole is indicated for adjuvant treatment of 
postmenopausal women with early HR+ breast cancer and first line and second line treatment 
of postmenopausal women with advanced HR+ breast cancer.
Anastrozole is administered orally once daily at a dose of 1 mg. Absorption of anastrozole is 
rapid and Cmax typically occurs within 2 hours of dosing under fasted conditions. The mean 
Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours 
when anastrozole was administered 30 minutes after food. Plasma concentrations approach 
steady-state levels after approximately 7 days of once daily dosing. The major circulating 
metabolite of anastrozole lacks pharmacologic activity. Anastrozole inhibited reactions 
catalyzed by CYP1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 
times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. 
Anastrozole had no inhibitory effect on reactions catalyzed by CYP2A6 or 2D6 in vitro. Hepatic 
metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination 
accounts for approximately 10% of total clearance. The mean elimination half-life of 
anastrozole is 50 hours. (Arimidex® Prescribing Information). Current treatment guidelines 
consider there is no compelling evidence showing meaningful efficacy or toxicity differences 
between the AIs letrozole, anastrozole and exemestane (NCCN breast cancer guidelines version 
3.2014)
For information on anastrozole and management of anastrozole related adverse events refer to 
the Arimidex® SmPC or Prescribing Information.


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1.5
Overview of goserelin
Goserelin (Zoladex®) is a synthetic decapeptide analog of gonadotropin releasing hormone 
(GnRH) indicated for prostatic carcinoma, endometriosis, endometrial thinning, and advanced 
breast cancer. Goserelin is administered subcutaneously every 28 days at a dose of 3.6 mg. 
Following subcutaneous administration of goserelin (3.6 mg for 2 months), Tmax was 12-15 
days post-dose in males and 8-22 days post-dose in females. The metabolism of goserelin is not 
CYP-mediated; rather it is metabolized by hydrolysis of C-terminal amino acids. More than 90% 
of a radiolabeled dose was excreted in the urine, with approximately 20% of the dose in urine 
accounted for by unchanged goserelin. The adverse events occurring in > 20% of women 
included hot flushes, headache, sweating, acne, emotional lability, depression, decreased libido, 
vaginitis, breast atrophy, seborrhea and peripheral edema (Zoladex® Prescribing Information).
For information on goserelin and management of goserelin related adverse events refer to the 
Zoladex® SmPC or Prescribing Information.
1.6
Potential for drug-drug interactions
No combinations of LEE011 and tamoxifen + goserelin or LEE011 and a NSAI + goserelin 
have been evaluated in the clinic to date.
1.6.1
Potential for a drug-drug interaction between LEE011 and tamoxifen
The prescribing information for tamoxifen suggests that tamoxifen may affect the metabolism 
of co-administered drugs. A significant increase in anticoagulant effect may occur when 
tamoxifen is co-administered with coumarin-type anticoagulants. These medications should be 
avoided if possible, otherwise careful monitoring of prothrombin time is recommended. In 
addition, tamoxifen has been shown to reduce letrozole plasma concentrations following co-
administration (Tamoxifen Prescribing Information).
Tamoxifen could potentially affect the metabolism of co-administered drugs that are substrates 
for CYP3A4 since in vitro data indicate tamoxifen is a reversible and time-dependent inhibitor 
of CYP3A4 (Zhao et al 2002) as well as an inducer of CYP3A4 (Desai et al 2002). LEE011 is 
mainly metabolized by CYP3A4 with a minor contribution by FMO3 based on in vitro data. 
Clinical drug interactions studies of tamoxifen and drugs that are mainly metabolized by 
CYP3A4 (e.g., gefitinib, palbociclib) resulted in no significant changes in exposure in the 
presence of steady-state levels of tamoxifen when compared with exposures when given alone 
(Cantarini et al 2005, Hoffman et al 2014). Therefore, based on these in vivo data, tamoxifen is 
not expected to affect LEE011 PK due to CYP-mediated interactions.
Tamoxifen is also an inhibitor of P-gp (Tamoxifen Prescribing Information) and could 
potentially affect substrates of this transporter. However, since LEE011 is a low-affinity 
substrate of P-gp with moderate permeability, LEE011 PK is not expected to be significantly
affected by inhibition of P-gp by tamoxifen.
LEE011 may increase the exposure of co-administered drugs that are substrates for CYP3A4 
due to time-dependent inhibition of the enzyme. In vitro studies indicate LEE011 is a reversible 
(Ki = 35 μM) and time-dependent inhibitor (KI = 5.06 μM, kinact = 0.0245 min-1) of CYP3A4. 
Tamoxifen is a substrate of CYP3A4/5, CYP2D6, and CYP2C9 (Nolvadex® Prescribing 
Information). In vitro, troleandomycin and ketoconazole (CYP3A4 inhibitors) reduced the 


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formation of N-desmethyltamoxifen (Stearns 2003); however the clinical significance is 
unknown. No clinical studies have been conducted to evaluate the effect of a strong inhibitor of 
CYP3A4/5 on the PK of tamoxifen. However, the effect of co-administration of strong 
CYP3A4/5 inducers (e.g., rifampicin, aminoglutethimide) with tamoxifen has been evaluated 
and resulted in reduced concentrations of tamoxifen and its metabolites (Lien 1990; Binkhorst 
2012). Based on this information, a potential DDI with co-administration of LEE011 cannot be 
fully excluded.
Simcyp modeling was conducted using in vitro and clinical data to estimate the magnitude of 
the potential DDI between tamoxifen and LEE011. A loading dose of tamoxifen (160 mg) 
followed by 20 mg tamoxifen daily was simulated to rapidly achieve steady-state levels of 
tamoxifen, after which LEE011 was added to the model at 600 mg dose daily for 21 days. At 
steady-state for both compounds, LEE011 (600 mg) was predicted to increase the exposure 
(AUC) of tamoxifen (20 mg) by 1.9- to 2.5-fold. Conversely, the modeling predicted a weak 
effect of tamoxifen on LEE011 exposure at steady-state, consistent with clinical observations 
from DDI studies with tamoxifen and CYP3A4 substrates (Cantarini et al 2005, Hoffman et al 
2014). The effect of LEE011 on the formation of the active metabolites of tamoxifen are 
unknown, therefore tamoxifen metabolites will be monitored in patients (as described in Section 
7).
1.6.2
Potential for drug-drug interaction between LEE011 and NSAIs 
(letrozole, anastrozole)
Letrozole and anastrozole are not expected to affect the metabolism of LEE011, which is mainly 
metabolized by CYP3A4 with a minor contribution by FMO3 based on in vitro data. Letrozole 
inhibits CYP2A6 (Ki = 4.6 µM) and CYP2C19 (Ki = 42 µM) in vitro (Jeong 2009); (Femara®
Prescribing Information), but is not an inhibitor of CYP3A4 or FMO3 and is therefore not 
expected to affect LEE011 metabolism. See Section 1.4.1.1 for preliminary clinical PK data for 
the combination of LEE011 (600 mg) and letrozole (2.5 mg).
Anastrozole inhibits reactions catalyzed by CYP1A2, CYP2C8/9, and CYP3A4 based on in 
vitro data, with Ki values that are approximately 30-fold higher than the mean steady-state 
Cmax values observed following 1 mg daily dosing of anastrozole. Anastrozole has no 
inhibitory effect on reactions catalyzed by CYP2A6 or CYP2D6 in vitro. Based on in vitro and 
in vivo results, it is unlikely that co-administration of anastrozole at 1 mg will affect other drugs 
as a result of CYP-mediated inhibition. (Arimidex® Prescribing Information).
LEE011 may increase the exposure of co-medications due to time-dependent inhibition of 
CYP3A4. In vitro studies indicate LEE011 is a reversible inhibitor of CYP3A4 (Ki = 35 μM) 
and a time-dependent inhibitor of CYP3A4 (KI = 5.06 μM, kinact = 0.0245 min-1). Letrozole is 
metabolized via CYP3A4 and CYP2A6 (Femara® Prescribing Information) and hence letrozole 
concentrations could be affected by co-administration with LEE011. Preliminary PK data for 
the combination of LEE011 (600 mg) and letrozole (2.5 mg) from a limited number of patients
indicate LEE011 and letrozole exposures are within the range of values observed for single 
agent LEE011 (Table 1-3) and letrozole (Table 1-4), respectively, and the combination is safe 
and tolerable (see Section 1.4.1.1).


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Anastrozole is metabolized by N-dealkylation, hydroxylation and glucuronidation. Anastrozole 
metabolism occurs mainly via CYP3A4 and UGT1A4 based on in vitro data (Kamdem et al 
2010). Therefore, anastrozole metabolism could be affected by coadministration of LEE011. 
However, anastrozole has been studied up to doses of 10 mg/day and all doses evaluated were 
well tolerated with no serious adverse events attributed to anastrozole (Plourde 1995). Therefore, 
LEE011 at 600 mg in combination with anastrozole at 1 mg is expected to be well tolerated in 
this study.
1.6.3
Low potential for drug-drug interactions with goserelin
The metabolism of goserelin is not CYP-mediated; rather hydrolysis of C-terminal amino acids 
is the major clearance mechanism. No formal clinical DDI studies have been conducted or 
reported with goserelin. Based on the available information, goserelin is not expected to affect 
the metabolism of nor be affected by co-administered drugs (Zoladex® Prescribing Information).
2
Rationale
2.1
Study rationale and purpose
Endocrine treatment is a standard treatment option for premenopausal women with advanced 
breast cancer. Patients commonly receive tamoxifen, either alone or in combination with an 
OFS agent, such as goserelin, which is approved for the palliative treatment of premenopausal 
and perimenopausal advanced breast cancer. Patients with advanced breast cancer may also 
receive OFS in combination with a hormonal treatment other than tamoxifen, such as AIs, 
similar to what postmenopausal women typically receive. Despite several treatment options, 
resistance to endocrine therapy and disease progression occur. There is a need for new 
therapeutic options targeting additional molecular pathways involved in breast cancer 
pathogenesis. This study will investigate LEE011 in combination with the two most accepted 
endocrine treatment options, therefore giving patients and treating physicians a choice of 
endocrine therapy.
Dysregulation of cell cycle checkpoints is common in cancer, including breast cancer. 
Preclinical data suggests that CDK4/6 inhibition may play a key role in the treatment of subsets 
of breast cancer by, for example, abrogating endocrine-resistant cell proliferation. Therefore, 
the addition of a CDK4/6 inhibitor such as LEE011 to standard endocrine therapy (tamoxifen 
and goserelin or letrozole/anastrozole and goserelin) is a promising therapeutic approach that 
will be explored in this study.
Letrozole and anastrozole are the two AIs that will be included in the study because they are 
the AIs that have been most widely studied in the postmenopausal setting.


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2.2
Rationale for the study design
This is a randomized, placebo-controlled two-arm study with the objective to evaluate the effect 
of adding LEE011 to tamoxifen and goserelin or a NSAI and goserelin in premenopausal 
patients with advanced breast cancer. The randomized, double-blind, placebo-controlled, 
multicenter, parallel group design is the gold standard design for phase III trials as it minimizes 
allocation bias, balancing both known and unknown prognostic factors in the assignment of 
treatments.
Randomization is stratified by the following factors:
1. Lung or liver metastases: (yes versus no)
2. Prior chemotherapy for advanced disease: (yes versus no)
3. Endocrine combination partner (tamoxifen and goserelin versus NSAI (letrozole or 
anastrozole) and goserelin)
The first two stratification factors are selected because of their well-recognized prognostic value 
and the third factor is selected to balance randomization within the two endocrine therapy 
groups.
2.3
Rationale for dose and regimen selection
The LEE011 dose and regimen selected for this study is 600 mg QD 21 days on/7 days off. In 
the FIH study of single agent LEE011 in adult patients with solid tumors [CLEE011X2101], 
the MTD of LEE011 was 900 mg QD with a 3 weeks on/1 week off schedule. The recommended 
dose for future development was 600 mg QD with a 3 weeks on/1 week off schedule, which 
showed an acceptable safety profile, lower risk for QTcF prolongation, adequate exposure, and 
preliminary evidence of disease stabilization with single agent. In the phase III study of 
LEE011/placebo (600 mg) combined with letrozole (2.5 mg once daily) in postmenopausal 
women with advanced breast cancer HR+ HER-2 negative [CLEE011A2301] the most recent 
DMC took place on October 7, 2015 and reviewed safety of 664 patients recommending to 
continue the study without changes.
The marketed drugs used in this study will be administered at doses according to their approved 
label. Based on available data, there is low probability of DDIs between LEE011 and other 
study treatments (Section 1.6), so approved doses will be used in this study.
The standard dose and regimen of tamoxifen will be used in this study (20 mg daily). Tamoxifen 
has been studied in metastatic melanoma patients at doses up to 240 mg daily (McClay 2001) 
and 320 mg daily (O’Day 2001) in combination with standard therapies, without reported dose-
limiting toxicities (DLT). At tamoxifen doses of 280 mg daily with cisplatin, the DLT was 
primarily hematologic (thrombocytopenia and septic neutropenia) and gastrointestinal. There 
were no episodes of thrombosis, except in patients with central venous catheters (McClay 2001; 
O’Day 2001). The combination of LEE011 (600 mg) with the well-established tamoxifen dose 
of 20 mg daily and goserelin, even in the event of a potential increase in tamoxifen exposure, 
is expected to be generally well tolerated.
The standard daily doses of NSAIs will be used in this study (2.5 mg letrozole or 1 mg 
anastrozole). Letrozole has been used in the clinic at doses up to 7.5 mg/day and studied at 
doses up to 12.5 mg/day. The observed toxicity at these higher dose levels was similar to that 


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at the dose level of 2.5 mg (Pritts 2011; Dixon 2001). Preliminary results from patients treated 
with the combination of LEE011 at 600 mg and letrozole at 2.5 mg suggest that the combination 
is tolerable. Anastrozole has been studied up to doses of 10 mg/day and all doses evaluated 
were well tolerated with no serious adverse events attributed to anastrozole (Plourde 1995). 
Therefore, LEE011 at 600 mg in combination with anastrozole at 1 mg is expected to be well 
tolerated in this study.
The standard dose of goserelin of 3.6 mg subcutaneously every 28 days will be used in this 
study as goserelin is not expected to affect the metabolism of nor be affected by co-
administration of other drugs.
2.4
Rationale for choice of combination drugs
Expression of the ER and/or PgR is one of the most important prognostic factors in invasive 
breast cancer and is detected in approximately 70% of cases. Estrogen deprivation therapy is 
the core treatment modality in patients with HR+ advanced breast cancer. Endocrine therapy 
options for premenopausal women with ER+ advanced breast cancer (locally advanced, 
recurrent, or metastatic breast cancer) include selective ER modulators (SERM; e.g. tamoxifen, 
raloxifene), and luteinizing hormone-releasing hormone agonists (LHRHa; e.g. goserelin).
Blocking estrogen signaling with tamoxifen has been the main approach in treatment for 
premenopausal women with ER+ breast cancer for over 35 years. Current guidelines also 
recommend treating premenopausal women with advanced HR+ breast cancer with an ovarian 
function suppression treatment and following treatment recommendations for post-menopausal 
women, such as non-steroidal AIs (NCCN breast cancer guidelines version 3.2014).
Ovarian suppression of estrogen release with LHRH agonists such as goserelin is effective in 
preventing relapse in premenopausal women with early stage ER+ breast cancer
(Klijn 2001). A meta-analysis of four randomized trials of combined tamoxifen and a LHRH 
agonist versus LHRH agonists alone demonstrated that the combination was superior to the 
LHRH 
agonist 
alone
in 
premenopausal 
women 
with 
advanced 
breast 
cancer 
(see Section 1.1.2).
Overexpression of cyclin D1 is seen in the majority of breast cancers, likely activating the 
CDK4/CDK6/E2F axis and promoting endocrine resistance. Therefore, using a CDK4/6 
inhibitor to block this activity may enhance efficacy of current treatment strategies 
(Yu 2006). Preclinical data with CDK4/6 inhibitors including LEE011 suggest a synergistic 
effect when the CDK4/6 pathway is inhibited in combination with anti-endocrine treatment 
(Section 1.1.3). Therefore, a combination approach of endocrine therapy and CDK4/6 inhibitors 
is a promising therapeutic approach in this patient population.
Additionally, clinical data from a Phase II open-label randomized trial of letrozole with or 
without palbociclib, a CDK4/6 inhibitor, showed that post-menopausal women treated with the 
combination achieved a statistically significant improvement in median progression PFS
compared to women who received letrozole alone (20.2 months and 10.2 months, respectively) 
and that the combination was well tolerated (Finn 2014). These data, although using another 
investigational agent belonging to the same class as LEE011, also support the investigation of 
the combination of the class of CDK4/6 inhibitors with hormonal agents such as letrozole and 
others.


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To determine whether treatment with tamoxifen or a 
NSAI + goserelin + LEE011 prolongs PFS compared 
to treatment with tamoxifen or a NSAI + goserelin + 
placebo in premenopausal women with HR+, HER2-
negative advanced breast cancer
The primary endpoint is PFS per local assessment and 
RECIST 1.1
Key secondary
Refer to Section 10.5.1
To determine whether treatment with tamoxifen or a 
NSAI + goserelin + LEE011 prolongs OS compared to 
treatment with tamoxifen or a NSAI + goserelin + 
placebo in premenopausal women with HR+, HER2-
negative advanced breast cancer.
OS
Other secondary
Refer to Section 10.5
To evaluate the safety and tolerability of LEE011 in 
combination with tamoxifen + goserelin or a NSAI + 
goserelin.
Frequency/ severity of adverse events, lab abnormalities
To evaluate the two treatment arms with respect to 
response rate and clinical benefit rate (CBR).
ORR as defined by RECIST 1.1. CBR, defined as 
percentage of patients with CR, PR per RECIST 1.1 or 
SD lasting 24 weeks or longer
To describe time to response (TTR) and duration of 
response (DOR) in each treatment arm.
Time to response and duration of response per RECIST 
1.1
To evaluate the two treatment arms with respect to 
time to deterioration of ECOG PS
Time to definitive deterioration of the ECOG PS from 
baseline
To evaluate patient reported outcomes for health-
related quality of life in the two treatment arms.
Time to 10% deterioration in the global health 
status/QOL scale score of the EORTC QLQ-C30
Change from baseline in the global health status/QOL 
scale score of the EORTC QLQ-C30


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Objective
Endpoint
Analysis


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Objective
Endpoint
Analysis


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4
Study design
4.1
Description of study design
This is a phase III randomized, double-blind, placebo-controlled global study comparing the 
combination of tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + LEE011 to 
tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + placebo in premenopausal women 
with HR+, HER2-negative advanced breast cancer. The study will consist of a 28-day screening 
phase, treatment phase which includes safety follow up, and post-treatment phase which 
includes the efficacy and survival follow up described in Figure 4-1.
Approximately 660 patients will be randomly assigned to one of the below treatment arms in 
1:1 ratio:
a. Tamoxifen (20 mg orally once daily) + goserelin (3.6 mg subcutaneously every 28 days) 
or NSAI (letrozole 2.5 mg orally once daily or anastrozole 1 mg orally once daily) + 
goserelin (3.6 mg subcutaneously every 28 days) + LEE011 (600 mg orally once daily on
days 1 to 21 in a 28 day cycle).
OR,
b. Tamoxifen (20 mg orally once daily) + goserelin (3.6 mg subcutaneously every 28 days) 
or NSAI (letrozole 2.5 mg orally once daily or anastrozole 1 mg orally once daily) + 
goserelin (3.6 mg subcutaneously every 28 days) + placebo (orally once daily on days 1 to 
21 in a 28 day cycle).
Randomization will be stratified by the presence of liver and/or lung metastases (yes versus no), 
prior chemotherapy for advanced disease (yes versus no), and Endocrine combination partner 
(tamoxifen and goserelin versus NSAI (letrozole or anastrozole) and goserelin).
Treatment with tamoxifen or NSAI in this study will be based on the patient’s prior (neo) 
adjuvant therapy for breast cancer:

If the patient has not received any prior endocrine therapy OR if ≥12 months have 
elapsed since the patient’s last dose of (neo) adjuvant therapy, then the patient is eligible 
to receive tamoxifen + goserelin OR a NSAI + goserelin for advanced breast cancer based 
on the investigator’s choice.

If tamoxifen or fulvestrant was the last prior (neo) adjuvant therapy and the last dose was 
given < 12 months prior to randomization, then the patient is eligible to receive a NSAI 
(letrozole or anastrozole) + goserelin for advanced breast cancer.

If letrozole, anastrozole, or exemestane was the last prior (neo) adjuvant therapy and the 
last dose was given < 12 months prior to randomization, then the patient is eligible to 
receive tamoxifen + goserelin for advanced breast cancer.

The choice of which NSAI (letrozole or anastrozole) to be used on study is left to the 
investigator’s choice.
PFS, as assessed by the local radiologists/investigators and using RECIST 1.1 criteria will be 
the primary endpoint. PFS as assessed through blinded independent central review will be used 
for supportive evidence of the primary efficacy endpoint.


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An independent data monitoring committee (IDMC) will be constituted and will monitor safety 
data as outlined in Section 8.6. A Steering Committee (SC) will be established, comprising of 
investigators and Novartis personnel participating in the trial, to ensure transparent management 
of the study according to the protocol through recommending and approving modifications as 
outlined in Section 8.7.
Following the statistically significant OS benefit demonstrated at the second OS analysis, with 
protocol amendment 6, study participants are unblinded, with an opportunity for those patients 
still on study treatment in the placebo combination arm to cross-over to the LEE011 
combination arm. Crossover is optional and will be conducted only upon documented consent 
of the study patient. The study will be closed when all study patients have either discontinued 
study treatment and completed the safety follow-up period, withdrawn consent, are lost to 
follow-up, or as soon as arrangements are made for ongoing access to study treatment for all 
patients still on study treatment, whichever happens first. 
Figure 4-1
Study design
a.
Treatment with tamoxifen or NSAI will be based on the patient’s prior hormonal adjuvant 
therapy.
b. After discontinuation of study treatment, all patients will be followed for safety for at least 
30 days except in case of death, loss to follow-up or withdrawal of consent.
c.
Efficacy follow up is through tumor assessment and for selected patient reported outcomes
every 8 weeks during the first 18 months and every 12 weeks thereafter until disease 
progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision.
d. Survival follow-up will be done every 12 weeks until at least 252 deaths have been 
documented.
* Following Protocol Amendment 6, study participants are unblinded, with an opportunity for those 
patients still on study treatment in the placebo combination arm to cross-over to the LEE011 
combination arm. Crossover is optional and will be conducted only upon documented consent of the 
study patient.


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4.1.1
Screening phase
Premenopausal women with HR+, HER2-negative advanced breast cancer will be screened for 
eligibility during the period up to 28 days immediately prior to starting the combination of 
tamoxifen or a NSAI + goserelin + LEE011 or tamoxifen or a NSAI + goserelin + placebo on 
study Day 1. During this time, the inclusion and exclusion criteria will be assessed and all 
screening assessments, laboratory tests, and procedures will be performed. Requested tissue 
will be retrieved, if available. Results of all screening/baseline evaluations must be reviewed 
by the investigator or his/her designee prior to patient enrollment into the study in order to 
assure that all inclusion and exclusion criteria have been satisfied.
All study patients must be thoroughly informed about all aspects of the study, including the 
study agents, visit schedule, required evaluations, and all regulatory requirements for informed 
consent. The signed informed consent must be obtained to participate in this study prior to the 
performance of any study-related activities. If the patient is unable to read, an impartial witness 
should be present during the entire informed consent discussion.
Eligibility will be determined according to the inclusion/exclusion criteria as described in 
Section 5. A list of procedures to be performed at the time of screening is summarized in Table 
7-1a. Patients must meet all eligibility criteria to be considered for enrollment in the study.
4.1.2
Treatment phase
Patient eligibility will be checked once all screening procedures are completed. The eligibility 
check will be embedded to the Interactive Response Technology (IRT) system. Please refer and 
comply with detailed guidelines in the IRT manual. IRT system will confirm the inclusion of 
eligible patients and randomly assign patients to one of the two treatment arms in a 1:1 ratio 
(see Section 4.1).
Patients may continue study treatment until disease progression, occurrence of unacceptable 
toxicity, withdrawal of consent by the patient, patient is lost to follow-up, or the sponsor 
terminates the study. Patients will be followed for survival regardless of treatment 
discontinuation for any reason, and regardless of achieving the primary endpoint, until the 
planned number deaths for final OS analysis have been documented (except if consent is 
withdrawn or patient is lost to follow-up).
4.1.3
Safety follow-up
After discontinuation of study treatment, all patients will be followed for safety for at least 30 
days except in case of death, loss to follow-up or withdrawal of consent. For details please refer 
to Section 7.
4.1.4
Efficacy follow-up
Patients who discontinue treatment for reasons other than disease progression will continue to 
be followed every 8 weeks for efficacy (i.e., tumor assessments and selected patient reported 
outcomes) during the first 18 months and every 12 weeks until 36 months, then change to as 
clinically indicated until disease progression, death, withdrawal of consent, loss to follow-up, 
or subject/guardian decision. If a patient starts a new antineoplastic treatment without 
withdrawing consent, the patient should continue to be followed for efficacy according to above 


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specified protocol schedule until disease progression, death, withdrawal of consent, loss to 
follow-up, or subject/guardian decision. For further details please refer to Table 7-1a and
Section 7.
4.1.5
Survival follow-up
All patients will be followed for survival once they discontinue study treatment and efficacy
evaluations until the final number of OS events have been reached or the study is stopped for 
other reasons. Survival follow-up will be conducted every 12 weeks or earlier if a survival 
update is required to meet safety or regulatory needs. Survival information can be obtained by 
clinical visits or telephone calls until death, the patient is lost to follow-up, or the patient 
withdraws consent for survival follow-up.
During the survival follow up, in addition to vital status, all subsequent anti-neoplastic therapies 
initiated after study treatment discontinuation will be collected along with the start/end date and 
date of disease progression on subsequent therapies
 
4.2
Timing of interim analyses and design adaptations
There is no planned efficacy interim analysis for the primary PFS endpoint. Interim analyses 
for OS will be conducted if PFS is statistically significant as detailed in Section 10.5.1 and 
Section 10.7.2.
4.3
Definition of end of the study
The end of treatment (EOT) for a given patient is defined as when the patient permanently 
discontinues all study treatment and all the end of treatment procedures are completed. The end 
of study (EOS) for a given patient is defined as when the patient discontinues from follow-up 
assessments as detailed in Table 7-1a.
If the primary endpoint, PFS, is statistically significant at the primary PFS analysis, data 
collection will continue during survival follow-up and End of Study will be declared after the 
final number of OS events are reached (or earlier if OS reaches statistical significance at any of 
the interim analyses for OS) and after all patients have completed the safety follow-up period 
(30 days after treatment discontinuation).
If the primary endpoint, PFS, is not statistically significant at the primary PFS analysis then 
End of Study will be declared after all patients have discontinued all components of study 
therapy and completed the safety follow-up period (30 days after treatment discontinuation).
Patients continuing to derive benefit from study treatment at the end of the study in the opinion 
of the investigator will be able to continue receiving trial therapy on a separate protocol. 
Alternatively Novartis will provide study treatment to the investigator as per local regulations.
Following the statistically significant OS benefit demonstrated at the second OS analysis, with 
protocol amendment 6, study participants are unblinded, with an opportunity for those patients 
still on study treatment in the placebo combination arm to cross-over to the LEE011
combination arm. Crossover is optional and will be conducted only upon documented consent 
of the study patient. The study will be closed when all study patients have either discontinued 


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study treatment and completed the safety follow-up period, withdrawn consent, are lost to 
follow-up, or as soon as arrangements are made for ongoing access to study treatment for all 
patients still on study treatment, whichever happens first. 
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.5 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study will include pre-menopausal women with HR+, HER2-negative, advanced breast 
cancer who received no prior hormonal therapy for advanced breast cancer and are eligible for 
endocrine therapy. The investigator or designee must ensure that only patients who meet all the 
following inclusion and none of the exclusion criteria are offered treatment in the study.
Written informed consent must be obtained prior to any screening study-related procedures.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient is an adult, female ≥ 18 years old and < 60 years old at the time of informed consent 
and has signed informed consent before any trial related activities are conducted and 
according to local guidelines.
2. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or patient 
has had a hysterectomy.
3. Patient is premenopausal or perimenopausal at the time of study entry.

Premenopausal status is defined as either:

Patient had last menstrual period within the last 12 months,
OR

If on tamoxifen or toremifene within 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.

Patients who have undergone bilateral oophorectomy are not eligible.

Perimenopausal status is defined as neither premenopausal nor postmenopausal (see 
exclusion criteria 3).


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4. Patient has advanced (locoregionally recurrent or metastatic) breast cancer not amenable 
to curative therapy (e.g. surgery and/or radiotherapy).
5. Patients who received (neo) adjuvant therapy for breast cancer are eligible:

If the patient has never received any prior endocrine therapy OR if ≥12 months have 
elapsed since the patient’s last dose of adjuvant therapy, then the patient is eligible to 
receive tamoxifen + goserelin or a NSAI + goserelin for advanced breast cancer based 
on the investigator’s choice.

If tamoxifen or fulvestrant was the last prior (neo) adjuvant therapy and the last dose 
was given < 12 months prior to randomization, then the patient is eligible to receive a 
NSAI (letrozole or anastrozole) + goserelin for advanced breast cancer.

If letrozole, anastrozole, or exemestane was the last prior (neo) adjuvant therapy and 
the last dose was given < 12 months prior to randomization, then the patient is eligible 
to receive tamoxifen + goserelin for advanced breast cancer.
6. Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or anastrozole) with or 
without goserelin or goserelin ≤ 28 days for advanced breast cancer prior to randomization 
are eligible. Patients must continue treatment with the same hormonal agent + goserelin 
during the study. No treatment interruption is required for these patients prior to 
randomization.
Note: Patients who are receiving goserelin for reasons other than for advanced breast 
cancer treatment are eligible (e.g endometriosis). Patients who received ≤ 28 days 
goserelin for advanced breast cancer are eligible.
7. Patients who have received up to 1 line of chemotherapy for advanced breast cancer and 
have been discontinued 28 days before randomization are eligible.
Note: If a cytotoxic chemotherapy regimen was discontinued for reasons other than 
disease progression and lasted less than 21 days, this regimen does not count as a prior 
line of chemotherapy.
8. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor 
positive and/or progesterone receptor positive breast cancer by local laboratory (based on 
most recently analyzed biopsy).
9. Patient has HER2-negative breast cancer (based on most recently analyzed biopsy) 
defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 
2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local 
laboratory testing.
10. Patient must have either:

Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria.
OR

If no measurable disease is present, then at least one predominantly lytic bone lesion 
must be present (patients with no measurable disease and only one predominantly 
lytic bone lesion that has been previously irradiated are eligible if there is documented 
evidence of disease progression of the bone lesion after irradiation).
11. Patient has ECOG PS 0 or 1.
12. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory):


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
Absolute neutrophil count ≥ 1.5 × 109/L.

Platelets ≥ 100 × 109/L.

Hemoglobin ≥ 9.0 g/dL.

Potassium, sodium, calcium (corrected for serum albumin), and magnesium within 
normal limits of the central laboratory or corrected to within normal limits with 
supplements before the first dose of study medication

INR ≤1.5.

Serum creatinine < 1.5 mg/dL.

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver 
metastases, ALT and AST should be < 5 × ULN.

Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin <1.5 
x ULN of the central laboratory in patients with well documented Gilbert’s 
Syndrome.
13. Must be able to swallow study therapy
14. Subjects must be able to communicate with the investigator and comply with the 
requirements of the study procedures.
15. Must be willing to remain at the clinical site as required by the protocol visit evaluation 
schedule.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient who has received a prior CDK4/6 inhibitor.
2. Patient has a known hypersensitivity to any of the excipients of LEE011 or goserelin or 
hormonal treatment assigned (tamoxifen or a NSAI (letrozole or anastrozole)).
3. Patient is postmenopausal. Postmenopausal 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 FSH and estradiol in the 
postmenopausal range per local normal range.

If taking tamoxifen or toremifene, and age <60, then FSH and plasma estradiol level 
in postmenopausal ranges per local laboratory normal range.
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or 
estradiol are needed to ensure menopausal status 
(NCCN Guidelines Version 3.2014).
4. Patients who currently have inflammatory breast cancer at screening.


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5. Patients who received any prior hormonal anti-cancer therapy for advanced breast cancer, 
except for ≤ 14 days of tamoxifen or NSAI or goserelin ≤ 28 days for advanced breast cancer 
prior to randomization.
6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to 
NCI CTCAE version 4.03 Grade ≤1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator's discretion).
7. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with 
the exception of adequately treated basal cell skin carcinoma, squamous cell skin carcinoma, 
non-melanomatous skin cancer or curatively resected cervical cancer.
8. Patient with CNS metastases.
Note: CNS involvement must be ruled out by assessments if a patient has any signs or 
symptoms indicating potential CNS metastases.
9. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
10. Patient has a known history of HIV infection (testing not mandatory).
11. Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, contraindicate patient participation in the clinical study (e.g., 
chronic pancreatitis, chronic active hepatitis, etc.).
12. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, 
including any of the following:

History of angina pectoris, symptomatic pericarditis, myocardial infarction, or 
coronary artery bypass graft (CABG) within 6 months prior to study entry

Documented cardiomyopathy

Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO)

Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block)

Long QT syndrome or family history of idiopathic sudden death or congenital long 
QT syndrome, or any of the following:

Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia

resting heart rate < 50 at rest, by the triplicate ECG

resting heart rate >90 at rest, by the triplicate ECG

Systolic blood pressure >160 or <90 mmHg

On screening, inability to determine the QTcF interval on the ECG (ie: 
unreadable or not interpretable) or QTcF >450 msec (using Fridericia’s 
correction). All as determined by the average of the triplicate screening ECG, per 
central review.


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13. Patient is currently receiving any of the following substances and cannot be discontinued 
7 days prior to the start of the treatment:

Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pomelos, star-fruit, and Seville oranges.

Medications with a known risk to prolong the QT interval or induce Torsades de 
Pointes that cannot be discontinued or replaced by safe alternative medication (e.g. 
within 5 half-lives or 7 days prior to starting study drug).

Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5.

Additionally, for patients receiving tamoxifen: known strong inducers or inhibitors of 
CYP2D6.

Herbal preparations/medications and dietary supplements (except for vitamins).
14. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects.
15. Patient is currently receiving warfarin or other Coumadin derived anti-coagulant, for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH), or fondaparinux is allowed.
16. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical applications 
(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local
injections (e.g., intra-articular).
17. Patient is concurrently using other antineoplastic agents (except for patients who are 
receiving ≤ 14 days of tamoxifen or NSAI or goserelin ≤ 28 days for advanced breast cancer 
prior to randomization).
18. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 
weeks prior to randomization, and who has not recovered to grade 1 or better from related 
side effects of such therapy (with the exception of alopecia) and/or if ≥ 25% of the bone 
marrow was irradiated.
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing of study treatment and for 21 days after stopping study medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Total hysterectomy or tubal ligation at least six weeks before taking study treatment.

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Combination of the following:


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a. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
21. Participation in a prior investigational study within 30 days prior to enrollment or within 5-
half lives of the investigational product, whichever is longer.
22. Not able to understand and to comply with study instructions and requirements.
23. Patient with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s best judgment
6
Treatment
6.1
Study treatment
For this study, the term “investigational drug” refers to Novartis study drug LEE011. The other 
drugs to be used in this study are tamoxifen, letrozole, anastrozole, and goserelin. Study 
treatment in this study refers to the triple combination of the investigational drug, 
LEE011/placebo, and tamoxifen/NSAI and goserelin. Refer to Section 4 for the criteria 
determining treatment with tamoxifen or NSAI.
Novartis will supply LEE011/placebo as 200 mg hard gelatin capsules as individual patient 
supply packaged in bottles. Tamoxifen, letrozole, anastrozole and goserelin will be procured 
locally as they are commercially available drugs in each participating country according to local 
practice and regulation. Storage conditions are described in the medication label. Tamoxifen, 
letrozole, anastrozole, and goserelin should be used in accordance with the locally approved 
label (SmPC). Medication labels will comply with the legal requirements of each country and 
be printed in the local language.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
The study met its primary efficacy endpoint (PFS) at the time of the primary analysis. It also 
met the key secondary efficacy endpoint of OS at the time of the pre-planned 2nd interim OS 
analysis. Given the demonstrated survival benefit, patients and investigators will be unblinded 
to the treatment allocation. Additionally, patients who remain on study treatment and are 
currently allocated to the placebo combination arm, will be given the opportunity to cross over 
to the LEE011 combination arm. 
Patients who are currently taking placebo in combination with tamoxifen (and goserelin), that 
request cross over to LEE011 combination treatment, must switch their endocrine partner from
tamoxifen to an NSAI; either letrozole or anastrozole per Investigator decision, prior to crossing 
over to LEE011. There needs to be a 35-day (5 half-lives) washout period from tamoxifen 
before starting LEE011, during which time the patients will be taking NSAI plus goserelin only. 
The rationale for this change in the background endocrine therapy is based on the increased 
incidence of significant QT prolongation events for the combination of tamoxifen and LEE011 
observed in the primary analysis of this study and, as such, the combination of ribociclib and 
tamoxifen is not recommended. This consideration does not apply to patients originally 
randomized to LEE011 plus tamoxifen and remaining on study treatment, as for those patients 


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any QT prolongation events have been managed via LEE011 dose modifications (Table 6-5).  
Those patients on the placebo arm who do not wish to cross-over from placebo to LEE011 can 
remain on their current treatment allocation. 
All of the study treatment cross-over changes will be managed by the study IRT system. 
Endocrine partner treatment will be managed locally. 
Unblinded study treatment period will conclude once a patient discontinues from the study 
treatment for any reason or the EOS is declared, whichever occurs first. 
6.1.1
Dosing regimen
LEE011 or LEE011 placebo will be given orally once daily on days 1-21 of each 28 day cycle. 
Days 22-28 will be a “rest” period from dosing with LEE011 or LEE011 placebo. Tamoxifen, 
letrozole, and anastrozole will be given orally once daily on a continuous daily schedule (e.g., 
days 1-28 of each 28 day cycle). Goserelin will be given as an injectable subcutaneous implant
on day 1 of every 28 day cycle. There will be no “rest” in the tamoxifen, letrozole, or anastrozole
schedule.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
LEE011/placebo
Capsules for oral use
600 mg
Days 1-21 of each 28 day cycle
Tamoxifen
Tablets for oral use
20 mg
Daily (all days of every cycle 
without interruption.)
Letrozole
Tablets for oral use
2.5 mg
Daily (all days of every cycle 
without interruption.)
Anastrozole
Tablets for oral use
1 mg
Daily (all days of every cycle 
without interruption.)
Goserelin
Subcutaneous implant
3.6 mg
Day 1 of each 28 day cycle
The study drugs will be administered as a flat-fixed dose, and not by body weight or body 
surface area. All study treatment drugs must be administered together at approximately the same 
time each day. All oral study treatment drugs can be administered with or without food.
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). Patients will be instructed to return unused study drugs 
to the site at discontinuation or completion of treatment. The site personnel will ensure that the 
appropriate dose of each study drug is administered and that the drug accountability is 
performed.
6.1.1.1
General dosing guidelines
The study treatments should be taken as follows:

LEE011/placebo is dosed orally for the first 21 days out of a 28 day cycle while 
tamoxifen, letrozole, or anastrozole are dosed orally daily (28 days out of the 28 day 
cycle). Goserelin is continuously released via a subcutaneous implant injected on Day 1 of 
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
Patients should be instructed to take the study treatment of LEE011/placebo capsules and 
one tablet of tamoxifen or letrozole or anastrozole together with a large glass of water
(~250 mL) at the same time each day. For the first cycle, patients must take 
LEE011/placebo in the morning 
. 
 
, patients can determine if they prefer morning or early afternoon dosing, 
but should maintain a consistent time regardless of AM or PM dosing. Evening doses are 
strongly not recommended.

In general, study treatment may be taken without regard to meals. Please see
Section 6.1.1.2 below for additional guidelines for scheduled visit days.

Patients should be instructed to swallow the capsules and tablets whole and not to chew, 
crush or open them.

Goserelin implant should be administered as a subcutaneous injection every 28 days using 
an aseptic technique under the supervision of a physician. Administration technique 
should be in accordance with the locally approved label (SmPC).

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the eCRF. Refer to Section 
6.4.1.5 for use of anti-emetic medications.

Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day.

Patients must avoid consumption of grapefruit, grapefruit hybrids, pomelos, star-fruit, 
Seville oranges or products containing their juice of each during the entire study and 
preferably for an additional 7 days before the first dose of study medications. These foods 
are known as CYP3A4 inhibitors and have a potential to increase exposure to LEE011. 
Orange juice is allowed.

Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4 or those 
with a known risk of QT prolongation are not permitted. 

Multivitamins are permitted.
6.1.1.2
Additional dosing guidelines for scheduled visit days
On days with fasting, (overnight fasting defined as at least 8-12 hours) biochemistry and/or lipid 
profile samples as outlined in Table 7-1a, Table 7-1b and Figure 6-1, the following additional 
guidelines should be followed:


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
The patient must be fasting overnight for all cycle visits for at least 8-12 hours prior to the 
blood collection for fasting glucose, lipid profile samples 
 
 Water is allowed during all fasting periods; however coffee, tea and juice are not 
permitted during the fasting period. After the fasting blood sample is obtained in the 
clinic, the patient may consume breakfast, if desired.

On scheduled visit days, patients must take study treatment in the clinic under the 
supervision of the Investigator or designee. On all other days patients will take the study 
treatment at home.

The patient may take her study treatment with or without food; however, dietary habits 
around the time of dosing should be as consistent as possible on days of 

If a pre-dose ECG measurement should be collected, then the ECG measurement should 
occur before dosing of the study treatment.
 
 
 
 

Post-dose ECGs 
 should be collected after dosing of the study 
treatment. ECG 
 collection will be performed according to Section 7.2.3
and Table 7-5.
Figure 6-1
Suggested study drug administration for scheduled visit days
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.3, Dose Modifications.
Patients who permanently discontinue any component of endocrine combination partner 
(tamoxifen/NSAI) for any reason must discontinue LEE011/placebo and goserelin and move to 
End of Treatment Phase, but will remain on study for efficacy and survival follow-up 
evaluations. Patients who permanently discontinue LEE011/placebo and/or goserelin for any 


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reason other than disease progression may continue on tamoxifen or a NSAI per investigator’s 
discretion until disease progression, unacceptable toxicity, death or discontinuation from study 
treatment due to any other reason and continue to be followed for safety and/or efficacy.
6.1.5
Treatment duration
Patients may continue study treatment until disease progression (radiologically documented 
according to RECIST 1.1), or until discontinuation of study treatment due to any other reason 
(see Section 7.1.5).
6.2
Dose escalation guidelines
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, LEE011/placebo dose 
adjustments are permitted in order to allow the patient to continue the study treatment.
Dose reductions are not permitted for goserelin, tamoxifen or NSAIs.
Any changes to the dose or interruption of dosing must be recorded on the Dosage 
Administration Record eCRF. All patients will be followed for AEs and for SAEs for 30 days 
following the last dose of study drug.
6.3.1.1
Tamoxifen
The established clinical dose of tamoxifen (20 mg/day) will be used in each arm and no dose 
modification of tamoxifen is planned in this study.
Following protocol amendment 6, patients who are currently taking placebo in combination 
with tamoxifen (and goserelin) and wish to cross over to the LEE011 combination treatment, 
must switch their endocrine partner from tamoxifen to an NSAI; either letrozole or anastrozole. 
A washout period of 5 half-lives (35 days) from tamoxifen is needed before LEE011 can be 
initiated, during which period the patient will be receiving NSAI and goserelin only.
For information on tamoxifen and management of tamoxifen related adverse events refer to the 
Tamoxifen SmPC or Prescribing Information.
6.3.1.2
Non-steroidal aromatase inhibitors (NSAIs)
The established clinical dose of letrozole (2.5 mg/day) and anastrozole (1 mg/day) will be used 
in each arm and no dose modification of letrozole or anastrozole is planned in this study.
For information on NSAIs (letrozole or anastrozole) and management of related adverse events 
refer to the Femara® or Arimidex® SmPC or Prescribing Information.


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6.3.1.3
Goserelin
The established clinical dose of goserelin (3.6 mg subcutaneous injection every 28 days) will 
be used in each arm and no dose modification of goserelin is planned in this study.
For information on goserelin and management of goserelin related adverse events refer to the 
Zoladex® SmPC or Prescribing Information.
6.3.1.4
LEE011/placebo
Management of severe or intolerable adverse reactions requires temporary dose reduction 
and/or interruption of LEE011 therapy. Refer to Table 6-2 for guidance.
Table 6-2
Dose modification guideline
LEE011/placebo
Dose
Number of capsules & strength
Starting dose
600 mg
3 x 200 mg capsules
First dose reduction
400 mg
2 x 200 mg capsules
Second dose reduction
200 mg
1 x 200 mg capsules
Recommendations for dose reduction, interruption or discontinuation of LEE011 in the 
management of adverse reactions are summarized in Table 6-3, Table 6-4, Table 6-5, Table 6-
6 and Table 6-7.
Clinical judgment of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. However, for events requiring a discontinuation in 
Table 6-3, Table 6-4, Table 6-5, Table 6-6 and Table 6-7 or listed in Section 7.1.5.1, treatment 
must be discontinued.
If a patient inadvertently doses on a rest day (e.g. days 22-28 of any given cycle), 
LEE011/placebo will be interrupted to ensure 7 consecutive rest days and avoid overdose. The 
visit schedule will not be adjusted.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used.


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Table 6-3
LEE011/placebo dose adjustment and management recommendations
for hematological adverse reactions (CTC AE v4.03)
Toxicity
Grade
Dose Adjustment and Management Recommendations
Thrombocytopenia
1
≥75 x 109/L
No dose adjustment required.
2
≥50 x 109/L – <75 
x 109/L
Dose interruption until recovery to grade 1.
Re-initiate LEE011/placebo at the same dose.
3
≥25 x 109/L - <50 x 
109/L
Dose interruption until recovery to grade 1.
Re-initiate LEE011/placebo at the same dose level.
●
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to grade 1 and reduce LEE011/placebo to the next 
lower dose level.
4
<25 x 109/L
Dose interruption until recovery to grade 1.
Re-initiate LEE011/placebo at the next lower dose level.
●
If toxicity recurs at grade 4: discontinue LEE011/placebo.
Absolute neutrophil 
count (ANC)
1
≥1.5 x 109/L
No dose adjustment required.
2
≥1.0 - <1.5 x 109/L
No dose adjustment required.
3
≥0.5 - <1.0 x 109/L
Dose interruption until recovery to >1.0 x 109/L.
Re-initiate LEE011/placebo at the same dose level.
●
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to > 1.0 x 109/L.
●
If resolved in ≤ 7 days, then maintain dose level.
●
If resolved in > 7 days, then reduce LEE011/placebo dose 
to the next lower dose level.
4
<0.5 x 109/L
Dose interruption until recovery to > 1.0 x 109/L.
Re-initiate LEE011/placebo at the next lower dose level.
●
If toxicity recurs at grade 4: temporary dose interruption until 
recovery to >1.0 x 109/L and reduce LEE011/placebo at the 
next lower dose level.
Febrile neutropenia
3
ANC <1.0 x 109/L 
with [a single 
temperature 
of >38.3°C
(101°F) or a 
sustained 
temperature of 
≥38°C
(100.4°F) for more 
than one hour]
Dose interruption until improvement of ANC ≥ 1.0 x 109/L and 
no fever. Restart at the next lower dose level.
●
If febrile neutropenia recurs, discontinue LEE011/placebo.
4
Life-threatening 
consequences;
urgent intervention 
indicated
Discontinue LEE011/placebo.


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Toxicity
Grade
Dose Adjustment and Management Recommendations
Anemia
(Hemoglobin)
1
≥10.0 – LLN g/dL
No dose adjustment required.
2
≥8.0 – <10.0 g/dL
No dose adjustment required.
3
<8.0 g/dL
Dose interruption until recovery to grade 2.
Re-initiate LEE011/placebo at the same dose.
4
Life-threatening 
consequences;
urgent intervention 
indicated
Discontinue LEE011/placebo.
Table 6-4
LEE011/placebo dose adjustment and management recommendations
for hepatic toxicities (CTC AE v4.03)
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN)
(confirmed 48-72h later by repeat testing)
Maintain dose level with LFTs monitored every two weeks
Grade 2 (> 1.5 – 3.0 x ULN) 
Dose interruption of LEE011/placebo
●
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose 
level
●
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
then reduce 1 dose level
●
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
●
If toxicity recurs after two dose reductions, discontinue 
LEE011/placebo
Grade 3 (> 3.0 – 10.0 x ULN) 
Dose interruption of LEE011/placebo.
●
If resolved to ≤ grade 1 in ≤ 21 days, lower 1 dose level of 
LEE011/placebo
●
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
●
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
discontinue LEE011 /placebo
Grade 4 (> 10.0 x ULN)
Discontinue LEE011 /placebo
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose 
interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated ALP and 
GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due to the indirect component only (i.e. 
direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert Syndrome, pharmacologic treatment, viral 
hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs.
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only.
Bilirubin will be fractionated if elevated.


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HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
AST or ALT
AST or ALT without bilirubin elevation > 2 x ULN
Same grade as baseline or increase from 
baseline grade 0 to grade 1
(confirmed 48 – 72 h later by repeat testing)
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or every two weeks in 
case of increase from baseline grade 0 to 1
Increase from baseline grade 0 or 1 to grade 2 
(> 3.0 – 5.0 x ULN)
Dose interruption of LEE011/placebo
●
If resolved to ≤ baseline grade in ≤ 21 days, then 
maintain dose level
●
If resolved to ≤ baseline grade in > 21 days or toxicity 
recurs, then reduce 1 dose level
●
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
●
If toxicity recurs after two dose reductions or recovery to 
≤ baseline grade is > 28 days, discontinue LEE011/placebo
Increase from baseline grade 0 or 1 to grade 3 
(> 5.0 – 20.0 x ULN)
Dose interruption of LEE011/placebo until resolved to ≤ 
baseline grade, then lower 1 dose level of LEE011/placebo
●
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
●
If recovery to ≤ baseline grade is > 28 days, discontinue 
LEE011/placebo
●
If toxicity recurs, discontinue LEE011/placebo
Increase from baseline grade 2 to grade 3 (> 
5.0 – 20.0 x ULN)
Dose interruption of LEE011/placebo until resolved to ≤ 
baseline grade, then lower 1 dose level of LEE011/placebo
●
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
●
If toxicity recurs after two dose reductions or recovery to 
≤ baseline grade is > 28 days, discontinue LEE011/placebo.
Grade 4 (> 20.0 x ULN)
Discontinue LEE011 /placebo
AST or ALT and concurrent Bilirubin
For patients with normal ALT AND AST AND 
total bilirubin at baseline: AST or ALT >3.0 x 
ULN≥ combined with total bilirubin > 2 x ULN 
without evidence of cholestasis
Or
For patient with elevated AST or ALT or total 
bilirubin at baseline; baseline: [AST or ALT >2 
x baseline AND >3.0 x ULN] OR [AST or ALT 
8.0 x ULN]- whichever is lower- combined 
with [total bilirubin
> 2x baseline AND >2.0 x ULN]
Discontinue LEE011/placebo
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose 
interruption/reduction. They include but are not limited to: concomitant medications, herbal preparations or 
dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive liver metastasis, and 
alcohol intake. 


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6.3.1.5
Additional follow-up for hepatic toxicities
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered as clinically important events. A 
study with ribociclib in non-cancer patients with varying degrees of hepatic impairment (mild, 
moderate, severe based on Child-Pugh classification) matched subjects with normal hepatic 
function was completed [CLEE011A2109]. Refer to [ribociclib Investigators Brochure] for 
more details.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT AND AST AND TBIL value at baseline: AST or ALT > 
3.0 x ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values [R value = (ALT/ULN)/ (ALP/ULN)]. It denotes the relative pattern of ALT 
and/or ALP elevation is due to cholestatic or hepatocellular liver injury or mixed type injury
In the absence of cholestasis, these patients must be immediately discontinued from study drug 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
Hepatic toxicity monitoring includes assessment of the following LFTs: albumin, ALT, AST, 
total bilirubin, direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), creatinine kinase, prothrombin time (PT)/INR and GGT. For 
patients with Gilbert Syndrome: total and direct bilirubin must be monitored, intensified 
monitoring applies to changes in direct bilirubin only.
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves:

Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values.

Obtaining a more detailed history of current symptoms.

Obtaining a more detailed history of prior and/or concurrent diseases including history of 
any pre-existing liver conditions or risk factors.

Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets.


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
Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).

Considering gastroenterology or hepatology consultations.

Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction.

Obtaining a PK sample, as close as possible to last dose of study drug

Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, thus met the definition of SAE (Section 8.2.1), and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.3.1.6
Additional follow-up for QTc prolongation
Table 6-5
LEE011/placebo dose adjustment and management recommendations 
for QTcF prolongation (CTC AE v4.03)
Grade
Dose Modification
For All Grades
1.
Check the quality of the ECG and the QT value and repeat if 
needed
2.
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If 
outside the normal range, interrupt LEE011/placebo administration, 
correct with supplements or appropriate therapy as soon as 
possible, and repeat electrolytes until documented as normal.
3.
Review concomitant medication usage for the potential to inhibit 
CYP3A4 and/or to prolong the QT interval.
4.
Check compliance with correct dose and administration of 
LEE011/placebo.
Grade 1*
QTc 450-480 ms
Perform steps 1-4 as directed in “For All Grades”. No dose adjustment 
required.
Grade 2*
QTc 481-500 ms
Interrupt LEE011/placebo. Perform steps 1-4 as directed in “For All 
Grades.”
Perform a repeat ECG within one hour of the first QTcF of ≥ 481 ms.
Repeat ECG as clinically indicated until the QTcF returns to < 481ms, 
restart LEE011/placebo with dose reduced by 1 dose level. Refer to Table 
6-2 for dosing schedule.
If QTcF ≥ 481 ms recurs, ribociclib should be reduced again by 1 dose 
level.
●
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due 
to QTcF ≥ 481 ms


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Grade
Dose Modification
Grade 3*
QTc ≥ 501 ms on at least two 
separate ECGs
Interrupt LEE011/placebo. Perform steps 1-4 as directed in “For All 
Grades.”
Perform a repeat ECG within one hour of the first QTcF of ≥501 ms.
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified 
specialist) and repeat cardiac monitoring as clinically indicated until the 
QTcF returns to < 481 ms.
●
If QTcF returns to < 481 ms, LEE011/placebo will be reduced by 1 dose 
level. Refer to Table 6-2 for dosing schedule.
●
If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For 
All Grades,” discontinue LEE011/placebo.
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due 
to QTcF ≥ 501 ms. 
If QTcF of ≥ 501 ms recurs, discontinue LEE011/placebo.
Grade 4*
[QT/QTc ≥ 501 or > 60 ms 
change from baseline]
and
[Torsades de pointes or
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia]
Discontinue LEE011/placebo. Perform steps 1-4 as directed in “For All 
Grades.”
●
Obtain local cardiologist (or qualified specialist) consultation and repeat 
cardiac monitoring as indicated until the QTcF returns to <481 ms
*All values refer to the average of triplicate measurements
6.3.1.7
Additional follow-up for ILD/pneumonitis
Table 6-6
LEE011 dose adjustment and management recommendation for 
ILD/pneumonitis (CTCAE v 4.03)
Grade
Dose Adjustment and Management Recommendations
1
(asymptomatic)
No dose adjustment required. Initiate appropriate medical therapy and monitor as clinically 
indicated.
2
(symptomatic)
Interrupt LEE011 dose until recovery to Grade ≤1, then resume LEE011 at the next lower 
dose level*. 
3 and 4
(severe)
Discontinue LEE011
* An individualized benefit-risk assessment should be performed before resuming LEE011
6.3.1.8
Guidance for all other adverse reactions
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium for 
all adverse reactions, if indicated. If electrolyte values are outside of the normal range, interrupt 
LEE011/placebo administration, correct electrolytes with supplements or appropriate therapy 
as soon as possible, and repeat electrolyte testing until documented normalization of the 
electrolytes.
For all other adverse events, including Toxic Epidermal Necrolysis (TEN), which is a grade 4 
event by CTCAE, please follow recommendations in Table 6-7.


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Table 6-7
LEE011/placebo dose adjustment and management recommendation 
for all other adverse reactions (CTC AE v4.03)
Grade
Dose Adjustment and Management Recommendations
1
No dose adjustment required. Initiate appropriate medical therapy and monitor.
2
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor.
Re-initiate LEE011/placebo at the same dose.
●
If the same toxicity recurs at grade 2, interrupt LEE011/placebo until recovery to grade 1. Re-
initiate LEE011/placebo at the next lower dose level.
3
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor.
Re-initiate LEE011/placebo at the next lower dose level.
●
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade 1 and reduce 
LEE011/placebo dose the next lower dose level.
●
If toxicity recurs at grade 3, discontinue LEE011/placebo.
4
Discontinue LEE011/placebo and treat with appropriate medical therapy.
6.3.1.8.1 Adjustment of starting dose in special populations
Renal impairment
Insufficient data are available to provide a dosage recommendation for LEE011 in patients with 
renal impairment. A study in non-cancer patients with varying degrees of renal impairment and 
matched subjects with normal renal function is ongoing [CLEE011A2116]. Refer to [ribociclib 
Investigators Brochure] for more details. Based on rat ADME data, LEE011 was predominantly 
excreted in the in the bile as metabolites, with limited excretion of unchanged drug in urine. 
Increases in tamoxifen serum concentrations did not occur in a 51 year-old woman with renal 
impairment who received tamoxifen for metastatic breast cancer, however further studies are 
lacking (Sutherland 1984).
Studies with goserelin in female patients with renal impairment do not indicate a need for dose 
adjustment with the use of the depot formulation (Zoladex® Prescribing Information 
AstraZeneca).
Renal impairment does not affect letrozole or anastrozole PK in humans (Femara® Prescribing 
Information Novartis, Arimidex® Prescribing Information AstraZeneca).
Patients with baseline renal impairment or with AST/ALT or bilirubin values beyond certain 
thresholds as specified in the eligibility criteria are excluded from the study. Patients who 
experience renal impairment of grade 2 or higher during the treatment period should discontinue 
treatment and should be followed for safety assessments.
6.3.2
Follow-up for toxicities
Patients who complete treatment or whose treatment is interrupted or permanently discontinued 
due to an adverse event or abnormal laboratory value must be followed at least once a week for 


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4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event. All 
patients will be followed up for safety up to 30 days following the last dose of study treatment 
(tamoxifen or a NSAI + goserelin + LEE011/placebo).
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Refer to Section 6.3.1 for details.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed.
Please consult the list of prohibited medications and the list of use with caution medications for 
further guidance.
The patient must be told to notify the investigational site about any new medications she takes 
after the start of the study treatment. All medications (other than study drugs) and significant 
non-drug therapies (including vitamins, herbal medicines, physical therapy and blood 
transfusions) administered within 30 days of study entry and during the study must be listed on 
the Concomitant medications/Significant non-drug therapies eCRF.
If patients take concomitant medications chronically, any change in dose or schedule of any 
concomitant medication throughout the study period should be clearly documented.
6.4.1.1
Bisphosphonates and denosumab
Bisphosphonates and denosumab are generally allowed with the following comments:

Chronic concomitant bisphosphonate/denosumab therapy for the prevention of bone 
metastasis is not permitted.

Bisphosphonate/denosumab therapy for the treatment of osteoporosis is permitted.

Bisphosphonate/denosumab therapy for the prevention of skeletal related events for 
patients with bone metastases is permitted.

If bisphosphonate/denosumab therapy is to be started after the first dose of study drug, 
prior consultation and approval by Novartis is required and the reason for its use must be 
clearly documented.
Patients taking concomitant medication chronically should be maintained at the same dose and 
dose schedule throughout the study period, as medically feasible. 
 
 
 
 
 


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6.4.1.2
Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially reducing LEE011 drug exposure to sub-
therapeutic levels. Systemic corticosteroid treatment should not be given during the study, 
except for:

Topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), 
eye drops or local injections (e.g., intra-articular);

A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency 
of 4 mg dexamethasone (e.g. for chronic obstructive pulmonary disease, or as an 
antiemetic)
6.4.1.3
Hematopoietic growth factors
Prophylactic use of WBC growth factors with LEE011/placebo is not recommended.
6.4.1.4
Palliative radiotherapy
Palliative radiation is permitted. It should not be delivered to a target lesion. Cumulative courses 
of RT should not encompass >25% of irradiated bone marrow. (See Appendix 4). 
If palliative radiotherapy is initiated after start of study treatment, the reason for its use must be 
clearly documented and progression as per RECIST 1.1 must be ruled out.
No dose modification of study treatment is mandated during palliative radiotherapy.
6.4.1.5
Use of antiemetic medications
LEE011 has low to minimal emetogenic potential according to the definition of antineoplastic 
agent emetogenicity (Grunberg et al, 2010). Antiemetic therapy can be used according to 
clinical guidelines for antineoplastic medications with low to minimal emetogenic potential for 
treatment and/or prevention of nausea and vomiting as a result of study treatment (NCCN 
Clinical Practice Guidelines in Oncology. Antiemesis, 2016; Roila F et al, 2016). 
Potential drug interaction between LEE011 and antiemetic medications should always be taken 
into consideration. An example of prohibited antiemetic medication is ondansetron that in 
combination with LEE011 may precipitate TdP. Refer to Table 14-1 and Table 14-2 of 
Appendix 1 for a list of medications that are prohibited or allowed to be used with caution.  
6.4.2
Concomitant therapy requiring caution
Medications to be used with caution during combined LEE011/placebo, tamoxifen/NSAI, and 
goserelin treatment in this study are listed below (see Table 14-2 in Appendix 1, this list is not 
comprehensive and is only meant to be used as a guide. Please contact the medical monitor with 
any questions). These medications should be excluded if possible. If they must be given based 
on the investigator’s judgment, then use with caution and consider a LEE011/placebo 
interruption if the concomitant medication is only needed for a short time:

Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease LEE011 exposure, 
respectively)


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
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (LEE011
may increase exposure to these medications)

Inhibitors of BSEP (based on in vitro data co-administration with LEE011 may lead to 
intrahepatic cholestasis)

Medications that carry a possible risk for QT prolongation (may precipitate QT 
prolongation and TdP)

Sensitive substrates of the renal transporters, MATE1/2 substrates and OCT1/2 substrates
(LEE011 has the potential to increase exposure to substrates of these transporters, 
although no animal or clinical data are available to support these statements)

Sensitive substrates of BCRP (LEE011 has the potential to increase exposure to substrates 
of these transporters, although no animal or clinical data are available to support these 
statements)

Substrates metabolized predominantly by CYP2C9 or CYP2D6 with a narrow therapeutic 
index (that could be affected by tamoxifen)

Substrates metabolized predominantly by CYP2C19 or CYP2A6 with a narrow 
therapeutic index (that could be affected by letrozole)
6.4.3
Prohibited concomitant therapy
The following medications are prohibited during combined LEE011/placebo, tamoxifen/NSAI, 
and goserelin treatment in this study (Table 14-1 in Appendix 1, this list is not comprehensive
and is only meant to be used as a guide. Please contact the medical monitor with any questions):

Strong inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease 
LEE011exposure, respectively)

Substrates of CYP3A4/5 with a narrow therapeutic index (LEE011 may increase exposure 
to these medications resulting in toxicity to these medications)

Medications with a known risk for QT prolongation and/or TdP (may precipitate QT 
prolongation and TdP in combination with LEE011)

Additionally, for patients receiving tamoxifen: strong inhibitors or inducers of CYP2D6 
(that could affect tamoxifen exposure)

Warfarin and coumarin derivatives (for patients receiving tamoxifen)

Other investigational and antineoplastic therapies

Herbal preparations/medications and dietary supplements that are strong inhibitors or 
inducers of CYP3A4/5 or those with a known risk of QT prolongation. These include but 
are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 
Patients should stop using these preparations/ medications at least 7 days prior to first dose 
of study treatment.
6.4.4
Drugs with QT prolongation
As far as possible, avoid co-administering medications with a “Known”, “Possible” or 
“Conditional” risk of TdP (qtdrugs.org) or any other medication with the potential to increase 
the risk of drug-related QT prolongation (e.g. via a potential DDI increasing the exposure of 


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LEE011/ placebo or the exposure of the QT prolonging drug). If concomitant administration of 
drugs with a known risk of TdP is required and cannot be avoided, LEE011/placebo must be 
interrupted (see Table 6-5). If during the course of the study, concomitant administration of a 
drug with “Possible risk” or “Conditional risk” of TdP is required, based on the investigator 
assessment and clinical need, study treatment may be resumed under close clinical and ECG 
monitoring to ensure patient safety. A list of drugs associated with QT prolongation and/or TdP 
is available online (qtdrugs.org). Medications with a known risk for QT prolongation are 
prohibited during study treatment.
Refer to the [LEE011 Investigators Brochure] and other drug package inserts and Appendix 1
for information on possible interactions with other drugs.  
6.4.5
Concomitant medications associated with menopausal status
It is important to consider potential drug-drug interactions when using concomitant medications 
associated with hot flushes and other anticipated symptoms associated with this indication/use 
of endocrine therapy. Please refer to Table 14-1 in Appendix 1 for further information on 
prohibited concomitant medications.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.) that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout her entire participation in the trial. The Subject No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential patient number 
suffixed to it, so that each subject is numbered uniquely across the entire database. Upon signing 
the informed consent form, the patient is assigned to the next sequential Subject No. available 
to the investigator through the Oracle Clinical RDC interface at that location.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Patients will be randomized to one of the two treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1.
Randomization will be stratified by the following factors:
1. Lung or liver metastases: (yes versus no)
2. Prior chemotherapy for advanced disease: (yes versus no)
3. Endocrine combination partner (tamoxifen and goserelin versus NSAI (letrozole or 
anastrozole) and goserelin)


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
Following protocol amendment 6, patients will be unblinded to their treatment allocation. 
Additionally, patients who are currently allocated to the placebo combination arm and still on 
study treatment, will be given the opportunity to cross over to the LEE011 combination arm. 
Those patients on the placebo arm who do not wish to cross-over from placebo to LEE011 can 
remain on their current treatment allocation.
6.5.3
Treatment blinding
This is a double blind study. In particular, patients, investigators, study team, or anyone 
involved in the study conduct will remain blinded to the identity of the treatment from the time 
of randomization until database lock. The local (or Novartis-designated) radiologists will 
remain blinded to the identity of the treatment from the time of randomization until final 
database lock.
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible to anyone involved in the conduct of the study. The identity of the treatments will be 
concealed by the use of investigational drugs (LEE011 or LEE011 matching placebo) that are 
identical in packaging, labeling, schedule of administration and in appearance. Confidentiality 
of randomization data is required to limit the occurrence of potential bias arising from the 
influence that the knowledge of treatment may have on the recruitment and allocation of patients.
Unblinding of study drug assignment will only occur for safety reasons in the case of patient 
emergencies (Section 8.3), for regulatory reporting purposes and at the conclusion of the study.
In rare cases when unblinding occurs because of safety reasons for emergency patient 
management, the actual treatment arm will not be communicated to any of the Novartis 
employees involved in running the trial in order to remain blinded.
An independent statistical group (external to Novartis), not involved in the trial conduct, will 
prepare data reports for the DMC. 
 


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 Details will be presented in the DMC charter.
Prior to the release of protocol amendment 6, the study met both its primary and key secondary 
endpoints. Given the demonstrated survival benefit from LEE011 treatment, patients will be 
unblinded to their treatment allocation. 
6.6
Study drug preparation and dispensation
Patients will be provided with an adequate supply of study drug for self-administration at home, 
including instructions for administration, until at least their next scheduled study visit. Patients 
will receive LEE011/placebo on an outpatient basis. The investigator shall provide the patient 
with instructions for LEE011/placebo administration according to the protocol.
Tamoxifen, letrozole, anastrozole, and goserelin should be dispensed according to local 
prescribing information and practice.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
6.6.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms and a [specific visit or 
dose/dose level]. Responsible site personnel will identify the study treatment package(s) to 
dispense to the patient by using the IRT and obtaining the medication number(s). Site personnel 
will add the patient number on the label. Immediately before dispensing the package to the 
patient, site personnel will detach the outer part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient.
Table 6-8
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
LEE011/placebo
Capsules in bottles
Study treatment packaging has a 2-part 
label.
A unique medication number is printed on 
each part of this label which corresponds to 
one of the two treatment arms.
Tamoxifen
Refer to local product information
Refer to local product information
Anastrozole
Refer to local product information
Refer to local product information
Letrozole
Refer to local product information
Refer to local product information
Goserelin
Refer to local product information
Refer to local product information


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6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to 
the instructions specified on the drug labels and in the [Investigator’s Brochure].
Table 6-9
Supply and storage of study treatments
Study treatments
Supply
Storage
LEE011/ placebo
Centrally supplied by Novartis
Refer to study treatment label
Tamoxifen
Locally
Refer to local product information
Letrozole
Locally
Refer to local product information
Anastrozole
Locally
Refer to local product information
Goserelin
Locally
Refer to local product information
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee, and will be verified by determinations of LEE011, tamoxifen,
NSAIs and goserelin in plasma.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1a and Table 7-1b list all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. The table indicates which assessments produce data to be entered into 
the database (D) or remain in source documents only (S) (“Category” column). Allowed visit 
windows are specified as follows:

There will be no visit window for Cycle 1 Day 1.

A general +/-3 day window is permitted on assessments to take into account scheduling over 
public holidays, if not explicitly specified otherwise. Restrict the use of windows before 
Cycle 3 Day 16 when feasible.
 

Radiological assessments must be performed as outlined in Table 7-1a and Table 7-1b. A 
visit window of +/- 7 days is allowed (The whole body bone scan should be performed 
within 42 days or 6 weeks prior to randomization).

Vital signs, physical exam, ECOG performance status, hematology, biochemistry, INR, 
lipid panel, and urinalysis should be performed within 14 days of randomization.
Note: If the physical examination, ECOG performance status, and/or laboratory screening
assessments were performed ≤ 7 days prior to the first dose of LEE011/placebo, then they 
do not need to be repeated on Cycle 1 Day 1.
 

A +/- 7 day window is permitted on the ECHO/MUGA scans.
 

Collection of FSH and/or estradiol (if necessary for determining pre-menopausal status for 
eligibility) and serum pregnancy test (β-hCG) (unless the patient has had a hysterectomy)
must occur within 28 days before starting study treatment.
All other screening assessments must be completed within 28 days before randomization. Every 
effort should be made to follow the schedule outlined in Table 7-1a.
At the time of protocol amendment 6, minimal follow up for all patients on study treatment is 
36 months. Central laboratory hematology, biochemistry and ECG assessments will cease and 
all tests should be performed locally. Patients originally randomized to the LEE011 arm and 
continuing with open label LEE011 plus endocrine treatment and patients in the placebo arm 
that elect to continue with their current treatment (i.e. endocrine treatment alone), should have 
safety assessments and clinic visits as frequently as clinically indicated, but not less frequently 
than every 12 weeks. Tumor assessments will continue as clinically indicated as described in 
Section 7.2.1.1 (see Table 7-1a). Instructions for patients electing to cross-over from placebo to 
LEE011 at the next scheduled visit: 


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Patients currently receiving placebo plus NSAI plus goserelin and electing to cross-over to 
LEE011 plus NSAI plus goserelin, can commence LEE011 on Day 1 of their next planned cycle.  
Of Note: Patients currently receiving placebo plus tamoxifen plus goserelin and elect to cross-
over to the LEE011 arm, must first switch from tamoxifen to an NSAI. At least 5 tamoxifen 
half-lives (35 days) must elapse, before LEE011 is added. See Section 6.1 for more details.
All patients commencing LEE011 after cross-over from placebo will need to have local 
hematology, electrolyte and liver function biochemistry tests every two weeks for the first 2 
cross over cycles of LEE011 treatment, then at the beginning of cross over cycles 3 to 6, then 
as clinically indicated, but not less frequently than every 12 weeks. They need to have ECG for 
QT assessment on the first day before the administration of LEE011. LEE011 should be 
initiated only in patients with QTcF values <450 msec. The ECGs should be repeated on cross 
over Cycle 1 Day 15, on cross over Cycle 2 Day 1 and then as clinically indicated. The 
assessment schedule for patients who will cross-over is presented in Table 7-1b. Consult Table 
6-3, Table 6-4 and Table 6-5 for monitoring frequency in cases of hematologic toxicity, liver 
function abnormalities or QT prolongation respectively.  


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Table 7-1a
Visit evaluation schedule – Patients that, after protocol amendment 6, continue with their originally randomized 
study treatment
Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Screening
Study Informed 
Consent
D
7.1.2
x
IRT Screening (after 
ICF signature)
S
7.1.2
x
Screening phase 
disposition
D
7.1.2
x
Patient History
Demography
D
7.1.2.3
x
Inclusion / Exclusion 
criteria
D
5
x
x
Relevant medical 
history / current medical 
conditions
D
7.1.2.3
x
ER and PgR status
D
7.1.2.3
x
HER2 status
D
7.1.2.3
x


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Diagnosis and extent of 
cancer
D
7.1.2.3
x
Prior antineoplastic 
therapy
D
7.1.2.3
x
Prior / concomitant 
medication
D
7.1.2.3
Continuous – up to 30 days after last dose
Randomization
Eligibility checklist 
(within IRT)
S
7.1.2.1
x
IRT – randomization
D
7.1.2
x
Physical Examination
Physical examination
S
7.2.2.1
x
(×)
x
x
Every third 
cycle
x
Performance status 
(ECOG)
D
7.2.2.4
x
(x)
x
x
x
x
Every third 
cycle
x
Height
D
7.2.2.3
x
Weight
D
7.2.2.3
x
x
x
As clinically 
indicated
x
Vital signs
D
7.2.2.2
x
x
x
x
x
x
Every third 
cycle
x


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Laboratory assessments
Hematology
D
7.2.2.5.1
x
(x)
x
x
x
x
Every third 
cycle
x
Biochemistry (including 
fasting glucose)
D
7.2.2.5.2
x
(x)
x
x
x
x
Every third 
cycle
x
Fasting Lipid panel
D
7.2.2.5.2
x
x
FSH (Local at 
screening for eligibility
S
5.2
x
FSH
D
7.2.2.5.5
x
Plasma estradiol (Local 
at screening for 
eligibility)
S
5.2
x
Coagulation
D
7.2.2.5.3
x
x
x
x
Urinalysis
D
7.2.2.5.4
x
x
x
x
Tumor Assessment


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Tumor Assessment
D
7.2.1.1
×
Every 8 weeks during the first 18 months, then every 12 weeks until 
36 months, and thereafter as clinically indicated until disease 
progression, death, withdrawal of consent, loss to follow-up, 
subject/guardian decision, and at EOT (If PR/CR is reported, 
confirmation of response is required; confirmatory assessment should 
be performed ≥ 4 weeks after response is first documented.)
x
Fluid/Tissue collection 
results (if available)
D
7.2.1
As clinically indicated until disease progression
Whole body bone scan
D
7.2.1
x (within 42 days prior to 
randomization)
As clinically indicated
Safety
Triplicate ECG 
(standard 12-lead)
D
7.2.2.7.1
x
x
x
x
x
x
x
For all 
cycles up to 
Cycle 6, 
then as 
clinically
indicated
x
ECHO or MUGA with 
EF
D
7.2.2.7.2
x
As clinically indicated
x
Serum Pregnancy Test 
(Local)
D
7.2.2.5.5
x
X


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Urine Pregnancy test 
D
7.2.2.5.5
x
x
x
Every third 
cycle
Concomitant 
medications/procedures
D
6.4
x
Continuous
x
x
Adverse events
D
8
x
Continuous
x
x
End of Phase 
Disposition
D
7
x
x


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
Liver biopsy for hepatic 
toxicity 
D
7.2.4.2
As clinically indicated in case of liver toxicity 
Patient Reported Outcome
EORTC QLQ-C30
D
7.2.6
x
EORTC QLQ-BR23
D
7.2.6
x
EQ-5D-5L
D
7.2.6
x
Treatment
Tamoxifen or NSAI
D
6
Daily
Goserelin
D
6
Days 1 of each cycle


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
Post- treatment 
Phase
Visit name
Screening
Cycle 1
Cycle
2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
within 15 
days 
from the 
last dose
Safety 
follow 
up
EOT + 
30 
days
Efficacy 
Follow 
up
Survival 
Follow 
up
(Every 
12 
weeks)
Treatment days
-28 to -1
-14 to -1
1
15
1
1
15
16
1
N/A
LEE011 / Placebo
D
6
Days 1-21 of each cycle
Discontinuation
IRT - discontinuation
S
7.1.5
x
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.6.2
x
x
x
x
Survival follow-up
D
7.1.6.3
x


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Table 7-1b
Visit evaluation schedule – Cross over treatment cycles for patients who cross over from placebo to LEE011 after 
protocol amendment 6
Category
Reference 
to Protocol 
Section
Treatment Phase
(only applies to cross-over patients for cross over treatment cycles – after that refer to 
Table 7-1a for schedule for EOT and post treatment phase assessments)
Visit name
Cross over 
   Cycle 1
Cross 
over
Cycle 2
Cross over 
Cycles 3-6
All subsequent 
Cross over
cycles
Treatment days
1
15
1
15
1
1
Physical Examination
Physical examination
S
7.2.2.1
x
x
x
Every 3rd cycle
Performance status 
(ECOG)
D
7.2.2.4
x
x
x
Every 3rd cycle
Weight
D
7.2.2.3
X
x
x
As clinically indicated
Vital signs
D
7.2.2.2
x
x
x
Every 3rd cycle
Laboratory assessments
Hematology
D
7.2.2.5.1
x
x
x
x
x
Every 3rd cycle
Biochemistry (including 
fasting glucose)
D
7.2.2.5.2
x
x
x
x
x
Every 3rd cycle
Coagulation
D
7.2.2.5.3
As clinically indicated
Tumor Assessments
Tumor Assessment
D
7.2.1.1
As clinically indicated
Fluid/Tissue collection 
results (if available)
D
7.2.1
As clinically indicated


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Category
Reference 
to Protocol 
Section
Treatment Phase
(only applies to cross-over patients for cross over treatment cycles – after that refer to 
Table 7-1a for schedule for EOT and post treatment phase assessments)
Visit name
Cross over 
   Cycle 1
Cross 
over
Cycle 2
Cross over 
Cycles 3-6
All subsequent 
Cross over
cycles
Treatment days
1
15
1
15
1
1
Whole body bone scan
D
7.2.1
As clinically indicated
Safety
Triplicate ECG (standard 
12-lead)
D
7.2.2.7.1
x
x
x
As clinically indicated 
ECHO or MUGA with EF
D
7.2.2.7.2
As clinically indicated
Urine Pregnancy test1
D
7.2.2.5.5
x
x
On cycle 3, then every 3rd cycle
Concomitant 
medications/procedures
D
6.4
Continuous
Adverse events
D
8
Continuous
Treatment
NSAI
D
6
Daily


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Category
Reference 
to Protocol 
Section
Treatment Phase
(only applies to cross-over patients for cross over treatment cycles – after that refer to 
Table 7-1a for schedule for EOT and post treatment phase assessments)
Visit name
Cross over 
   Cycle 1
Cross 
over
Cycle 2
Cross over 
Cycles 3-6
All subsequent 
Cross over
cycles
Treatment days
1
15
1
15
1
1
Goserelin
D
6
Day 1 of each cycle
LEE011*
D
6
Days 1-21 of each cycle
*Those patients in placebo + tamoxifen combination arm that will cross over to LEE011 combination therapy should complete a wash-out period for tamoxifen of 5 half 
lives (35 days) before initiation of LEE011. During this period, those patients can be treated with NSAI (letrozole or anastrazole) plus goserelin.
1 Patients may have urine or serum pregnancy tests as per Investigator discretion or local requirements.


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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to randomization or within 1 to 14 days prior to randomization for selected assessments (see 
Table 7-1a for list of assessments to be performed).
Note: Any screening assessment that is done outside the screening window (Day -28 to Day -1 
or Day -14 to Day -1 as applicable) must be repeated prior to randomization.
Re-screening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (i.e. IRT randomization). In this case the Subject No 
assigned to the patient initially will be used and the patient will be identified with this number 
throughout her entire participation to the study.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range before screen 
failing the patient. If the repeated laboratory result meets the criteria, that result may be used to 
determine eligibility. If the repeated laboratory result does not meet the criteria, the patient will 
be considered a screening failure. In case rescreening occurs, all evaluations re-assessed should 
meet the eligibility criteria. A new informed consent form must be signed only if there is an 
interruption in the patient’s eligibility evaluation and the investigator chooses to re-screen the 
patient following screen failure; the 28 day screen period does not apply to the informed consent 
process. If a new informed consent form is signed, adverse events and medical history will be 
assessed relative to the new informed consent date.
Assessments of patient reported outcomes should be collected prior to any clinical assessments, 
drug dosing or diagnostic testing.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization, including before signing the main study ICF can be considered 
as the baseline images for this study.
7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 


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experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details).
7.1.2.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Date of birth and initials (where permitted), sex, race, ethnicity, source of 
patient referral)

Diagnosis and extent of cancer (including staging at study entry and histology/cytology)

Medical history (e.g., important medical, surgical, and allergic conditions from the patient’s 
medical history which could have an impact on the patient’s evaluation) / current medical 
conditions (e.g., all relevant current medical conditions which are present at the time of 
signing informed consent). Ongoing medical conditions, symptoms and disease which are 
recorded on the Medical History eCRF should include the toxicity grade.

ER, PgR and HER2 status

All prior antineoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for cancer prior to the 
administration of study drug.

All medications and significant non-drug therapies taken within 30 days before the first dose 
is administered. They must be recorded on the Prior and Concomitant medication or 
Surgical and medical procedures eCRF page and updated on a continual basis if there are 
any new changes to the medications.

Patient-reported outcome questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23, EQ-
5D-5L, 
(See Section 7.2.6).
Furthermore the following assessments will be performed:

Vital signs

Height, weight

Physical examination

Performance status (ECOG)

Laboratory evaluations (hematology, , INR, chemistry, lipid panel, urinalysis)

ECG

ECHO/MUGA

Radiological assessments (e.g. CT Scan)
7.1.3
Run-in period
Not applicable.
7.1.4
Treatment period
Patients will be treated with tamoxifen or a NSAI + goserelin + LEE011 or tamoxifen or a 
NSAI + goserelin + placebo until disease progression, unacceptable toxicity, withdrawal of 
consent by the patient, patient is lost to follow up, death, discontinuation from the study 


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treatment due to any other reason or the sponsor terminates the study. For details of assessments, 
refer to Table 7-1a.
7.1.5
End of treatment visit including study completion and study treatment 
discontinuation
Patients who completely discontinue study treatment should be scheduled for an End of 
Treatment (EOT) visit within 15 days following the date study treatment is permanently 
discontinued, at which time all of the assessments listed for the EOT visit will be performed. 
For details of assessments, refer to Table 7-1a. If the decision to discontinue the patient occurs 
at a regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit.
An End of phase disposition eCRF page should be completed, giving the date and reason for 
stopping the study treatment. If a withdrawal occurs, or if the patient fails to return for visits, 
the investigator must determine the primary reason for a patient’s premature withdrawal from 
the study and record this information on the EOT eCRF page. The EOT visit is not considered 
the end of the study.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of study treatment.
If a patient discontinues study treatment, but continues study assessments, the patient remains 
on study until such time as she completes protocol criteria for ending study assessments. At that 
time, the reason for study completion should be recorded on the End of Post Treatment Phase 
Disposition CRF page.
The Investigator must contact the IRT to register the subject’s discontinuation.
7.1.5.1
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time.
If a patient decides to discontinue from the study treatment, the investigator must make 
reasonable effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision 
and record this information in the patient’s chart and on the appropriate CRF pages. They may 
be considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being.
Patients may be withdrawn from the study treatment if any of the following occur:

Adverse Event (including, but not limited to QTcF ≥ 501 msec, confirmed at repeated 
ECG measurements and recurrent after dose adjustment was performed; documented 
episode of ventricular tachycardia, or ventricular fibrillation)

Lost to follow-up

Physician decision

Progressive Disease


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
Protocol deviation

Study terminated by sponsor

Technical problems
Patients must be withdrawn from the study treatment if any of the following occur:

Pregnancy

Death

Subject/Guardian decision
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation:

Adjustments to study treatment that result in discontinuation. Please refer to Section 6.3.

Use of prohibited medication. Please refer to Section 6.4.3.
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1. If they fail to return for these 
assessments for unknown reasons, reasonable effort (e.g. telephone, email, letter) should be 
made to contact them as specified in Section 7.1.5.
Patients who discontinue study treatment should undergo an End of Treatment (EOT) visit 
followed by a 30 day safety follow-up.
7.1.5.2
Replacement policy
Not applicable.
7.1.6
Follow-up period
7.1.6.1
Safety follow-up
All patients will be followed up for safety up to 30 days after last dose of study treatment 
(tamoxifen/NSAI + goserelin + LEE011/placebo). Patients whose treatment is interrupted or 
permanently discontinued due to an AE, including abnormal laboratory value, must be followed 
until resolution or stabilization of the event, whichever comes first. This could include all study 
assessments appropriate to monitor the event.
7.1.6.2
Efficacy follow-up
For patients who discontinue treatment for reasons other than disease progression, death, lost 
to follow-up, or withdrawal of consent, tumor assessments (see Section 7.2.1) and selected 
patient reported outcomes (see Section 7.2.6) must continue to be performed every 8 weeks 
during the first 18 months and every 12 weeks until 36 months, then change to as clinically 
indicated until disease progression, death, lost to follow-up, or withdrawal of consent. At that 
time, the reason for study completion should be recorded on the End of Post treatment phase 
Disposition eCRF page. If a patient starts a new anti-cancer therapy prior to progression, tumor 
evaluations should continue with the same above schedule (Table 7-1a) until disease 
progression is documented. In addition, all new anticancer therapies given after the last dose of 


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the study drug, until disease progression, death, lost to follow-up, or withdrawal of consent will 
be recorded in the eCRFs.
7.1.6.3
Survival follow-up
All patients will be followed for survival status every 12 weeks (see Section 4.1.5) including 
documentation of the start of new antineoplastic therapy, until death, lost to follow-up, or 
withdrawal of consent. Additional survival assessments may be performed outside the 12 weeks 
follow up schedules if a survival update is required for an interim assessment to meet safety or 
regulatory needs.
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs.
During the survival follow up, subsequent anti-neoplastic therapies initiated after study 
treatment discontinuation will be collected along with the start/end date and date of disease 
progression on subsequent therapies.
7.1.6.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
Disposition CRF.
7.1.7
End of post-treatment follow-up visit
Prior to collecting survival follow-up information, the end of post treatment phase disposition 
eCRF page will be completed once a patient has discontinued study treatment, completed safety 
follow-up, and can no longer perform efficacy assessment.
End of post-treatment follow-up may occur for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Progressive disease

Protocol deviation

Study terminated by the sponsor

Technical problems

Subject/guardian decision

Death


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7.1.8
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Imaging tumor assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Appendix 3) based on RECIST Version 1.1 (Eisenhauer et al 2009). Further details 
regarding blinded independent review committee (BIRC) assessment will be provided in the 
BIRC charter. The central review of the scans will be carried out in a blinded fashion for a 
randomly selected subgroup of patients (see Section 9.3.6). The decision regarding patient 
management will remain with the local investigator.
Patients should have at least one documented measurable lesion (per RECIST v1.1) or in the 
absence of measurable disease, have at least one predominantly lytic bone lesion at study entry.


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Imaging assessments will be performed at screening within 28 days prior to randomization and 
subsequently every 8 weeks following randomization during the first 18 months and every 12 
weeks until 36 months, then change to as clinically indicated. See Table 7-2 for details of 
assessments. The 8-week,12 week, or as clinically indicated interval should be respected 
regardless of whether study treatment is temporarily withheld.
After baseline, all assessments should be performed within ±7 days of the scheduled day of 
assessment. The same method of assessment and the same technique should be used to 
characterize each individual and reported lesion at baseline and during follow up.
If a patient discontinues treatment for reasons other than radiological documentation of 
progression of disease, an efficacy assessment should be performed at the time of End of 
Treatment unless a CT/MRI for tumor measurement was performed within 21 days. Efficacy 
assessments should continue as per the scheduled visit per Table 7-1a, Table 7-1b and Table 7-
2.
To the extent possible, each lesion should be assessed using the same imaging method 
throughout the study.
All patients will undergo CT or MRI of the chest, abdomen and pelvis at baseline and 
subsequent scheduled visits per Table 7-1a, Table 7-1b and Table 7-2. The preferred imaging 
methodology is CT with intravenous (i.v.) contrast. However, if at baseline, a patient is known 
to have a contraindication to CT i.v. contrast media or develops a contraindication during the 
trial, a non-contrast CT of chest (MRI is not recommended due to respiratory artifacts) plus 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.
A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET)) should be 
acquired at baseline for all subjects if not collected previously within 42 days (6 weeks) prior 
to randomization. Skeletal lesions identified on the whole body bone scan at baseline, which 
are not visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at baseline 
and followed at scheduled visits using localized CT, MRI or x-ray. Whole body bone scans
need not be repeated after baseline unless clinically indicated.
Color photography, including a metric ruler to estimate the size of the lesion, must be acquired 
for all skin lesions present at baseline per instructions provided in the manual from the 
designated vendor. These should be followed throughout the study according to the schedule 
outlined in Table 7-2.
Other metastatic disease sites will be followed by CT or MRI, as clinically indicated.
Chest x-ray or ultrasound should not be used to assess tumor lesions. Partial Response (PR) and 
Complete Response (CR) must be confirmed by repeat assessments performed not less than 4 
weeks and after the criteria for objective response are first met. In case tumor assessment is 
performed <8 weeks from the first assessment of an objective response to confirm PR/CR, 
subsequent tumor assessments should revert back to the protocol schedule outlined in Table 7-
1a. Positron Emission Tomography (PET)/CT may be used only if the CT component is of 
similar diagnostic quality as a CT performed without PET, including the utilization of oral and 
i.v. contrast media. At the discretion of the Investigators, FDG-PET scans may be performed to 
document progressive disease per RECIST 1.1 (Appendix 3). If possible, a single radiologist 


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should perform all tumor response evaluations for an individual patient. Any lesions in 
previously irradiated areas should not be considered measurable unless they have experienced 
progression since the radiotherapy. Any pre-existing radiographic findings which may mimic 
metastatic disease and any prior radiotherapy should be recorded in the eCRF.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization (and 42 days for the whole body bone scan), including before 
signing the main study ICF can be considered as the baseline images for this study.
Results from tissue or body fluid collection should be recorded in the eCRF to complement 
radiographic findings.
All study imaging performed, including any intercurrent or off-schedule imaging studies 
acquired (e.g., to fulfill a progression or response criterion), should be submitted to the 
designated imaging CRO for quality control promptly after acquisition. If an off-schedule 
imaging assessment is performed to confirm response or if progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Physical exam tumor assessments, photography, pathology/histology and cytology results, as 
well as information regarding prior interventions, pre-existing radiographic findings that mimic 
metastatic disease at baseline/screening and on-study interventions should be captured in the 
appropriate eCRFs and may be transmitted to the imaging CRO for additional review if 
appropriate.
Radiology review from the blinded independent review committee has been completed. 
Therefore, patients’ radiological and photography data images should no longer be transmitted 
to the imaging CRO.
Table 7-2
Imaging collection plan
Procedure
Screening: day −28 to 
day -1
Treatment phase*
End of 
treatment*
Post-Treatment 
Phase
CT or MRI 
(Chest, 
Abdomen, 
Pelvis)
Mandated 
Every 8 weeks during 
the first 18 months,  
every 12 weeks until 
36 months, then 
change to as 
clinically indicated(+/-
7 days)
Mandated
Every 8 weeks 
during the first 18 
months and every 
12 weeks until 36 
months, then 
change to as 
clinically indicated
until disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
subject/guardian 
decision (+/- 7 
days)
Brain CT or
MRI
Only if suspected brain 
metastases
Only if suspected brain metastases
Whole body 
bone scan**
Mandated, within 42 days 
(6 weeks) prior to 
randomization. 
As clinically indicated
As clinically 
indicated
As clinically 
indicated


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Procedure
Screening: day −28 to 
day -1
Treatment phase*
End of 
treatment*
Post-Treatment 
Phase
Bone X-ray, CT 
or MRI
Only if skeletal 
abnormalities identified by 
whole body bone scan (or 
skeletal survey) at 
screening, which are not 
visible in the chest, 
abdomen, pelvis CT/MRI.
If bone lesion at 
screening, every 8 
weeks during the first 
18 months and every 
12 weeks until 36 
months, then change 
to as clinically 
indicated (+/- 7 days)
Mandated only if 
bone lesion at 
screening
If bone lesion at 
screening, every 
8 weeks during 
the first 18 
months and every 
12 weeks until 36 
months, then 
change to as 
clinically indicated
(+/- 7 days)
Skin color 
Photography
Only if skin lesions at 
screening
If skin lesions at 
screening, every 8 
weeks during the first 
18 months and every 
12 weeks until 36 
months, then change 
to as clinically 
indicated (+/- 7 days)
Mandated if skin 
lesions at 
screening
If skin lesions at 
screening, every 
8 weeks during 
the first 18 
months and every 
12 weeks until 36 
months, then 
change to as 
clinically 
indicated(+/- 7 
days)
CT or MRI of 
any disease 
outside of 
chest, 
abdomen and 
pelvis (e.g., 
neck)
Only if suspected lesion at 
screening
If lesion identified at 
screening, every 8 
weeks during the first 
18 months and every 
12 weeks until 36 
months, then change 
to as clinically 
indicated (+/- 7 days)
Mandated if 
lesion at 
screening
If lesion identified 
at screening, 
every 8 weeks 
during the first 18 
months and every 
12 weeks until 36 
months, then 
change to as 
clinically indicated
(+/- 7 days)
*Tumor evaluation at EOT is required for patients who discontinue study treatment before the first scheduled 
post-baseline tumor assessment (week 8) and for patients whose previous tumor assessment did not 
demonstrate PD and was done more than 21 days prior to end of treatment visit.
** Whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body bone MRI, 
sodium fluoride positron emission tomography (NaF PET) or fluorodeoxyglucose (FDG) PET.
Note: All scans will be acquired and analyzed for primary endpoint locally and sent to the CRO designated by 
Novartis for central imaging interpretation. Central collection should continue until the primary PFS analysis has 
been conducted.
 
 
 
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examinations, ECOG performance status, height 
and weight, vital signs, ECG, patient reported outcomes, laboratory assessments including 
hematology, chemistry, lipid panel
 and INR as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.3.


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7.2.2.1
Physical examination
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph-nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site. Physical examination 
is to be performed according to the visit schedule as outlined in Table 7-1a and Table 7-1b.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) will be monitored as per the visit 
schedule (see Table 7-1a and Table 7-1b). Blood pressure (systolic and diastolic) and pulse 
should be measured after the patient has been sitting for approximately five minutes.
7.2.2.3
Height and weight
Height and body weight will be measured as outlined in the visit schedule (see Table 7-1a and 
Table 7-1b).
7.2.2.4
Performance status
The performance status will be assessed according to the ECOG performance status scale (Table 
7-3) (Oken 1982) following the schedule given in Table 7-1a and Table 7-1b.
Table 7-3
ECOG performance status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
Following protocol amendment 6, clinical laboratory analyses (Hematology, Chemistry, 
Coagulation, Urinalysis, Lipid Panel) are to be performed by the local laboratory, as per the 
schedule in Table 7-1a and Table 7-1b. 
Novartis must be provided with a copy of the laboratory’s certification (if applicable), and a 
tabulation of the normal ranges and units of each parameter collected in the eCRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 


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reported via an updated tabulation indicating the new effective date. Additionally, if at any time 
a patient has laboratory parameters obtained from a different (outside) laboratory, Novartis must 
be provided with a copy of the certification and a tabulation of the normal ranges and units for 
this laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
patients in the study and evaluating any abnormalities for clinical significance.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used.
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) adverse event or when the treating physician cannot wait for central 
laboratory results for decision making (e.g. dose modifications). In this particular situation, if 
possible, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis.
The results of the local laboratory will be recorded in the eCRF if any the following criteria are 
met:

A treatment decision was made based on the local results, or

There are no concomitant central results available, or

Local lab results document an adverse event not reported by the central lab, or

Local lab results document an adverse event where the severity is worse than the one 
reported by the central lab
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the Common Terminology Criteria for 
Adverse events (CTCAE) version 4.0.3. Additional analyses are left to the discretion of the 
investigator.
Table 7-4
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Complete blood count (CBC) including total white blood cell count (WBC) with 
differential (neutrophil count including lymphocyte, monocyte, eosinophil, and basophil 
counts) RBC, hemoglobin (Hgb), hematocrit (Hct), and platelet count.
Biochemistry (with 
fasting glucose)
Total proteins, albumin, total bilirubin, direct bilirubin, indirect bilirubin, AST, ALT, GGT, 
bicarbonate, calcium, corrected calcium, chloride, creatinine kinase, alkaline 
phosphatase, amylase, lipase, magnesium, sodium, potassium, urea or BUN, uric acid, 
serum creatinine, and fasting glucose
Fasting Lipid Panel
Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides (fasting)
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
If there are any significant findings on the dipstick then a microscopic evaluation should 
be measured: Microscopic Panel (WBC and RBC sediments, Casts, Crystals, Bacteria, 
Epithelial cells)
Coagulation
INR
Other Test
FSH, 


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Test Category
Test Name
7.2.2.5.1 Hematology
Hematology tests are to be performed according to the Visit Schedules outlined in Table 7-1a
and Table 7-1b. For details of the Hematology panel refer to Table 7-4. Note: If the laboratory 
screening assessments were performed ≤ 7 days prior to the first dose of LEE011/placebo, then 
they do not need to be repeated on Cycle 1 Day 1.
Hematology should be assessed on the scheduled day, even if study drug is being withheld.
7.2.2.5.2 Biochemistry
Biochemistry tests are to be performed according to the Visit Schedules outlined in 
Table 7-1a, Table 7-1b and Table 7-4. Note: If the laboratory screening assessments were 
performed ≤ 7 days prior to the first dose of LEE011/placebo, then they do not need to be 
repeated on Cycle 1 Day 1.
Biochemistry should be assessed on the scheduled day, even if study drug is being withheld.
7.2.2.5.3 Coagulation
INR is to be performed according to the Visit Schedules outlined in Table 7-1a and Table 7-1b. 
If the coagulation blood sample collected at screening is clotted when received by central 
laboratory for testing or the central laboratory results of only the coagulation are delayed, the 
patient is still eligible to enter the study with a local INR test ≤1.5.
7.2.2.5.4 Urinalysis
Urinalysis is to be performed according to the Visit Schedules outlined in Table 7-1a and Table 
7-4.
7.2.2.5.5 Additional laboratory tests
FSH,
 and serum or urine pregnancy tests (patients who have undergone a 
hysterectomy do not need pregnancy tests performed) are to be performed according to the Visit 
Schedules outlined in Table 7-1a, Table 7-1b and Table 7-4. At screening, a serum pregnancy 
test should be performed regardless of the age of the patients, while at baseline, during the study, 
and at the end of trial, urinary pregnancy tests are sufficient. Serum pregnancy tests may be 
performed where locally required or per Investigator discretion. 
FSH 
 will be collected locally at screening for eligibility, while during the study, 
FSH will then be collected by the central laboratory.
Note:
 
 


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7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
Following protocol amendment 6, central ECG collection ceases and all ECGs should be read 
locally.


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Standard triplicate 12 lead ECG assessments will be performed after the patient has been resting 
for 5-10 minutes prior to each time point indicated in Table 7-5 below. Triplicate ECGs should 
be taken approximately 2 minutes apart. The combined QTcF values from these triplicate ECGs
will be averaged to provide a single value for each time point. Eligibility will be based on the 
average of the triplicate ECGs conducted at screening.
Timing of study procedures:
*ECG assessments are to be done prior
 (if applicable).
Table 7-5
Central ECG collection plan
Cycle
Patients
Day
Time
ECG Type
Screening
All
-14 to -1
Anytime
Triplicate 12 Lead
1
All
Day 1
Pre-dose1
Triplicate 12 Lead 
All
Day 152
Pre-dose1
Triplicate 12 Lead
All
2 h post-dose (± 15 
min)
Triplicate 12 Lead
All
4 h post-dose (± 15 
min)
Triplicate 12 Lead
2
All
Day 1
Pre-dose1
Triplicate 12 Lead
3
All
Day 1
Pre-dose1
Triplicate 12 Lead


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Cycle
Patients
Day
Time
ECG Type
3
All
Day 152
Pre-dose1
Triplicate 12 Lead
All
2 h post-dose (± 15 
min)
Triplicate 12 Lead
4
All
Day 1
Pre-dose1
Triplicate 12 Lead
5
All
Day 1
Pre-dose1
Triplicate 12 Lead
6
All
Day 1
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 
min)
Triplicate 12 Lead
All other cycles
As clinically 
indicated
Anytime
Triplicate 12 Lead
EOT
Anytime
Triplicate 12 Lead
Unscheduled ECG
Anytime
Triplicate 12 Lead
1 The exact date and time of dosing must be recorded on the appropriate eCRF.
2 ECG assessments are to be done prior
 (if applicable)
ECG Schedule of assessments for cross over patients: 
Patients 
Cross Over Cycle 
Day / time 
ECG type 
All 
1
1/Pre-dose 
Triplicate 12 Lead
All 
1 
15/anytime 
Triplicate 12 Lead
All 
2 
1/ anytime 
Triplicate 12 Lead
All 
All other cycles as clinically indicated 
Triplicate 12 Lead
In order for an accurate evaluation of baseline QTcF, a total of three 12-lead ECGs will be 
performed pre-dose on Cycle 1 Day 1.
Note: In order to ensure ECG evaluation is received from the central laboratory for eligibility 
assessment, it is advisable to perform the ECG at least 24 hours prior the scheduled 
randomization date.
If any of the triplicate readings include an abnormal ECG or an average QTcF value of ≥ 481
is obtained at any time after randomization, study treatment must be interrupted, repeat ECG 
(triplicate) and follow management guidelines detailed in Table 6-5.
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected in triplicate. Local cardiologist ECG assessment may be performed at any 
time during the study at the discretion of the investigator.


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All ECGs including unscheduled triplicate ECGs with clinically relevant findings, collected 
during the study should be transmitted to the central laboratory and will be centrally reviewed 
by an independent reviewer. The results of the centrally assessed ECGs are electronically 
transferred into the clinical database. Any original ECG not transmitted to a central laboratory 
should be forwarded for central review. Interpretation of the tracing must be made by a qualified 
physician and documented on the ECG CRF page. Each ECG tracing should be labeled with 
the study number, patient initials (where regulations permit), patient number, date, and kept in 
the source documents at the study site. Clinically significant ECG abnormalities present at 
screening when the patient signed informed consent should be reported on the Medical History 
CRF page. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the Adverse Events CRF page.
In the event that a QTcF value of > 500 ms is observed or if an unscheduled ECG is performed 
for safety reasons, 
 record the time 
and date of the last study drug intake to determine the drug exposure.
Following protocol amendment 6, central ECG collection ceases and all ECGs should be read 
locally. 
. 
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
Cardiac imaging will be performed by Multiple Gated acquisition (MUGA) scan or 
Echocardiogram (ECHO) in order to assess the left ventricular ejection fraction (LVEF). This 
assessment will be performed according to the schedule given in Table 7-1a and Table 7-1b.
The same technique (MUGA or ECHO) must be used during the course of the trial, and the 
method used will be recorded in the eCRF. Only clinically significant abnormalities should be 
reported in the Adverse Events eCRF.
In case a patient develops left ventricular systolic dysfunction while on study treatment dose 
adjustment guidelines described in Table 6-7 must be followed.


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7.2.3.1
Analytical method
Sample analysis will be performed by Novartis or a Novartis designated laboratory using 
validated methods. Plasma concentrations of LEE011 (and any relevant metabolites such as 
LEQ803), tamoxifen (and any relevant metabolites such as N-desmethyltamoxifen, 4-
hydroxytamoxifen, and endoxifen), letrozole and anastrozole will be measured using a liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) methods with a lower limit of 
quantification (LLOQ) of approximately 1.00 ng/mL, 10 ng/mL, 2 ng/mL, and 10 ng/mL for 
LEE011, tamoxifen, letrozole, and anastrozole, respectively. Any results below the LLOQ and 
any missing samples will be recorded accordingly.
Leftover plasma from analysis may be used for exploratory metabolite assessments or other 
bioanalytical purposes (e.g., cross check between different sites, stability assessment). Given 
the exploratory nature of the work, the analytical method used for those assessments will not 
be validated.


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7.2.6
Patient reported outcomes
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) and breast cancer specific questionnaire 
(EORTC QLQ-BR23, version 1.0) 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 EORTC QLQ-C30, 
EORTC QLQ-BR23 and the EQ-5D-5L are recognized reliable and valid measures (Aaronson 
1993, Sprangers 1996, Rabin 2001) frequently used in clinical trials of patients with advanced 
or metastatic breast cancer.
 
In addition to 
 all health-related quality of life questionnaires, EORTC QLQ-
C30, EORTC QLQ-BR23, and the generic health utility measure EQ-5D-5L will be 
administered before any study drug administrations at the visits indicated in Table 7-1a,
Table 7-14 and Table 7-15. Collection of all PRO measures (e.g., EORTC QLQ-C30, EORTC 
QLQ-BR23, EQ-5D-5L
) have a ± 3 day window unless otherwise indicated.
All questionnaires should be administered in the patient’s local language prior to any interaction 
with the study investigator. This is to avoid potentially biasing patients or their responses to 
study questionnaires. Patients should be given sufficient space and time to complete all study 


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questionnaires and all administered questionnaires should be reviewed for completeness. If 
missing responses are noted, patients should be encouraged to complete any missing responses. 
Attempts should be made to collect responses to all questionnaires for all patients, including 
from those who discontinue prior to the study evaluation completion visit, however, if patients 
refuse to complete questionnaires, this should be documented in study source records. Patient’s 
refusal to complete study questionnaires are not protocol deviations.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records.
If an AE or SAE is confirmed then the physician should record the event as instructed in Section 
8 of this protocol. Investigators should not encourage the patients to change responses reported 
in questionnaires.
Following protocol amendment 6, no additional PRO measures should be collected from any 
patients.
7.2.6.1
EORTC QLQ-C30 and EORTC QLQ-BR23
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). The EORTC QLQ-BR23 is used in conjunction 
with the EORTC QLQ-C30 and provides information on an additional 23 items specifically 
related to breast cancer. It incorporates five multi-item scales to assess systemic therapy side 
effects, arm symptoms, breast symptoms, body image and sexual functioning. In addition, 
single items assess sexual enjoyment, hair loss and future perspective.
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a high / 
healthy level of functioning; a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale / item represents a high level of symptomatology / 
problems. All scoring will follow the scoring procedures defined by the EORTC Scoring 
Manual (Fayers et al 2001).
7.2.6.2
EQ-5D-5L
The EQ-5D-5L (Version 4.0) is a standardized measure of health utility that provides a single 
index value for one’s health status. The EQ-5D-5L is frequently used for economic evaluations 
of health care and has been shown to be a valid and reliable
instrument 
(The EuroQol Group 1990, Rabin 2001). The EQ-5D-5L contains one item for each of five 
dimensions of HRQOL (i.e., mobility, self-care, usual activities, pain or discomfort, and anxiety 
or depression). Response options for each item vary from having no problems (e.g., “…no 
problems walking about”), moderate problems (e.g., “…some problems walking about”), or 
extreme problems (e.g., “…unable to walk about”). Patient responses to the five dimensions of 
HRQOL reflect a specific health state that corresponds to a population preference weight for 


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that state on a continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging 
from 0 to 100) is also included to capture patient’s rating of their overall health status. Higher 
scores of the EQ-5D-5L represent better health states. All scoring and handling of data will 
follow the User’s Guide defined by the EuroQoL Group (Rabin 2011).
The EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D-5L should be administered as per 
Table 7-1a and Table 7-14.
Table 7-14
Patient reported outcomes collection plan
Patient Questionnaire
Cycle
Day
Time
EORTC QLQ-C30
EORTC QLQ-BR23
EQ-5D-5L
Screening
-28 to Day -1
Prior to any clinical 
assessments, drug 
dosing or diagnostic 
testing.
Subsequent cycles
Every 8 weeks after 
randomization during the first 
18 months, then every 12 
weeks until 36 months, and 
thereafter align with the 
efficacy assessments until
disease progression, death, 
withdrawal of consent, loss to 
follow-up, subject/guardian 
decision
End of treatment
Day of EOT visit
Safety follow-up
Day of Safety follow-up visit
Efficacy follow-up
Continue collection every 8 
weeks after randomization 
during the first 18 months and 
every 12 weeks thereafter until
36 months, then align with the 
efficacy assessments until
disease progression, death, 
withdrawal of consent, loss to 
follow-up, subject/guardian 
decision 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study but is collected as seriousness criteria; rather, information about deaths 
will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 


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(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in 
Section 8.2.1, and which seriousness criteria have been met
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
If the event worsened, the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined, a new entry for this event should be reported in the CRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 


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followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent.

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition.

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 


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occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Instructions 
regarding the SAE submission process and requirements for signatures are to be found in the 
investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Following protocol amendment 6, the emergency unblinding procedures are no longer 
applicable as all patients will be centrally unblinded and made aware of their study treatment.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.


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8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data monitoring committee
An independent data monitoring committee (IDMC) will be established to assess the safety 
 
 
 The IDMC will be responsible for reviewing the safety 
results and overseeing the safety data accruing in the trial at regular intervals, approximately
every six months. Also, if requested by the IDMC Chair, additional safety reviews may be 
performed.
The IDMC will consist of at least two oncologists and one biostatistician and will be formed 
prior to the randomization of the first patient. Detailed recruitment status and interim safety 
reports will be provided to the IDMC on a regular basis. Recruitment will not be interrupted. 
Details will be provided in the IDMC charter.
 
 
To ensure trial integrity and blinding are maintained, processes will be established and 
documented in the appropriate study documents (e.g. Data Handling Plan, DMC Charter) and 
an independent team within Novartis will be formed to receive and submit these data. 
 
8.7
Steering committee
The SC will be established comprising investigators participating in the trial, and Novartis 
representatives from the Clinical Trial Team.
The SC will be an advisory board for the study according to the protocol through recommending 
modifications as circumstances require. The SC will be consulted for protocol amendments as 
appropriate. Together with the clinical trial team, the SC will also develop recommendations 
for publications of study results. The details of the role of the SC will be defined in a SC charter. 
The SC will not have access to unblinded trial data.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why


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
Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 


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have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.3.1
ECG data collection
ECG data will be collected via 12-lead digital ECG machines and analyzed locally. 


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9.3.4
IRT data collection
Patient eligibility and enrollment will be tracked using an Interactive Response Technology. 
The system will be supplied by a vendor, who will also manage the database for that system.
9.3.5
Central laboratory
Following protocol amendment 6, laboratory samples will be collected and analyzed locally
and the results will be entered directly into the CRF.
9.3.6
Central radiology
Radiological imaging and photography data will be acquired by the sites and interpreted locally. 
Additionally, radiological and photography data will be transmitted by the sites to the CRO 
designated by Novartis to undergo quality checks and central review by a blinded independent 
review committee (BIRC). The BIRC will perform an assessment of PFS data for a randomly 
selected subgroup of patients. An independent random sampling process will select all scans 
(and relevant information) from approximately 40% of randomized patients (see Section 10.8), 
whose BIRC randomization identity will be unknown to the investigators. If consistency of 
treatment effect is not established, the BIRC may perform an assessment of PFS data for all 
patients.
Tissue and fluid collections results and pre-existing radiographic findings will be recorded in 
the eCRF and may be transmitted to the imaging CRO for review if appropriate. Further details 
regarding BIRC assessment will be provided in the BIRC charter. The central review of the 


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scans will be carried out in a blinded fashion. The decision regarding patient management will 
remain with the local investigator.
Note: Once the radiology review from the blinded independent review committee has been 
completed, patients’ radiological and photography data images should no longer be transmitted 
to the imaging CRO. Novartis will notify all sites when central imaging submission for the trial 
is complete.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis.
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel.
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Novartis personnel (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and the treatment codes will be unblinded and made available 
for data analysis. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from all centers participating in the trial will be combined, so that an 
adequate number of patients are available for analysis. Novartis and/or a designated CRO will 
perform all analyses. Any data analyses performed independently by any investigator should be 
submitted to Novartis before publication or presentation.


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10.1
Analysis sets
10.1.1
Full analysis set
The full analysis set (FAS) comprises all randomized patients. Following the ITT principle, 
patients will be analyzed according to the treatment and strata they have been assigned to during 
the randomization procedure. The FAS will be the primary population for all the efficacy 
analyses.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study medication defined 
as tamoxifen/NSAI, goserelin, LEE011 or placebo. Patients will be analyzed according to the 
study treatment they actually received. Actual treatment refers to the treatment that the patient 
was randomized to, unless the alternative treatment was received throughout the trial.
10.1.3
Per-protocol set
The per-protocol set (PPS) will include the subset of the patients in the FAS without major 
protocol deviations. All protocol deviations or conditions leading to exclusion from the PPS 
will be detailed in the data handling plan and analysis plan. Sensitivity analyses of the primary 
endpoint of PFS may be performed using data from the PPS if the FAS and PPS differ and if 
the primary analysis is significant.
 
 
10.1.5
Crossover analysis set
The crossover analysis set includes all patients in the placebo arm of the Safety set who elected 
to crossover to receive LEE011 combination therapy and received at least one dose of LEE011. 
This population will be used for the analysis of crossover phase data. The crossover phase refers 
to the time from first dose of LEE011 treatment following crossover until withdrawal from the 
study or death.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristic/prognostic data will be 
summarized descriptively by treatment group using data from the FAS. Categorical data will 
be presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used for the analyses below.


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The actual dose and duration of tamoxifen/NSAI, goserelin, LEE011 and placebo treatment, as 
well as dose intensity (computed as the ratio of actual dose received to actual duration) and the 
relative dose intensity (computed as the ratio of the dose intensity to planned dose 
received/planned duration), will be listed and summarized using descriptive statistics. The total 
daily doses of tamoxifen/NSAI, goserelin, LEE011 and placebo for each patient will be 
summarized using descriptive statistics (e.g. mean, median, and mode).
Concomitant medications and significant non-drug therapies will be listed by patient and 
summarized by ATC (Anatomical therapeutic chemical classification system) term for each 
treatment group. These summaries will include medications starting on or after the start of study 
treatment or medications starting prior to the start of study treatment and continuing after the 
start of study treatment. Any prior concomitant medications or significant non-drug therapies 
starting and ending prior to the start of study treatment will be listed.
Compliance to the study drug will be assessed by the number of dose reductions and dose 
interruptions.
The duration of exposure to study treatment and each component of study treatment will also 
be summarized for the crossover phase in patients who crossed over to LEE011 combination 
therapy after unblinding (i.e. using the Crossover analysis set).
10.4
Primary objective
The primary objective in the study is to determine whether treatment with tamoxifen or a NSAI
+ goserelin + LEE011 prolongs PFS compared to treatment with tamoxifen or a NSAI + 
goserelin + placebo in premenopausal women with HR+, HER2- advanced breast cancer who 
received no prior hormonal therapy for advanced breast cancer.
10.4.1
Variable
The primary efficacy endpoint of the study is PFS, defined as the time from the date of 
randomization to the date of the first documented progression or death due to any cause. If a 
patient has not had an event, PFS will be censored at the date of the last adequate tumor 
assessment (see RECIST 1.1 in Appendix 3 for further details). Clinical deterioration without 
objective radiological evidence will not be considered as documented disease progression. PFS
will be assessed via a local radiology assessment according to RECIST 1.1. PFS as assessed 
through blinded independent central review will be used for supportive evidence of the primary 
efficacy endpoint.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be the comparison of PFS between the two treatment groups 
using a stratified log-rank test at one-sided 2.5% level of significance.
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested to address the primary efficacy objective:
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0
where θ1 is the log-hazard ratio (Tamoxifen or a NSAI+goserelin+LEE011 arm vs. tamoxifen
or a NSAI+goserelin + placebo arm) of PFS.


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The primary efficacy endpoint PFS will be analyzed based on the FAS according to the 
treatment group patients were randomized and the strata they were assigned at randomization 
(strata formed using the randomization factor as obtained via IRT). PFS will be estimated using 
the Kaplan-Meier method. The median PFS along with 95% confidence intervals will be 
presented by treatment group. A stratified Cox regression model will be used to estimate the 
hazard ratio of PFS, along with 95% confidence interval. The primary analysis for PFS will be 
performed after approximately 329 PFS events have been documented per local assessment.
In addition to the primary analysis in all patients, the treatment effect in terms of PFS for
1. tamoxifen + goserelin + LEE011 vs. tamoxifen + goserelin + placebo, and
2. NSAI + goserelin + LEE011 vs. NSAI + goserelin + placebo
will be estimated using separate Cox regression models. Estimated hazard ratios with 
corresponding 95% CIs will be presented for each subgroup. PFS will be estimated using 
Kaplan-Meier methodology within each subgroup.


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10.4.3
Handling of missing values/censoring/discontinuations
PFS will be censored if no PFS event is observed before the cut-off date. The censoring date 
will be the date of last adequate tumor assessment before this date. If a PFS event is observed
after two or more missing or non-adequate tumor assessments, then PFS will be censored at the 
last adequate tumor assessment. If a PFS event is observed after a single missing or non-
adequate tumor assessment, the actual date of event will be used (see RECIST 1.1 
Appendix 3).
10.4.4
Supportive analyses
PFS as assessed by BIRC will be used for supportive evidence of the primary efficacy endpoint. 
A sample-based BIRC audit approach (Section 9.3.6) will be used to assess PFS by BIRC. Two 
methods will be used to summarize the data from the sample-based BIRC assessment of PFS. 
The NCI (National Cancer Institute) method (Dodd et al. 2011), uses an auxiliary variable 
estimator of the log-hazard ratio that combines information from patient-level investigator 
assessment from all patients and the BIRC assessment of patients randomly selected (see 
Section 9.3.6) for central review. This estimate and its one-sided 95% CI will be provided. 
Details of the sample size calculation for the BIRC assessment are provided in Section 10.8. 
The NCI method will be used for audit sample size determination and summary of treatment 
effect (HR, 95% CI) based on the supportive BIRC assessment.
The data from the BIRC assessment generated following the sampling scheme as above will 
also be summarized using the method proposed by Amit et al. 2011, referred to as the PhRMA 
(Pharmaceutical Research and Manufacturers of America) method. With this approach, the 
differential discordance of early discrepancy rate (EDR) and late discrepancy rate (LDR) 
between the two arms will be estimated as the rate on the tamoxifen or a 
NSAI+goserelin+LEE011 arm minus the rate on the tamoxifen or a NSAI+goserelin+placebo 
arm. The EDR and LDR results will also be summarized by treatment arm. Further definitions 
and details will be provided in the analysis plan.
As a sensitivity analysis, the distribution of PFS will be compared between the treatment groups 
using an unstratified log-rank test and the hazard ratio along with the associated 95% confidence 
interval resulting from an unstratified Cox model will be presented.
The primary analysis for PFS may be repeated with data based on the PPS if the primary analysis 
is statistically significant. A sensitivity analysis will be performed in which PFS is censored at 
date of the last adequate tumor assessment before any new antineoplastic therapy is started.
Other sensitivity analyses may be performed such as (1) including PFS events even if the events 
are recorded after two or more missed assessments, (2) backdating events occurring after 
missing tumor assessments.
In addition to the subgroup analyses for patients receiving tamoxifen and those receiving NSAI 
(Section 10.4.2), subgroup analyses will be performed on each level of stratification factors if 
the primary analysis is significant. The analysis will include Kaplan-Meier summaries and 
estimation of hazard ratios from un-stratified Cox regression models. Additional subgroup 
analyses to assess the homogeneity of treatment effect based on demographic and baseline 
disease characteristics may be performed; details about the subgroups to be included will be 
provided in the study analysis plan.


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Patterns of censored data will be examined by the treatment groups using descriptive statistics 
(the numbers of censored patients and reasons for censoring).
Since the primary endpoint of PFS was met at the time of the primary analysis, no further formal 
analyses of PFS are planned. If any descriptive analyses of PFS are performed after allowing 
patients ongoing on study treatment in the placebo arm to crossover to the LEE011 combination 
arm (permitted after the study had met its primary and key secondary endpoints), appropriate 
sensitivity analyses will be considered and described in the SAP, for example censoring PFS at 
the last adequate tumor assessment prior to crossover for patients in the crossover analysis set.
10.5
Secondary objectives
The secondary objectives in this study are to compare the two treatment groups with respect to 
OS, and evaluate ORR, CBR, time to response, duration of response, time to definitive 
deterioration in the quality of life and ECOG PS, and safety. OS is identified as the key 
secondary endpoint. A hierarchical testing strategy will be taken to control overall type-I error 
rate; therefore OS will be statistically evaluated and interpreted only if the primary efficacy 
endpoint PFS is significantly different between the 2 treatment groups.
10.5.1
Key secondary objective(s)
The key secondary objective of the study is to determine whether treatment with tamoxifen or 
a NSAI + goserelin + LEE011 prolongs OS compared to treatment with tamoxifen or a NSAI
+ goserelin + placebo.
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died, then OS will be censored at the date of last known date patient 
alive.
Assuming proportional hazards model for OS, the following statistical hypothesis for OS will 
be tested using a stratified log-rank test (stratified according to randomization stratification 
factors) at the one-sided 2.5% level of significance:
H02: θ2 ≥ 0 vs. Ha2: θ2 < 0
where θ2 is the log-hazard ratio (tamoxifen or a NSAI+goserelin+LEE011 arm vs. tamoxifen or 
a NSAI+goserelin+placebo arm) of OS.
The analyses for OS will be based on the FAS. The distribution of OS will be compared between 
the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance.
The final OS analysis will not be performed at the time point of the primary PFS analysis, but 
after additional follow-up. Therefore, a three-look design is considered for OS.
OS will be hierarchically tested in the following way:
1. The first potential time point for OS analysis will be at the time of the primary PFS 
analysis, when 123 deaths are expected. If PFS is statistically significant at this stage, OS 
will also be tested.
2. If OS is not statistically significant at this stage, the 2nd OS analysis will be planned after 
approximately 189 deaths.


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3. If OS is not statistically significant at this stage, a final analysis is planned after 
approximately 252 deaths have been recorded.
4. If PFS is not statistically significant at the primary analysis, then OS will not be tested.
The type I error probability for OS tests will be controlled by using a Lan-DeMets (O’Brien-
Fleming) alpha spending function at the one-sided type I error of α=0.025. This guarantees the 
protection of the overall level α = 2.5% across the two hypotheses and the repeated testing of 
the OS hypotheses in the interim and the final analyses (Glimm 2010).
The distribution function of OS will be estimated using the Kaplan-Meier method. The median 
OS along with 95% confidence intervals will be presented by treatment group. The stratified 
Cox regression will be used to estimate the hazard ratio (HR) of OS, along with 95% confidence 
interval.
Since the key secondary endpoint of OS was met at the second interim analysis, no further 
formal analyses of OS are planned. If any descriptive analyses of OS are performed after 
allowing patients ongoing on study treatment in the placebo arm to crossover to the LEE011 
combination arm (permitted after the study met its primary and key secondary endpoints), 
appropriate sensitivity analyses will be considered and described in the SAP, for example 
censoring OS at the date of first LEE011 treatment for patients in the crossover analysis set. 
10.5.2
Other secondary efficacy objectives
10.5.2.1 Overall response rate
Overall response rate is defined as the proportion of patients with best overall response (BOR) 
of complete response (CR) or partial response (PR) according to RECIST 1.1.
ORR will be calculated based on the FAS according to the ITT principle; however patients with 
only non-measurable disease at baseline will be included in the numerator if they achieve a 
complete response. ORR will be presented by treatment group along with approximate 95% 
confidence intervals. The Cochran-Mantel Haenszel chi-square test (stratified by baseline 
stratification factors) will be used to compare the two treatment groups with respect to the ORR 
at one-sided 2.5% level of significance. As a supportive analysis, ORR as assessed by the 
blinded independent central review will be calculated by treatment group and presented along 
with the approximate 95% confidence intervals. As a sensitivity analysis, ORR for patients with 
measurable disease at baseline will be calculated and presented by treatment group together
with approximate 95% confidence intervals.
10.5.2.2 Clinical benefit rate
Clinical Benefit is defined as CR or PR, or SD for 24 weeks or longer. CR, PR and SD are 
defined according to RECIST 1.1. CBR will be calculated based on the FAS; however patients 
with only non-measurable disease at baseline will be included in the numerator if they achieve 
a complete response. CBR will be summarized for the two treatment groups using descriptive 
statistics. The Cochran-Mantel Haenszel chi-square test (stratified by baseline stratification 
factor) at 2.5% one-sided level of significance, will be used to compare the two treatment groups 
with respect to the CBR. As a supportive analysis, CBR as assessed by the blinded independent 
central review will be summarized for the two treatment groups using descriptive statistics.


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10.5.2.3 Time to response
Time to response is the time from the date of randomization to the first documented response 
(CR or PR, which must be confirmed subsequently) according to RECIST 1.1. All patients in 
the FAS will be included in time to response calculations. Patients who do not achieve a 
confirmed response will be censored at the maximum follow-up time (i.e. first patient first visit 
to last patient last visit used for the analysis) for patients who had a PFS event (i.e. either 
progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. 
Time to response data will be listed and summarized by treatment group. Distribution of time 
to response will be estimated using Kaplan-Meier method if sufficient number of responses are 
recorded.
10.5.2.4 Duration of response
Duration of Overall Response (DoR) applies only to patients whose best overall response is CR 
or PR according to RECIST 1.1. The start date is the date of first documented response (CR or 
PR) and the end date is the date defined as first documented progression or death due to 
underlying cancer. In other words, the start date should be determined using the time that the 
response was first determined and not using the time the response was confirmed. If a patient 
had not had an event, duration will be censored at the date of last adequate tumor assessment. 
DoR will be listed and summarized by treatment arm using the FAS.
10.5.2.5 ECOG performance status
ECOG PS scale as described in Table 7-3 will be used to assess physical health of patients. An 
analysis of time to definitive deterioration of the ECOG PS by one category of the score from 
baseline will be performed using the FAS. Deterioration is considered definitive if no 
improvement in ECOG PS is observed at a subsequent time of measurement during the 
treatment period following the time point where the deterioration is observed.
Patients that have not worsened at the data cut-off point will be censored at the date of last 
assessment prior to data cut-off. Kaplan-Meier method will be used to estimate the distribution 
of time to definitive worsening and median time to definitive worsening will be presented along 
with a 95% confidence interval. A stratified log-rank test at one-sided 2.5% level of significance 
will be used to compare the distribution of time to definitive worsening between the 2 treatment 
arms.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
Safety will be summarized using the safety set. All listings and tables will be presented by 
treatment group. Subgroup analyses by endocrine therapy (tamoxifen vs. NSAI) may also be 
performed. In addition, for the final study report, safety data for patients who crossed over to 
the LEE011 combination arm after the study had met its primary and key secondary endpoints, 
will be summarized using the crossover analysis set. The analyses will comprise a subset of 
those described below for the safety set and the details will be specified in the SAP.
The overall observation period will be divided into three mutually exclusive segments:


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1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). SEC will be defined at project level 
and may be regularly updated. The grouping of AEs in SEC according to project standards will 
be specified in the project level master statistical analysis and/or the study statistical analysis 
plan.
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported by treatment group.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistics and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used.
In some cases (e.g., white blood cell differentials), the lower limits of normal ranges used in 
CTCAE definition have to be replaced by a clinical meaningful limit expressed in absolute 
counts.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

Frequency table for newly occurring on-treatment grades 3 or 4

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high)


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
Classification to compare baseline to the worst on-treatment value.

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan.


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10.5.3.4 Other safety data
10.5.3.4.1
ECG

Shift table from baseline to worst on-treatment result for overall assessments

Listing of ECG evaluations for all patients with at least one abnormality.
10.5.3.4.2
Vital signs

Shift table from baseline to worst on-treatment result

Table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability will be studied in terms of dose reductions and drug interruptions due to AE. 
Reasons for dose reductions and interruptions will be listed and summarized by treatment.
10.5.4
Patient-reported outcomes
Health-related quality of life questionnaires
The EORTC QLQ-C30 questionnaire along with the disease-specific breast cancer module 
(EORTC QLQ-BR23) and the EQ-5D-5L will be used to assess patient’s QoL data. The global 
health status/QoL scale score of the EORTC QLQ-C30 is identified as the primary patient-
reported outcome variable of interest. Physical functioning, emotional functioning and social 
functioning scale scores of the EORTC QLQ-C30, the breast cancer symptoms scale score of 
the EORTC QLQ-BR23 and the visual analog scale of the EQ-5D-5L are identified as 
secondary patient-reported outcome variables of interest.
Scoring of raw QoL data and methods for handling of missing items or missing assessments 
will be handled according to scoring manuals for each respective patient questionnaire (Fayers 
et al 2001, Rabin 2011). The number of patients completing each patient questionnaire and the 
number of missing or incomplete assessments will be summarized by each treatment group for 
each scheduled assessment time point for the EORTC QLQ-C30, EORTC QLQ-BR23 
questionnaires, and EQ-5D-5L. No formal statistical tests will be performed on PRO data and 
hence no multiplicity adjustment will be applied. The FAS will be used for analyzing PRO data.
Descriptive statistics will be used to summarize the scored scales for the EORTC questionnaires 
and the EQ-5D-5L at each scheduled assessment time point. Additionally, change from baseline 
in the domain scores at the time of each assessment will be summarized. Patients with an 
evaluable baseline score and at least one evaluable post baseline score during the treatment 
period will be included in the change from baseline analyses.
The distribution of time to definitive 10% deterioration in the global health status/QoL from 
EORTC questionnaires will be assessed in the two treatment arms. The time to definitive 10% 
deterioration is defined as the time from the date of randomization to the date of event, which 


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is defined as at least 10% relative to baseline worsening of the corresponding scale score 
(without further improvement above the threshold) or death due to any cause. If a patient has 
not had an event, time to deterioration will be censored at the date of the last adequate PRO 
evaluation. If a patient did not have any baseline PRO assessment, time to deterioration will be 
censored at the date of randomization. The distribution will be presented descriptively using 
Kaplan-Meier curves. Summary statistics from Kaplan-Meier distributions will be determined, 
including the median time to definitive 10% deterioration along with two-sided 95% CI. 
Additionally, time to definitive deterioration with different cutoff definitions (e.g. 5%, 15%) 
may be specified in the analysis plan as deemed appropriate. A stratified Cox regression will 
be used to estimate the hazard ratio, along with two-sided 95% CI. In addition, a longitudinal 
analysis will be performed to evaluate the two treatment groups with respect to changes in the 
global health status/QoL over time.
Similar survival and longitudinal analyses will be performed to evaluate the two treatment 
groups for physical functioning, emotional functioning and social functioning scale scores of 
the EORTC QLQ-C30 and the breast cancer symptoms scale score of the EORTC QLQ-BR23 
as additional PRO analyses to facilitate the interpretation of these data.


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10.7
Interim analysis
10.7.1
Progression free survival
No PFS interim analysis is planned in this study. The primary PFS analysis will be performed 
after approximately 329 PFS events have been documented per investigator assessment.
10.7.2
Key secondary endpoint: overall survival
Overall survival will be compared between the two treatment groups, provided the primary 
endpoint PFS is statistically significant favoring the test treatment arm (tamoxifen or a NSAI + 
goserelin + LEE011). A hierarchical testing procedure will be adopted in this study and the OS 
analyses will be performed only if the primary efficacy endpoint PFS is statistically significant.
A maximum of three analyses are planned for OS: at the time of the primary analysis for PFS 
(provided PFS is significant), at which point a total of 123 deaths are expected, after 
approximately 189 events have been documented, and a final analysis for OS when 252 deaths 
are expected (expected 40 months from date of first patient to be randomized).
An α-spending function according to Lan-DeMets (O’Brien-Fleming), (as implemented in East 
6.3) along with the testing strategy outlined below will be used to maintain the overall type I 
error probability (Lan and DeMets 1983). This guarantees the protection of the 2.5% overall 
level of significance across the two hypotheses and the repeated testing of the OS hypotheses 
in the interim and the final analysis (Glimm 2010). The trial allows for the stopping of the study 
for a superior OS result, provided the primary endpoint PFS has already been shown to be 
statistically significant favoring the test treatment arm (tamoxifen or a NSAI + goserelin +


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LEE011). Further, the exact nominal p-values that will need to be observed to declare statistical 
significance at the time of these analyses for OS will depend on the number of OS events that 
have been observed at the time of these analyses and the α for OS already spent at the time of 
earlier analyses.
The projected timing of interim analysis is summarized in Table 10-1.
Table 10-1
Estimated timelines for interim and final analyses
Months after 
randomization of 
the first patient
PFS
events
Cumulative Power 
(%) 
against a hazard 
ratio of 0.67
OS
events
Cumulative 
Conditional Power (%)
against hazard ratio 
of 0.7
22
329 (100%)
95
123 (49%)
15
30
--
--
189 (75%)
54
40
--
--
252(100%)
80
Statistical significance of OS will only be declared if significance for primary PFS analysis has been declared
At the time of primary PFS analyses, both PFS and interim OS analysis will be performed by 
the Sponsor’s clinical team. Investigators and patients will remain blinded to study treatment 
and all patients will continue to be followed for OS until the final OS analysis (or earlier if OS 
reaches statistical significance at any of the interim analyses).
Since the study has met its primary endpoint (PFS) and key secondary endpoint (OS), any 
analysis and update after protocol amendment 7 will be descriptive. 
10.8
Sample size calculation
The assumption of median PFS of 9 months in the control arm (tamoxifen/NSAI + goserelin) 
for sample size calculation is based on the meta analysis of 4 trials in premenopausal advanced 
breast cancer treated with combination of tamoxifen and luteinizing hormone-releasing 
hormone agonist (Klijn 2001) and the results of the letrozole study in breast cancer patients 
(Mouridsen 2003). It is expected that the addition of LEE011 will result in 33% reduction in 
the hazard rate (corresponding to an increase in median PFS to 13.4 months assuming PFS has 
an exponential model assumption).
If the true hazard ratio is 0.67 (under alternative hypothesis), a total of 329 PFS events provide
95% power at a one-sided overall 2.5% level of significance to reject the null hypothesis (hazard 
ratio=1). Considering a recruitment period of approximately 18 months at a uniform rate of 33 
patients/month, 600 patients will need to be randomized to the two treatment arms in a 1:1 ratio. 
Assuming about 10% patients will be lost to follow-up for PFS, a total of 660 patients will need 
to be randomized. Given the above assumptions, it is estimated that the 329th PFS event will be 
observed at approximately 22 months from the date of first patient randomized in the study. 
The sample size calculation was conducted with software package East 6.3.
It is expected that both the endocrine treatment types (tamoxifen and NSAI) will have an 
adequate number of patients randomized
for the respective subgroup analyses 


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(Section 10.4.2). However, this will be monitored closely in a blinded fashion and the protocol 
may be amended for further randomization in a given group if enrollment is found to be slow.
Audit size calculation for BIRC assessment of PFS
The audit size of the sample-based BIRC assessment will be 40% of all randomized patients. 
Based on the audit size calculation approach proposed by Dodd et al (2011), assuming 
investigator and BIRC assessments are similar and the estimated log of investigator-based HR 
is -0.40 (i.e. HR=0.67), the audit size of 40% will ensure that the upper bound of a one-sided 
95% CI for BIRC-based log-hazard ratio has 86% probability of being below zero (i.e. HR < 1) 
if the correlation between investigator assessment and BIRC assessment is 0.7 (the estimated 
correlation based on data from the BELLE-2 [CBKM120F2302] study in metastatic breast 
cancer).
10.9
Power for analysis of key secondary variables
10.9.1
Power for analysis of overall survival
OS will be compared between the two treatment arms, provided that the primary endpoint, PFS, 
is statistically significant. Based on available data (Klijn 2001, Jonat 1995) the median OS in 
control arm is expected to be around 33 months. It is hypothesized that test treatment arm 
(LEE011 + tamoxifen or a NSAI + goserelin) will result in a 30% reduction in the hazard rate 
for OS (corresponding to an increase in median survival to 47 months under the exponential 
model assumption). If the true hazard ratio is 0.7 (under alternative hypothesis), a total of 252
deaths need to be observed to have 80% power at a one-sided overall 2.5% level of significance 
to reject the null hypotheses (hazard ratio = 1) using a log-rank test and a 3-look group 
sequential design. Based on the same number of patients that are planned to be enrolled in this 
study to detect the primary endpoint, it is estimated that these 252 deaths will be observed at 
approximately 40 months from the date of first patient to be randomized. Therefore the 
estimated time for the final OS evaluation will be 18 months after the primary analysis of the 
PFS endpoint has been conducted. The power calculation was conducted with software package 
East 6.3.


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11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given her understanding. If the patient is capable of doing 
so, she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents. The date 
when a subject’s Informed Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
If there is any question that the patient will not reliably comply, they should not be entered in 
the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.


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


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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
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FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
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23-Jun-2014)


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14
Appendices
14.1
Appendix 1 - Concomitant medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or LEE011 and/or tamoxifen.
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Oncology Clinical Pharmacology guidance, Drug-Drug Interaction and Co-
Medication Considerations (v07, release date: Jan 2018), which was compiled from the Indiana 
University 
School 
of 
Medicine’s 
P450 
Drug 
Interaction 
Table 
(medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.p
df), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation and/or torsades de pointes 
(TdP), refer to the CredibleMeds® website (qtdrugs.org/). Please contact the medical monitor 
with any questions.


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Table 14-1
List of prohibited medications during study drug treatment
Category
Drug Name
Strong CYP3A4/5 inhibitors
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), posaconazole, 
ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole
Strong CYP3A4/5 inducers
Apalutamide, avasimibe2,3, carbamazepine, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)2,3
Strong CYP2D6 inhibitors 
or inducers (for patients 
receiving tamoxifen)
Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine
CYP3A4/5 substrates with 
NTI1
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine,
(dihydroergotamine), ergotamine, fentanyl, lomitapide5, lovastatin, nicardipine, 
nisoldipine, pimozide, quinidine, simvastatin, sirolimus, tacrolimus
Medications with a known 
risk for QT prolongation4
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, cocaine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, levomethadyl, mesoridazine, methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, probucol, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, 
terlipressin, terodiline, terfenadine, thioridazine, vandetanib
CYP2C9 with NTI (for 
patients receiving 
tamoxifen)
Warfarin, coumarin anticoagulants
Herbal preparations/ 
medications or dietary 
supplements
Herbal preparations/medications or dietary supplements known as strong 
inducers or inhibitors of CYP3A4/5 or those with a known risk of QT 
prolongation are prohibited throughout the study. These include, but are not 
limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and 
ginseng. Patients should stop using these herbal medications or dietary 
supplements 7 days prior to first dose of study drug.
Other investigational and 
antineoplastic therapies
Other investigational therapies must not be used while the patient is on the 
study. Anticancer therapy (chemotherapy, hormonal therapy, including but not 
limited to all SERMS [including raloxifene], biologic or radiation therapy [except 
for palliative radiotherapy as outlined in the protocol], and surgery) other than 
the study treatments must not be given while the patient is on the study 
medication. If such agents are required, then the patient must discontinue study 
drug.


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Category
Drug Name
1 NTI = narrow therapeutic index 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) or drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective 
concentrations in the blood..
2 Herbal product
3 P-gp inducer
4 The list provided is as of December 2019.Check https://www.crediblemeds.org/healthcare-providers/drug-list 
for the most updated list. 
5 Drug has warning for risk of hepatotoxicity.As far as possible, avoid co-administration of QT prolonging drugs 
or any other drugs with the potential to increase the risk of drug-related QT prolongation (e.g., via a potential 
DDI that increases the exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list of 
drugs with a known risk, possible risk, or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) 
is available online at qtdrugs.org.
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers.


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Table 14-2
List of medications to be used with caution during study drug 
treatment
Category
Drug Name
Moderate CYP3A4/5 
inhibitors
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida), cimetidine, 
crizotinib, diltiazem, faldaprevir, imatinib, isavuconazole, netupitant, nilotinib,
tofisopam, Schisandra sphenanthera (nan wu wei zi), verapamil
Moderate CYP3A4/5 
inducers
Bosentan, dabrafenib, efavirenz, etravirine, genistein, lopinavir5, modafinil, 
nafcillin, telotristat
Sensitive CYP3A4/5 
substrates1
Alpha-dihydroergocryptine, apixaban, aprepitant, atorvastatin, avanafil, 
bosutinib, brotizolam, budesonide, buspirone, cannabinoids6, cannabidiol6, 
cobimetinib, darifenacin, dasatininb, ebastine, eletriptan, eplerenone, 
everolimus, grazoprevir, ibrutnib, isavuconazole, ivabradine ivacaftor, 
lumefantrine, lurasidone, maraviroc, midazolam, perospirone, quetiapine, 
ridaforolimus, rivaroxaban, sildenafil, simeprevir, ticagrelor, tilidine, tolvaptan, 
triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin
BSEP inhibitors
Alectinib, atorvastatin, bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, mifepristone,
pioglitazone, reserpine,rifamycin, simeprevir, telmisartan,timcodar, troglitazone, 
velpatasvir
MATE1/2 substrates3
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varencicline
OCT1/2 substrates4
Amantadine, carboplatin, cisplatin, cephalexin, cephradine, ipratropium, 
lamivudine, linagliptin, metformin, oxyplatin, oxybutynin, phenformin, picoplatin, 
pilsicainide, pindolol, ranitidine, sorafenib, tropisetron, trospium, umeclidinium,
and zidovudine
BCRP substrates
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl 
estradiol, sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax
Medications that carry a 
possible risk for QT 
prolongation2
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine,
atazanavir, atomoxetine, bedaquiline, bendamustine, bortezomib, bosutinib, 
buprenorphine, cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib, 
clozapine, cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, 
epirubicin,eribulin mesylate, ezogabine(retigabine), famotidine, felbamate, 
fingolimod, flupentixol, gemifloxacin, granisetron, hydrocodone-ER, iloperidone, 
imipramine (melipramine), isradipine, ketanserin, lapatinib, lenvatinib, 
leuprolide, loperamide, lithium, melperone, midostaurin, mifepristone,
mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, nilotinib, norfloxacin, 
nortriptyline, nusinersen, ofloxacin, olanzapineosimertinib,oxytocin, 
paliperidone, palonosetron, panabinostat, pasireotide, pazopanib, perflutren 
lipid microspheres, perphenazine, pilsicainide, pimavanserin, pipamperone, 
promethazine, prothipendyl, quetiapine, ranolazine, rilpivirine, risperidone, 
romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, telavancin, 
tetrabenazine, tipiracil/trifluridine, tizanidine, tolterodine, toremifene,
trimipramine, tropisetron, vardenafil, vemurafenib, venlafaxine,vardenafil, 
ziprasidone
CYP2C19 or CYP2A6 
substrates with NTI (for 
patients receiving 
letrozole)
S-mephenytoin
CYP2C9 or CYP2D6 with 
NTI (for patients receiving 
tamoxifen)
Phenytoin


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Category
Drug Name
1 Sensitive substrates include drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a potent inhibitor.
2 The list provided is as of January 2018. Check crediblemeds.org/healthcare-providers/drug-list for the most 
updated list.
3 MATE1 and MATE2 share considerable substrate specificity. 
4 OCT1 and OCT2 share considerable substrate specificity.
5 Lopinavir and atazanavir are prohibited when combined with ritonavir (see Table 14-1)
6 Based on data that, exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy THC, increased 
by ~2-3 folds when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al, Springerplus. 2013; 2: 
236
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers.


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14.2
Appendix 2 - Patient reported outcomes
Figure 14-1
EORTC QLQ - C30


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Note: The questionnaire provided here is a sample for information purposes only.
Paper questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents.


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Figure 14-2
EORTC QLQ-BR23


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Note: The questionnaire provided here is a sample for information purposes only.
Paper questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents.


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Figure 14-3
EQ-5D-5L


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Note: The questionnaire provided here is a sample for information purposes only.
Paper questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents.


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14.3
Appendix 3 - Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.2: 11-Feb-2016
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
11-Feb-2016
List of contributors
Authors (Version 3.2):
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):


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


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1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 2 and the definition of best response in Section 
3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and rules for 
determination of best response. Section 3.2 is summarizing the “time to event” variables and 
rules which are mainly derived from internal discussions and regulatory consultations, as the 
RECIST criteria do not define these variables in detail. Section 4 of this guideline describes 
data handling and programming rules. This section is to be referred to in the RAP (Reporting 
and Analysis Plan) to provide further details needed for programming.
2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 
92; 
205-16 
and 
revised 
RECIST 
guidelines 
(version 
1.1) 
(Eisenhauer et al 2009) European Journal of Cancer; 45:228-247.
Indicate the assessment schedule for tumor assessments in the protocol. Frequency of tumor re-
evaluation while on treatment should be adapted to the type and schedule of treatment, and the 
type of tumor treated. It should also be clearly stated how patients are followed for progression 
after discontinuation of study treatment.
It is assumed that all information which is considered for assessment of the tumor is captured 
in the RECIST eCRF, i.e. not merged from several sources.
2.1
Definitions
2.1.1 Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 3.2.9.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.


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
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including 
small lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes 
with 10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
If any lesion should be handled differently, this must be clearly stated and justified in the 
protocol, e.g. tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable, and the conditions under which such lesions should be considered 
must be defined in the protocol when appropriate.
2.1.2 Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
3.2.9.
2.2
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:


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
All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
If different window for baseline assessments is allowed in the protocol this must be justified in 
the protocol.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.
If head and neck tumors and those of extremities are evaluated in the study, please specify the 
methods in detail in the protocol.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases, PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned.


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
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size and can be assessed using calipers.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.
 
 
 
 
 
 
 
 

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).
When pathological response is being used, the protocol must clearly state details on how 
pathological responses are documented.


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


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For cancers which are known to metastasize to bone, the protocol should specify if and how 
bone lesions should be handled, e.g., if they should be followed throughout the study by CT, 
MRI or x-ray.
2.4
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 2-1) and non-target lesions (Table 2-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 2-3) as well as the presence or absence of new lesions.
 
 
 
 
2.4.1 Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
2.4.1.1
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.


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2.4.1.2
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
2.4.2 Determination of target lesion response
Table 2-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the investigator 
or central reviewer using expert judgment based on the available information (see Notes on target lesion 
response and methodology change in Section 2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:


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
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 2-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.

For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.

Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.


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
The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.

A change in method for the evaluation of one or more lesions will usually lead to an 
UNK target lesion response unless there is progression indicated by the remaining 
lesions which have been evaluated by the same method. In exceptional circumstances 
an investigator or central reviewer might over-rule this assignment to put a non-UNK 
response using expert judgment based on the available information. E.g. a change to a 
more sensitive method might indicate some tumor shrinkage of target lesions and 
definitely rule out progression in which case the investigator might assign an SD 
target lesion response; however, this should be done with caution and conservatively 
as the response categories have well defined criteria.
2.4.3 Determination of non-target lesion response
Table 2-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, PR 
or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer does 
prevail.
2. It is recommended that the investigator and/or central reviewer should use expert judgement to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.


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


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Table 2-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 2.4
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 3.2.9 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
3.1
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.


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Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

-For non-randomized trials where response is the primary endpoint, confirmation is 
needed.

-For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).
The protocol should state if randomization or start of treatment is used as start date (baseline). 
This is then used in all definitions.
If a different minimum follow-up period is required to classify for best overall response= ’stable 
disease’, this must be specified in the protocol.

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).
If PD in a different follow-up period is considered to classify for best overall 
response=’progressive disease’, this must be specified in the protocol.
The protocol should state if discontinuation due to ‘Disease progression’ or death due to study 
indication is considered PD even if this was not accompanied by documentation of PD based 
on tumor measurements. This depends on Phase of the study and the primary endpoint (e.g. 
Phase III studies in which progression-free survival is primary endpoint should consider only 
documented PD, whereas Phase I and II studies may consider all clinical deteriorations PD). 
The following sentence therefore is only applicable if this is specified in the protocol:
Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)


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The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.


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Specify which determination of best overall response will be considered primary (and delete 
the other terms in the text). If a central blinded review is used (e.g. in an open-label study in 
which response is the primary endpoint), the best overall response evaluated by the central 
blinded review will always be considered the primary response.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR, or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
3.2
Time to event variables
The protocol should state which of the following variables is used in that study.
3.2.1 Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 


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patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.
3.2.2 Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
3.2.3 Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
3.2.5 Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is
typically related to intolerance of the study drug. In some protocols, time to treatment failure 


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


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


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Start dates
State in the protocol if date of randomization or date of start of treatment is to be used for all 
definitions. For randomized studies specify exactly where the randomization date comes from, 
e.g. from IVRS, or if start of treatment is used as randomization date. For non-randomized 
studies please specify which treatment start date is taken if more than one treatment is to be 
given.
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.
If applicable, if patients who discontinued due to ‘Disease progression’ are considered to be PD 
solely based on clinical deterioration, then add the following text in the protocol:
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, the 
date of discontinuation is used as date of progression.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 3.2.10).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 


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used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.
In comparative studies with long follow-up period and therefore extended visit schedule, it may 
be useful to collect the survival status at a pre-specified cut-off within a limited timeframe for 
all patients with no documented death. In this case, this requires a contact to be made with the 
patient or with any reliable source of information on the patient’s status, but not requiring a 
specific visit to be scheduled

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
If this is applicable for the study, it should be specified in the protocol if new cancer therapy is 
considered an event or endpoints are censored.
3.2.9 Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
The protocol should state clearly whether patients with non-measurable disease only at baseline 
will be allowed into the study. If patients with non-measurable disease only are allowed to be 
enrolled then the statistical section should describe clearly how data from these patients will be 
incorporated into the primary analysis and main analyses of the key secondary endpoints. In 
studies where presence of measurable disease is expected to have a relatively large impact on 
the primary endpoint, this factor can even be considered as a stratification factor in the 
randomization process.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
For studies which specifically exclude patients with non-measurable disease only at baseline 
the pre-specified analysis plan should describe how to handle data from these types of patients 
if they are enrolled by error or if central readers do not identify measurable disease despite 
investigators having declared the contrary, or conversely perhaps they do identify measurable 
disease when it has not been identified at the local site. It is recommended for these types of 
studies that patients with non-measurable disease identified through the local site evaluation be 
included in the list of protocol violations. However, decisions on exclusion from a per protocol 
analysis should relate to whether the patient has measurable disease according to the primary 
data source. For example, if the primary data source is from a central independent review then 
patients with non-measurable disease only according to this central review should be excluded 
from the relevant per protocol analyses.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 3-1.


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Table 3-1
Overall lesion response at each assessment: patients with non-
target disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 2.4
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
Study teams may also want to perform sensitivity analyses excluding patients from the analysis 
of ORR (e.g. possibly as part of a per-protocol type analysis). Similar considerations should be 
given to other endpoints which rely on a clear distinction being made between a PR and a SD 
response.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
3.2.10 Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 3.2.8, and using the draft FDA guideline on endpoints 
(Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) as a 
reference, the following analyses can be considered:


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Table 3-2
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) Ignore clinical progression and follow 
situations above
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and 
follow situations above (ITT approach)
(2) Date of last adequate assessment prior to 
new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.=Definitions can be found in Section 3.2.8
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 3.2.8.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 


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be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 3-2 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:


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
Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
4.1
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
4.2
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment


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
No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of the patient from the trial.
4.3
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
4.4
Medical validation of programmed overall lesion response
In order to be as objective as possible, the RECIST programmed calculated response assessment
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgement in determining response in these types of situations, and therefore as a consequence, 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses
may be re-evaluated by clinicians (based on local investigator data recorded in the eCRF or 
based on central reviewer data entered in the database) at Novartis or external experts. In 
addition, data review reports will be available to identify assessments for which the 
investigators’ or central reader’s opinion does not match the programmed calculated response 
based on RECIST criteria. This may be queried for clarification. However, the investigator or 
central reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.


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Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
4.5
Programming rules
The following should be used for programming of efficacy results:
4.5.1 Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
4.5.2 Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 3.2.8). If all measurement dates have no day 
recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
4.5.3 Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
4.5.4 Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
4.5.6 Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.


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For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 3-2)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 3.2.8. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.


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5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.4
Appendix 4 - Bone Marrow Reserve in Adults
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol. 5, 255-258, 1961
MARROW DISTRIBUTION OF THE ADULT
SITE
MARROW
wt. (g)
FRACTION 
RED MARROW 
AGE 40
RED MARROW 
wt. (g)
AGE 40
% TOTAL RED 
MARROW
CRANIUM AND
MANDIBLE
Head:
Cranium
Mandible
165.8
16.4
0.75
0.75
136.6
124.3
12.3
13.1
13.1
HUMERI, 
SCAPULAE, 
CLAVICLES
Upper Limb Girdle :
2 Humerus, head & 
neck
2 Scapulae
2 Clavicles
26.5
67.4
21.6
0.75
0.75
0.75
86.7
20.0
50.5
16.2
8.3
8.3
STERNUM AND
RIBS
Sternum
Ribs:
1 pair
2
3
4
5
6
7
8
9
10
11
12
39.0
10.2
12.6
16.0
18.6
23.8
23.6
25.0
24.0
21.2
16.0
11.2
4.6
0.6
All 0.4
23.4
82.6
4.1
5.0
6.4
7.4
9.5
9.4
10.0
9.6
8.5
6.4
4.5
1.8
2.3
7.9
10.2
PELVIC BONES
Sacrum
2 os coxae
194.0
310.6
0.75
0.75
145.6
233.0
13.9
22.3
36.2
FEMUR
2 Femoral head
and neck
53.0
0.75
40.0
3.8

SAP_003.pdf: 
Clinical Development
LEE011 (ribociclib)
CLEE011E2301 (MONALEESA-7) / NCT02278120
A Phase III randomized, double-blind, placebo-controlled 
study of LEE011 or placebo in combination with tamoxifen 
and goserelin or a non-steroidal aromatase inhibitor (NSAI) 
and goserelin for the treatment of premenopausal women 
with hormone receptor positive, HER2-negative, advanced 
breast cancer
Statistical Analysis Plan (SAP) - Final CSR
Author:
Trial Statistician
Document type:
SAP Documentation
Document status:
Final
Release date:
09-Jan-2023
Number of pages:
29
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Confidential
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SAP 
CLEE011E2301
Document History – Changes compared to previous version of SAP.
Version
Date
Changes
Final
09-Jan-2023
First version


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Confidential
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SAP 
CLEE011E2301
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Objectives ................................................................................................................9
2
Definitions and general methodology ...............................................................................10
2.1
Definitions .............................................................................................................10
2.1.1
Study drug and study treatment.............................................................10
2.1.2
Date of first administration of study drug.............................................11
2.1.3
Date of last administration of study drug..............................................11
2.1.4
Date of first administration of study treatment .....................................11
2.1.5
Date of last administration of study treatment ......................................11
2.1.6
Study day...............................................................................................12
2.1.7
Baseline.................................................................................................12
2.1.8
On-treatment assessment/event.............................................................12
2.1.9
Last contact date....................................................................................13
2.2
Data included in the analysis .................................................................................14
2.3
Analysis sets ..........................................................................................................14
2.3.1
Full analysis set (FAS)..........................................................................14
2.3.2
Safety Set ..............................................................................................14
2.3.3
Cross-over analysis set..........................................................................15
2.3.4
Patient classification..............................................................................15
3
Statistical methods used in reporting.................................................................................15
3.1
Background and demographic characteristics .......................................................15
3.1.1
Basic demographic and background data..............................................15
3.2
Protocol deviation summaries................................................................................15
3.3
Groupings for analysis...........................................................................................16
3.4
Patient disposition..................................................................................................16
3.5
Study treatment......................................................................................................16
3.5.1
Duration of study treatment exposure...................................................16
3.5.2
Cumulative dose and average daily dose ..............................................17
3.5.3
Dose intensity and relative dose intensity.............................................17
3.5.4
Dose reductions, or interruptions..........................................................19


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SAP 
CLEE011E2301
3.5.5
Discontinuation of study treatment components...................................19
3.6
Concomitant and post-treatment therapy...............................................................20
3.7
Safety evaluation ...................................................................................................20
3.7.1
Adverse events (AEs)............................................................................20
3.7.2
Laboratory data .....................................................................................23
3.7.3
Vital signs..............................................................................................24
3.7.4
ECG.......................................................................................................25
3.7.5
Cardiac imaging (MUGA / ECHO) ......................................................26
3.7.6
Urinary Analysis ...................................................................................26
3.7.7
Other safety data ...................................................................................26
4
Details of the statistical analysis........................................................................................27
4.1
Duration of follow-up............................................................................................27
Appendix 1
CTC grades for laboratory values in Novartis Oncology......................28


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List of tables
Document History – Changes compared to previous version of SAP........................................2
Table 1-1
Study objectives ......................................................................................9
Table 2-1
Last contact date data sources...............................................................13
Table 2-1
Patient classification based on protocol deviations and non-
protocol deviation criteria .....................................................................15
Table 3-1
Planned dose intensity...........................................................................18
Table 3-2
Clinically notable ECG values..............................................................25
List of figures
Figure 1-1
Study Design ...........................................................................................9


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List of abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ATC
Anatomical Therapeutic Chemical
BOR
Best overall response
CI
Confidence Interval
CBR
Clinical benefit rate
CR
Complete response
CRF
Case Report Form
CRS
Case retrieval sheet
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dosage administration Record
DI
Dose Intensity
DOR 
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC QLQ-
C30
European Organization for Research and Treatment of Cancer Core 30-
item Quality of Life Questionnaire
EOT
End of treatment
ER
Estrogen receptor
FAS
Full analysis set
HER2
Human epidermal growth factor receptor 2
HR 
Hazard Ratio
HR 
Hormone receptor
MBC
Metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NMQ
Novartis MedDRA queries
ORR 
Overall response rate 
OS
Overall survival 
PD
Progressive disease
PDI
Planned dose intensity
PDS
Programming Datasets Specifications
PFS
Progression-free survival
PR
Partial response
PS
Performance Status
PT
Preferred term
QTcF
QT interval corrected by Fridericia method
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria In Solid Tumors


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SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SD
Standard deviation
SMQ
Standardized MedDRA queries
SOC
System organ class
TFL
Tables Figures and Listings
TBIL
Total Bilirubin


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1
Introduction
This document describes the detailed statistical methodology to be used for the final Clinical 
Study Report (CSR) for the study CLEE011E2301, a phase III, randomized, double-blind, 
placebo-controlled study of LEE011 (ribociclib) or placebo in combination with tamoxifen and 
goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of 
premenopausal women with hormone receptor positive, HER2-negative, advanced breast 
cancer. 
The content of this SAP is based on protocol amendment 7 (clee011e2301-v07--protocol). All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock and unblinding of the study data.
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in the Tables, Figures & Listings (TFL) shells and Programming Datasets 
Specifications (PDS), respectively.
1.1
Study design
This is a phase III randomized, double-blind, placebo-controlled global study comparing the 
combination of tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + LEE011 to 
tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + placebo in premenopausal women 
with HR+, HER2-negative advanced breast cancer. 
A total of 672 patients were randomly assigned to one of the below treatment arms in an 1:1 
ratio:
a. [Tamoxifen or a NSAI (letrozole or anastrozole)] + goserelin + LEE011 
OR,
b. [Tamoxifen or a NSAI (letrozole or anastrozole)] + goserelin + placebo.
Randomization was stratified by the presence of liver and/or lung metastases (yes versus no), 
prior chemotherapy for advanced disease (yes versus no), and endocrine combination partner 
(tamoxifen and goserelin versus NSAI (letrozole or anastrozole) and goserelin).
Following the statistically significant PFS and OS benefit, with protocol amendment 6, study 
participants were unblinded, with an opportunity for those patients still on study treatment in 
the placebo combination arm to cross-over to the LEE011 combination arm. Crossover was
optional and was conducted only upon documented consent of the study patient.
The study design is summarized in Figure 1-1.


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Figure 1-1
Study Design
1.2
Objectives
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1. PFS, as assessed by the local radiologists/investigators and using RECIST 1.1 criteria 
is the primary endpoint. Overall survival is a key secondary endpoint. Both PFS and OS have 
been tested statistically significant and results have been summarized by previous study reports. 
Table 1-1
Study objectives
Objective
Endpoint
Primary 
To determine whether treatment with tamoxifen or a NSAI 
+ goserelin + LEE011 prolongs PFS compared to 
treatment with tamoxifen or a NSAI + goserelin + placebo 
in premenopausal women with HR+, HER2-negative 
advanced breast cancer
PFS per local assessment and RECIST 1.1
Key secondary
To determine whether treatment with tamoxifen or a NSAI 
+ goserelin + LEE011 prolongs OS compared to treatment 
with tamoxifen or a NSAI + goserelin + placebo in 
premenopausal women with HR+, HER2-negative 
advanced breast cancer.
OS
Other secondary
To evaluate the safety and tolerability of LEE011 in
combination with tamoxifen + goserelin or a NSAI + 
goserelin.
Frequency/ severity of adverse events, lab 
abnormalities
To evaluate the two treatment arms with respect to 
response rate and clinical benefit rate (CBR).
ORR as defined by RECIST 1.1. CBR, defined as 
percentage of patients with CR, PR per RECIST 
1.1 or SD lasting 24 weeks or longer
To describe time to response (TTR) and duration of 
response (DOR) in each treatment arm.  
Time to response and duration of response per 
RECIST 1.1
To evaluate the two treatment arms with respect to time to 
deterioration of ECOG PS.
Time to definitive deterioration of the ECOG PS 
from baseline


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Objective
Endpoint
To evaluate patient reported outcomes for health-related 
quality of life in the two treatment arms.
Time to 10% deterioration in the global health 
status/QOL scale score of the EORTC QLQ-C30
Change from baseline in the global health 
status/QOL scale score of the EORTC QLQ-C30
2
Definitions and general methodology
2.1
Definitions
2.1.1
Study drug and study treatment
Study drug is defined as ribociclib or matching placebo.


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Study treatment is defined as ribociclib + (tamoxifen or a NSAI) + goserelin, or matching 
placebo + (tamoxifen or a NSAI) + goserelin.
Cross-over open-label ribociclib treatment will refer to ribociclib drug administered to 
patients randomized to placebo plus tamoxifen/NSAI plus goserelin arm who subsequently 
cross-over to ribociclib plus NSAI plus goserelin (cross-over period).
Cross-over open-label ribociclib plus NSAI plus goserelin treatment will refer to the 
combination of drugs ribociclib plus NSAI plus goserelin administered during the cross-over 
period.
2.1.2
Date of first administration of study drug
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 DAR CRF. 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.
For analyses related to the cross-over period, date of first administration of cross-over open-
label ribociclib treatment is defined as the first date when a non-zero dose of cross-over open-
label ribociclib treatment is administered and recorded on the DAR CRF, after the date of cross-
over recorded on the cross-over Details CRF. 
2.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on the DAR CRF. Similar definitions apply for the 
other components of study treatment.
For analyses related to the cross-over period, date of last administration of cross-over open-
label ribociclib treatment is defined as the last date when a non-zero dose of cross-over open-
label ribociclib treatment is administered and recorded on the DAR CRF, after the date of 
crossover recorded on the cross-over Details CRF.
2.1.4
Date of first administration 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 CRF. The 
date of first administration of study treatment will also be referred to as the start of study 
treatment.
For analyses related to the cross-over period, date of first administration of cross-over open-
label ribociclib plus NSAI plus goserelin treatment is equal to the date of first administration of 
cross-over open-label ribociclib treatment. 
2.1.5
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF.
For analyses related to the cross-over period, date of last administration of cross-over open-
label ribociclib plus NSAI plus goserelin treatment is defined as the last date when a non-zero 


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dose of any component of the cross-over open-label ribociclib plus NSAI plus goserelin 
treatment was administered and recorded on the DAR CRF during the cross-over period. 
2.1.6
Study day
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 study day will be displayed in data listings.
For analyses related to the cross-over period, study day is defined as above, with the reference 
date being the date of first administration of cross-over open-label ribociclib treatment.
2.1.7
Baseline
For safety evaluations (e.g., laboratory assessments and ECG), the last available assessment 
before or on the start date 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.
For cross-over analyses, the last available assessment before or on the date of first dose of cross-
over open-label ribociclib treatment will be used as the ‘baseline’ assessment. 
2.1.8
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. 
Double-blind on-treatment period:
An on-treatment assessment/event is defined as any assessment/event in the following time 
interval:
[date of first administration of study treatment, the earliest between the date of last 
administration of study treatment + 30 days and the date of first administration of cross-over 
open-label ribociclib plus NSAI plus goserelin treatment – 1 day], i.e., including the lower and 
upper limits. 
The double-blind on-treatment period is the default on-treatment period used in the analyses 
unless specified otherwise.
Cross-over on-treatment period:


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An on-treatment assessment/event is defined as any assessment/event in the following time 
interval: [date of first administration of the cross-over open-label ribociclib plus NSAI plus 
goserelin treatment, date of last administration of the cross-over open-label ribociclib plus 
NSAI plus goserelin 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 3.5.1).
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.  
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 2.1.4 and 2.1.5, respectively.
2.1.9
Last contact date
For patients not known to have died at the analysis cut-off, the last contact date will be derived 
using the last complete date among the following:
Table 2-1
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last date patient was known to be alive from 
Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
Date of discontinuation/study phase completion 
from end of treatment disposition page
No condition.
Date of discontinuation/Study phase completion 
from end of post treatment follow up phase 
disposition page
No condition
Date of ECG assessment
At least 1 non-missing parameter value
Date of PRO assessment
At least 1 non-missing answer to questionnaire
Tumor (RECIST) assessment date
For non-target lesion: non-missing lesion status
For target lesion: non-missing lesion diameter
For new lesion: “Is there a new lesion?” yes
Laboratory sample collection date
At least 1 non-missing parameter value


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Source data
Conditions
Vital signs date
At least one non-missing parameter value
Concomitant medication date
At least one non-missing name of medication
Body fluid/Tissue Collection date
Non-missing result (positive/negative tumor cells)
Cardiac imaging date
Non-missing LVEF or overall interpretation
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No dates post cut-off date will be used. Completely imputed
dates (e.g.,the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring coming from ‘Survival information’ eCRF. 
2.2
Data included in the analysis
The statistical analyses will be performed using all data collected in the database up to the data 
cutoff date. Any data collected beyond the cutoff date will not be included in the analysis and 
will not be used for any derivations.
2.3
Analysis sets
2.3.1
Full analysis set (FAS)
The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment and stratum they were assigned 
to at randomization. 
2.3.2
Safety Set
The Safety Set consists of all patients who received at least one dose of any component of study 
treatment and have at least one post-baseline safety assessment. Patients will be analyzed 
according to the treatment actually received. Treatment actually received refers to the treatment 
the patient was randomized to, unless the alternative treatment was received throughout the 
trial. If a patient takes at least one dose of the randomized treatment then the treatment actually 
received is the randomized treatment. The statement that a patient has no AE constitutes a safety 
assessment. Occurrence of a death constitutes a safety assessment as well.


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2.3.3
Cross-over analysis set
The cross-over analysis set includes all patients in the placebo arm of the Safety set, who elected 
to cross-over to receive ribociclib combination therapy and received at least one dose of cross-
over open-label ribociclib. 
2.3.4
Patient classification
Patients may be excluded from the analysis sets defined above based on the protocol deviations 
entered in the database and/or on specific subject classification rules as defined in Table 2-1.
Table 2-1
Patient classification based on protocol deviations and non-protocol 
deviation criteria
Analysis set
Protocol deviations leading to
exclusion
Non-protocol deviation criteria 
leading to exclusion
FAS 
No written informed consent
NA
Safety set
No written informed consent
No post-baseline safety 
assessment or no dose of study 
treatment
Cross-over analysis 
set
No written informed consent
NA 
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets.  The date on which 
a patient withdraws full consent is recorded in the eCRF. 
3
Statistical methods used in reporting
3.1
Background and demographic characteristics
The FAS will be used for all baseline disease characteristics and demographic summaries and 
data listings.
3.1.1
Basic demographic and background data
Qualitative data (e.g., race, ECOG performance status, etc.) will be summarized by means of 
contingency tables by treatment arm and quantitative data (e.g.,age, body weight, etc.) will be 
summarized by appropriate descriptive statistics (mean, standard deviation, median, minimum, 
and maximum) by treatment arm.
3.2
Protocol deviation summaries
The number and percentage of patients in the FAS with any protocol deviation will be tabulated 
by deviation category (as specified in the Study Specification Document) and by treatment arm.
Additional protocol deviation summaries will be provided to address the potential impact of 
COVID-19 pandemic. The number and percentage of patients in the FAS with any protocol 


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deviation with relationships to COVID-19 will be summarized by deviation category and by 
treatment arm.
All protocol deviations will be listed.
3.3
Groupings for analysis
The number and percentage of patients in each analysis set (definitions are provided in Section 
2.3) will be summarized by treatment arm. 
3.4
Patient disposition
Patient disposition for all randomized patients will be summarized based on FAS. There will be 
one combined by-treatment summary showing:
1. Number (%) of patients treated/untreated.
2. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of treatment’ page)
3. Number (%) of patients who crossed over and are still on-treatment (based on the 
‘Crossover details’ page and absence of the ‘End of treatment’ page)
4. Number (%) of patients who discontinued study treatment (based on the ‘End of 
Treatment’ page)
5. Number (%) of patients who crossed over and discontinued study treatment (based on 
the ‘Crossover details’ page and the ‘End of treatment’ page)
6. Reasons for study treatment discontinuation (based on ‘End of Treatment’ page)
7. Number (%) of patients who entered the post-treatment evaluations (based on ‘End of 
Treatment’ page)
8. Number (%) of patients who discontinued from the post-treatment evaluations (based 
on ‘End of post treatment follow up disposition’ page)
9. Reasons for discontinuation from the post-treatment evaluations phase (based on ‘End 
of post treatment follow up disposition’ page).
10. Number (%) of patients who entered survival follow-up.
3.5
Study treatment
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. The number of patients with dose 
reductions/interruptions, and the reasons, will be summarized based on the safety set. Duration 
of exposure to cross-over open-label ribociclib plus NSAI plus goserelin treatment will be 
summarized and listed and the number of patients with dose reductions/interruptions and the 
reasons, will be listed based on the cross-over analysis set.
Details of the derivations and summaries are provided in the following sections.
3.5.1
Duration of study treatment exposure
The duration of exposure to study treatment will be calculated as


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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 any single component of study treatment will be calculated as
Duration of exposure (days) = (last date of exposure to study treatment component) – (date of 
first administration of study treatment component) + 1.
The last date of exposure is defined as follows for the study treatment components:

For ribociclib/placebo, tamoxifen, anastrozole, and letrozole: the last date of exposure is 
defined as the date of last administration of the corresponding medication;

For goserelin, the last date of exposure is defined as the date of last administration of 
goserelin + 27 days. 

If a patient died or was lost to follow-up within date of last administration + 27 days, 
then the last date of exposure is the 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 by treatment arm. In addition, the duration of exposure to study treatment will be 
categorized into time intervals (e.g., <3 months; 3-<6 months; 6-<9 months, etc); frequency 
counts and percentages will be presented for the number of patients in each interval.
For analyses related to the cross-over on-treatment period, duration of exposure of cross-over 
open-label ribociclib plus NSAI plus goserelin treatment will be calculated as above 
considering the combination of drugs ribociclib plus NSAI plus goserelin administered during 
the cross-over on-treatment period.
3.5.2
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 by 
treatment arm for each component of study treatment. Patients with no exposure to the study 
treatment component will be excluded from the corresponding summary.
3.5.3
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure to each study treatment 
component is defined as follows: 
For tamoxifen, letrozole, and anastrozole, DI is defined as
DI (mg/day) = Cumulative dose (mg) / duration of exposure to study treatment component 
(days).
For goserelin, DI is defined as
DI (mg/28 days) = Cumulative dose (mg) / {[(date of last administration of goserelin + 27) –
(date of first administration of goserelin) + 1] / 28},


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to account for the goserelin dosing schedule in the DI computation.
For ribociclib/placebo, DI is defined as
DI (mg/day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib/placebo 
(days),
where adjusted duration of exposure (days) to ribociclib/placebo represents the number of 
ribociclib/placebo dosing days a patient would be expected to have received per protocol, given 
their duration of exposure to ribociclib/placebo as defined in Section 3.5.1. Since 
ribociclib/Placebo follows a 3-weeks on, 1-week off schedule, the adjusted duration of exposure 
to ribociclib/placebo is the duration of exposure to ribociclib/placebo minus the planned off 
days. The adjusted duration of exposure to ribociclib/placebo is therefore 21 x (# completed 28 
day cycles) + min(21, duration of last incomplete cycle).
For example, if the duration of exposure to ribociclib/placebo is 66 (corresponding to two cycles 
and 10 days), then the adjusted duration of exposure to ribociclib/placebo is 21*2+10=52. If the 
duration of exposure to ribociclib/placebo is 108 days (corresponding to three cycles and 24 
days), then the adjusted duration of exposure is 21*3+21=84 days.
Specifically, let D1 represent the duration of exposure to ribociclib/placebo as defined in 
Section 3.5.1. Then the adjusted duration of exposure is defined as 
D=21*[D1/28]+min(21,D1-28*[D1/28]) days, 
where [x] stands for the integer part of x. In this equation [D1/28] is the number of completed 
cycles, and D1-28*[D1/28] is the additional number of days in the last, incomplete cycle (if 
any). For example, if D1=30 then [D1/28]=1, D1-28*[D1/28]=2, and D=23. If D1=7 then D=7; 
if D1=22 then D=21; if D1=28 then D=21, etc.
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 each study treatment component is displayed in Table 
3-1. Note that DI will also be calculated and reported in the units displayed in Table 3-1, 
whereas duration of exposure itself will be summarized in months.
Table 3-1
Planned dose intensity
Medication
PDI (dose unit/unit of time)
Ribociclib/placebo
600 mg/day
Tamoxifen
20 mg/day
Letrozole
2.5 mg/day
Anastrozole
1 mg/day
Goserelin
3.6 mg/28 days
Relative dose intensity (RDI) is defined as:
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).  
DI and RDI will be summarized separately for each of the study treatment components.


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3.5.4
Dose reductions, or interruptions
The number and percentage of patients with dose reductions, interruptions or delays, and the 
reasons, will be summarized by treatment arm as outlined below for double-blind on-treatment 
period. The dosage administration record of ribociclib will be listed for cross-over open-label 
ribociclib plus NSAI plus goserelin treatment for the cross-over on-treatment period. 
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 600 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. 
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 ribociclib 600mg – 0mg – 400mg, the 
400mg dose will be counted as a reduction.
If due to dosing error, a patient took a dose during the dosing break with a dose that is lower 
than the previous dose, this will not be considered as dose reduction. For example, a patient 
took 600 mg from day 1-21, and mistakenly took 200 mg per day on day 22-28 which is 
supposed to be a dosing break. The patient resumed 600 mg dosing on day 29. This will not be 
considered as dosing reduction. 
Dose reductions and interruptions will be tabulated separately.  Dose escalations are not allowed 
according to the protocol and will not be counted in these summaries.
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.
3.5.5
Discontinuation of study treatment components
The reasons for discontinuation of each study treatment component will be summarized by
treatment arm for the double-blind on-treatment period, based on the information on the 
component DAR CRF for patients who have the “dose permanently discontinued” box checked.
Partial discontinuation: Partial discontinuation refers to discontinuation of ribociclib/placebo 
or goserelin, respectively, while continuing on study treatment.
For ribociclib/placebo, partial discontinuation is defined as the event when the last non-zero 
dose of ribociclib/placebo is more than 21 days before the last non-zero dose of study treatment, 
with the permanent discontinuation box checked in the ribociclib/placebo DAR page.
For goserelin, partial discontinuation is defined as the last non-zero dose of goserelin plus 27 
days being more than 21 days before the last non-zero dose of study treatment, with the 
permanent discontinuation box checked on the goserelin DAR page.
Partial discontinuation of ribociclib/placebo will be summarized by treatment for the double-
blind on-treatment period.


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The reaons for discontinuation and partial discontinuation will be listed using the cross-over 
analysis set separately.
3.6
Concomitant and post-treatment therapy
Concomitant therapies
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. 
Concomitant medications will be summarized by lowest ATC class, preferred term and 
treatment arm. The summary will include medications starting on or after the start of study 
treatment but no later than 30 days after last dose of study treatment or before the start of open-
label ribociclib plus NSAI plus goserelin treatment
The safety set will be used for all concomitant medication tables and listings.
Concomitant medications will be listed also for the cross-over period using the cross-over 
analysis set. Any concomitant therapies starting more than 30 days after the last date of cross-
over open-label study treatment will be flagged in the listing. 
3.7
Safety evaluation
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory/ECG values that fall outside of pre-determined ranges. Other safety data 
(e.g., vital signs and special tests) will be considered as appropriate.
All safety outputs will use the safety set. The safety summary tables will include ‘double-
blinded 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
or the date of the day prior to the start of cross-over open-label ribociclib plus NSAI plus 
goserelin treatment. The AEs started before the first dose but worsening during the treatment 
period are also considered as ‘on-treatment’ events. 
Key safety analyses that include data from the cross-over on-treatment period will also be 
performed on the cross-over analysis set. See Section 2.1.8 for more details on the definition of 
‘on-treatment’ event during the cross-over on-treatment period.
3.7.1
Adverse events (AEs)
3.7.1.1
Coding of AEs
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.


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3.7.1.2
Grading of AEs
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 project; if an AE results in death it will be documented in the outcome (“fatal”). 
Information on deaths will also be collected on the ‘Death’ CRF. 
3.7.1.3
General rules for AE Reporting
AE summaries will include all AEs starting on or after study Day 1 (i.e., on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last administration 
of study treatment or the date of the day prior to the start of cross-over open-label ribociclib 
plus NSAI plus goserelin treatment (see Section 2.1.5). All AEs will be listed. AEs starting 
prior to study Day 1 and AEs starting later than 30 days after the last treatment date or the date 
of the day prior to the start of cross-over open-label ribociclib plus NSAI plus goserelin
treatment will be flagged in the listings. AEs starting during the cross-over on-treatment period 
will be listed separately.
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.
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 sort order for 
the preferred term will be based on their frequency in the ribociclib arm.
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.
3.7.1.4
AE summaries
The following adverse event summaries will be produced by treatment group:

Summary of deaths and adverse events

Adverse events, irrespective of causality, by primary system organ class, preferred term 
and maximum grade 


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
Adverse events with suspected relationship to study treatment by primary system organ 
class, preferred term and maximum grade 

Most common grade 3-4 adverse events, irrespective of causality, by preferred term and 
maximum grade (greater than x% in either arm)

Adverse events, irrespective of causality, by primary system organ class and maximum 
grade

Adverse events, irrespective of causality, by preferred term and maximum grade 

Adverse events with suspected relationship to study treatment by preferred term and 
maximum grade

On treatment deaths by preferred term

Deaths, by primary system organ class and preferred term 

Serious adverse events, irrespective of causality, by primary system organ class and 
preferred term and maximum grade 

Serious adverse events with suspected relationship to study treatment, by primary 
system organ class, 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 

Adverse events requiring additional therapy, irrespective of causality, by primary 
system organ class, preferred term and maximum grade 

On-treatment deaths and SAEs with fatal outcome, by SOC and PT
AEs of interest will also be summarized. See Section 3.7.1.5 for the grouping details.
Subgroup analyses by endocrine combination partner subgroups (tamoxifen and goserelin; 
NSAI and goserelin) will be performed for the analysis of adverse events, irrespective of 
causality, by primary system organ class, preferred term and maximum grade.
Separate summaries will be provided for adverse events, deaths and serious adverse events
occurring during the cross-over on-treatment period for the cross-over analysis set.
3.7.1.5
Grouping of adverse events of special interest
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to ribociclib. 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 a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 


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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 double-blinded on-treatment period will be summarized.
Summaries of these AESIs will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, etc.). 
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. The most up-to-date version of the CRS will be used at the time of the analysis.
3.7.1.6
Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables will be 
provided for the safety set and the cross-over analysis set population: 1) adverse events which 
are not serious adverse events with an incidence greater than 5% by system organ class and 
preferred term and 2) serious adverse events and SAE suspected to be related to study treatment
by system organ class and preferred term..
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
3.7.2
Laboratory data
When analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected no later than 30 
days after the last administration of study treatment or the date of the day prior to the start of 
open-label ribociclib plus NSAI plus goserelin treatment.
Laboratory data will be classified (by biostatistics/statistical programming) into CTC grades 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The 
calculation of laboratory CTC grades will be based on the observed laboratory values only;
clinical assessments will not be taken into account. The criteria to assign CTC grades 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.
The following summaries will be produced for the laboratory data (by laboratory parameter):


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
Number and percentage of patients with each CTC grade as their worst post-baseline 
value (regardless of the baseline status). Each patient will be counted only for the 
worst grade observed post baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value 
will be produced for hematology and biochemistry laboratory parameters with CTC 
grades.

For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges.
Number and percentage of patients meeting categorical liver function test criteria, including 
ALT, AST and ALT/AST (>3x, 5x, 8x, 10x, 20x ULN), Total Bilirubin (>1x, 2x ULN), ALP 
(>1.5x, 2x, 3x, 5x, 8x, 10x ULN), combined categories of ALT/AST and total bilirubin (e.g., 
ALT/AST>3x UNL & total bilirubin > ULN) as well as Hy’s Law criteria (ALT or AST > 3 x 
ULN and TBIL >= 2 x ULN and ALP < 2 x ULN). For the combined categories, the assessments 
need not to be concurrent, i.e., patients are counted based on their most extreme value for each 
parameter (highest in the case of ALT, AST and TBIL; lowest in the case of ALP). Listing of 
patients with CTC grade 3 or 4 laboratory abnormalities will be produced and those assessments 
collected later than 30 days after the last double-blinded study treatment date and before the 
day of the start of cross-over open-label ribociclib plus NSAI plus goserelin treatment will be 
flagged in the listing.
Separate listing will be provided for the cross-over analysis set and those assessments collected 
later than 30 days after the last cross-over open-label study treatment date will be flagged in the 
listing.
3.7.3
Vital signs
Vital signs assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height, weight, body temperature, heart rate, and 
systolic and diastolic blood pressure.
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline

Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline.

Body temperature: ≥ 39.1°C

Heart 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

Body temperature: ≤ 35°C

Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm
The following summaries will be produced for each vital sign parameter:


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
Summary statistic for change from baseline to the worst post-baseline value (in both 
directions, i.e., from baseline to highest post baseline and from baseline to lowest post 
baseline value).

Number and percentage of patients with at least one post-baseline vital sign 
abnormality (in both directions, i.e., both elevated and below normal values).
In addition, patients with clinically notable vital sign abnormalities will be listed by treatment 
arm. Patients with notable values starting or worsening during the cross-over on-treatment 
period will be listed separately. The assessments collected later than 30 days after the last 
treatment date or after the start of cross-over open-label ribociclib plus NSAI plus goserelin
treatment will be flagged.
3.7.4
ECG
All analyses of ECG data will be based on the average of all available replicate ECGs at each  
time point for each patient. For unscheduled assessments, 15-minute windows will be applied 
to group assessments for averaging.
The following parameters will be assessed: QT, QTcF, QTcB, PR, and QRS intervals in msec, 
heart rate (bpm), and the overall interpretation if clinically significant abnormalities are present. 

The number and percentage of patients with notable abnormalities will be summarized. 

Summary statistics and shift tables will be presented. 

ECG findings will be listed by treatment

ECG findings and patients with notable values starting or worsening during the cross-
over on-treatment period will be listed separately.
Table 3-2
Clinically notable ECG values
ECG parameter (unit) 
Clinically notable criteria 
QT, QTcF, QTcB (ms) 
New > 450
New > 480
New > 500
Increase from Baseline > 30 
Increase from Baseline > 60 
PR duration (ms)
Increase > 25% from baseline and to PR duration > 200,
New >200
QRS duration (ms)
Increase > 25% from baseline and to QRS duration > 110,
New >110
Heart Rate (bpm) 
< 50 and decrease from Baseline of > 25% 
> 100 and increase from Baseline of > 25% 


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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 average of the last ECG measurements 
(replicates taken on or before date of first dose of study treatment). The percentage of patients 
having notable ECG interval values is based on the number of patients at risk for the change 
with a value at baseline and post-baseline.
Subgroup analyses by endocrine combination partner subgroups (tamoxifen and goserelin; 
NSAI and goserelin) will be performed for clinically notable ECG values.
3.7.5
Cardiac imaging (MUGA / ECHO)
Shift tables comparing baseline to worst post-baseline cardiac imaging (MUGA or ECHO) 
overall interpretation will be provided. Percentages will be based on all patients in the Safety 
set.
Note: If there is any change in the methodology used throughout the study compared to baseline, 
the post-baseline values for which the methodology differs from baseline will be discarded in 
the tables presenting comparisons to baseline.
Descriptive statistics of the left ventricular ejection fraction (LVEF) at baseline, worst post-
baseline value and change from baseline to worst post-baseline value will be provided.
A listing of patients with newly occurring clinically significant abnormality will be produced 
by treatment arm.
ECG data of patients with abnormal values starting or worsening during the cross-over on-
treatment period will be listed separately.
3.7.6
Urinary Analysis
The following parameters will be summarized using a shift table to compare baseline to the 
worst-post baseline values: urine bilirubin dipstick, urine blood dipstick, urine glucose dipstick, 
urine ketones dipstick, urine leukocyte dipstick, and urine nitrate dipstick. For all these 
parameters, both negative and trace are considered as normal and the more pluses, the worse. 
The urine pH dipstick will be summarized using a shift table with low/normal/high 
classifications based on laboratory reference ranges.
3.7.7
Other safety data
Data with notable values from other tests will be listed, and any other information collected will 
be listed as appropriate.
Notable values collected later than 30 days after the last study treatment date or after the start 
of cross-over open-label ribociclib plus NSAI plus goserelin treatment will be flagged in the 
listings. Notable values starting or worsening during the cross-over on-treatment period will be 
listed separately.


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4
Details of the statistical analysis
4.1
Duration of follow-up
Study follow-up will be summarized using the following methods:

Summary of duration between randomization and cut-off date is defined as follows:

Randomization (recruitment) period = (Date of last patient randomized - Date of first 
patient randomized + 1) / 30.4375 (months)

Duration between randomization and data cut-off date = (Cut-off date – Date of 
randomization + 1) / 30.4375 (months). This item will be summarized overall.
All summaries will be reported in months.  


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Appendix 1
CTC grades for laboratory values in Novartis Oncology


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CLEE011E2301 
Clinical Development 
LEE011 (Ribociclib) 
CLEE011E2301 (MONALEESA-7) / NCT02278120
A Phase III randomized, double-blind, placebo-controlled 
study of LEE011 or placebo in combination with tamoxifen 
and goserelin or a non-steroidal aromatase inhibitor (NSAI) 
and goserelin for the treatment of premenopausal women 
with hormone receptor positive, HER2-negative, advanced 
breast cancer 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 2 
Release date: 
27-Sep-2017
Number of pages: 
78 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document history – LEE011E2301 Statistical Analysis Plan (SAP). 
Version 
Date 
Changes 
1.0 
18-
Feb-
2015 
First approved version 
2.0 
5-Jun-
2017 
Amendment 1 
Amendment rationale: to incorporate changes to the analysis plan due to protocol 
amendments and implement changes to align with Novartis guidelines and 
program standards 
 
 
Main changes: 
• 
Change document name to Statistical Analysis Plan (SAP) for alignment with 
updated process  
• 
Remove interim futility and efficacy analyses for PFS to reflect protocol 
amendments 
• 
Update analyses based on BIRC assessment of imaging data to reflect 
change to an audit-based assessment 
• 
• 
Update definition of Safety Set to reflect the latest Novartis Oncology 
standard definition 
Specific other changes 
• 
Clarified that Asian vs. non-Asian analyses are based on race, not ethnicity 
• 
Change “LEE011” to “ribociclib” in multiple places throughout the document 
Section 1 
• 
Update introduction to refer to the protocol version the SAP is based on 
Section 2.1 
• 
Update last contact date derivation details based on the latest SAP template 
and the data panels available in the study 
Section 2.3 
• 
Update definition of per protocol set to include requirement of at least one 
dose and remove requirement of evaluable for efficacy 
• 
Update list of protocol deviations leading to exclusion from per protocol set 
• 
Section 2.4 
• 
Update section title to refer to therapies since it’s not limited to medications 
• 
Remove detailed list of prohibited medications and replace with reference to 
protocol 
• 
Expand on description of specific impact of concomitant therapies on 
analyses and clarify here and elsewhere that palliative radiation and continue 
of combination therapy alone after end of study treatment will not be 
considered as new antineoplastic therapies 
Section 2.5 
• 
Clarify definition of PD too late as reason for unknown BOR 
• 
Update calculation of missing tumor assessments to align with Novartis 
RECIST macro 
• 
Remove detailed algorithm for waterfall plot construction 


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Version 
Date 
Changes 
Section 3.2 
• 
Clarify use of IRT data versus CRF data for variables related to stratification 
factors 
• 
Include definitions for disease-free interval and endocrine sensitivity 
• 
Add clarification for biopsy to be considered separately from other prior 
antineoplastic surgeries 
• 
Add further details for summary of prior antineoplastic therapies 
Section 3.5 
• 
Add summary in disposition table for number of patients entering survival 
follow-up 
Section 3.6 
• 
Clarify last date of exposure to goserelin for patients who died or were lost to 
follow-up 
• 
Update dose intensity calculations to use duration of exposure to treatment 
component rather than duration of exposure to study treatment 
• 
Adjust DI calculation for goserelin to consider the dosing schedule (once 
every 28 days) 
• 
Remove calculation of RDI on a per-patient basis across treatment 
components 
• 
Add further details for definitions of dose interruption, delay and reduction 
• 
Add specific definitions of partial discontinuation of ribociclib/placebo and 
goserelin 
Section 3.7 
• 
Separate concomitant and post-treatment therapies 
• 
Add summary for first and second new systemic antineoplastic medication 
after discontinuation of study treatment 
Section 3.8 
• 
Clarify how the different sources of overall lesion response are used 
• 
Specify the primary analysis will be based on FAS including all data up to the 
cutoff date 
• 
Add table of censoring rules to section 3.8.1.1  
• 
Clarify that allocation of patients to NSAI/tamoxifen subgroups for supportive 
efficacy analyses are based on IRT stratification data 
• 
Increase the number of time points at which Kaplan-Meier estimates of 
survival probabilities are produced 
• 
Add details of audit-based BIRC assessment of PFS 
• 
Clarify details of multivariate Cox regression models for PFS and OS 
• 
Remove some of the minor supportive analyses for PFS, namely summary of 
difference in days to progression per local and central review, summary of 
missing tumor assessments, and time to first and second tumor assessment  
• 
 
 
• 
Clarify summary of time to response for responders is a descriptive summary 
• 
Clarify parts of the definition of time to definitive deterioration in ECOG PS 


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Version 
Date 
Changes 
• 
For EQ-5D-5L PRO, change “index score” to “visual analog scale” for 
consistency with the protocol 
• 
Clarify the repeated measures analyses of PROs 
Section 3.9 
• 
Clarify conventions for AE reporting 
• 
Update list of AE tables to be produced 
• 
Change “Clinically notable AEs” to “AEs of special interest” to match standard 
definition, and clarify/update description of these 
• 
Include some additional details regarding laboratory parameter and CTC 
grade derivations 
• 
Update list of liver function test criteria to be summarized and clarified that 
combined categories need not be concurrent 
• 
Include box plot of laboratory parameters 
• 
Add analyses of time to first occurrence of laboratory toxicities 
• 
Add description of analysis to be performed for urinalysis 
• 
Clarify how averaging of unscheduled ECGs is performed 
• 
Clarify notable ECG values to be summarized 
• 
Add analysis of time to grade 2 or worse QT prolongation 
• 
Section 3.10 
• 
• 
 
 
• 
Broaden definition of evaluable ribociclib/LEQ803 concentration to ribociclib 
doses of 200 mg, 400 mg, and 600 mg
 
ribociclib dose 
• 
 
 
• 
 
• 
Added linear model to summarize Ctrough 
• 
 
  
• 
 
 
• 
Remove PK-ECG model and add graphical summaries of PK-ECG and PK-
liver function 
• 
 
• 
 
Section 3.11 
• 
 
 


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Version 
Date 
Changes 
• 
Clarify details of analyses to be performed 
Section 3.13 
• 
Section 3.14 
• 
Update interim analysis descriptions due to protocol amendments 
Section 3.16 – 3.18 
• 
Update sample size calculation to reflect changes in protocol amendments 
Section 4 
• 
Update analysis descriptions for clarity and remove extraneous details and 
SAS code from analysis descriptions 
• 
Clarified analysis for duration of follow-up 
 
3.0 
27-
Sep-
2017 
Amendment 2 
Amendment rationale: to clarify some analysis conventions and terminology used 
 
 
List of changes: 
• 
Section 2.1.7: Clarify the definition of baseline as it relates to RECIST-based 
endpoints, to consider baseline valid if within seven days of treatment start 
date. 
• 
Section 2.3.2: Remove one redundant sentence from the definition of the 
Safety set to avoid potential confusion 
• 
Section 2.3: Include a section on withdrawal of informed consent to ensure 
data after withdrawal of consent are not included in analyses. 
• 
Section 3.2.2:  
• 
Add number of metastatic sites summary to diagnosis and extent of 
cancer summary 
• 
Simplify de novo/DFI definitions 
• 
Change endocrine resistant/sensitive terminology to more generic 
wording 
• 
Section 3.8.1.5:  
• 
Specify that NSAI/tamoxifen subgroup analyses will be based on 
assigned combination partner per CRF, for consistency with other 
subgroup analyses. The analysis according to IRT stratification factor are 
part of a separate analysis. 
• 
Change endocrine resistant/sensitive terminology as described for 
Section 3.2.2 
• 
Section 3.8.2.2: Change endocrine resistant/sensitive terminology as 
described for Section 3.2.2 
• 
Section 3.11.6.2: Remove reference to “each time point” since only baseline 
data are included 
• 
 
 


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Version 
Date 
Changes 
• 
Section 3.13: Delete bullet point indicating PFS 
 may be identical if 
adequate tumor assessments continue after initiation of next-line therapy, to 
avoid potential confusion 
 
 Remove no baseline assessment as censoring 
reason. 
• 
• 
Section 4.2.5: 
• 
Increase the number of samples for bootstrap correlation estimate. 
Specify window for comparison of timing of response assessments. 
 


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Table of contents 
Table of contents ................................................................................................................. 7 
List of tables ...................................................................................................................... 11 
List of figures .................................................................................................................... 11 
1 
Introduction ....................................................................................................................... 14 
1.1 
Study Design .......................................................................................................... 14 
1.2 
Objectives .............................................................................................................. 15 
2 
Definitions and general methodology ............................................................................... 17 
2.1 
Definitions ............................................................................................................. 17 
2.1.1 
Study drug and study treatment ............................................................. 17 
2.1.2 
Date of first administration of study drug ............................................. 17 
2.1.3 
Date of last administration of study drug .............................................. 17 
2.1.4 
Date of first administration of study treatment ..................................... 17 
2.1.5 
Date of last administration of study treatment ...................................... 18 
2.1.6 
Study day ............................................................................................... 18 
2.1.7 
Baseline ................................................................................................. 18 
2.1.8 
On-treatment assessment/event ............................................................. 19 
2.1.9 
Last contact date .................................................................................... 19 
2.2 
Data included in the analysis ................................................................................. 20 
2.3 
Analysis sets .......................................................................................................... 20 
2.3.1 
Full analysis set (FAS) .......................................................................... 20 
2.3.2 
Safety set ............................................................................................... 20 
2.3.3 
Per protocol set ...................................................................................... 21 
21 
2.3.5 
Patient classification .............................................................................. 21 
2.4 
Concomitant therapies with specific impact on the analysis ................................. 22 
2.5 
Implementation of RECIST ................................................................................... 23 
2.5.1 
Overall lesions response for patients with only non-measurable 
lesions at baseline .................................................................................. 23 
2.5.2 
Disease progression ............................................................................... 23 
2.5.3 
Best overall response (BOR) ................................................................. 23 
2.5.4 
Change in imaging modality ................................................................. 24 
2.5.5 
Determination of missing adequate assessments .................................. 25 
2.5.6 
No baseline tumor assessments ............................................................. 26 
2.5.7 
Construction of waterfall graphs ........................................................... 27 


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3 
Statistical methods used in reporting ................................................................................. 28 
3.1 
Enrollment status ................................................................................................... 28 
3.2 
Background and demographic characteristics ....................................................... 28 
3.2.1 
Basic demographic and background data .............................................. 28 
3.2.2 
Diagnosis and extent of cancer ............................................................. 28 
3.2.3 
Medical history ...................................................................................... 29 
3.2.4 
Prior anti-neoplastic therapy ................................................................. 29 
3.2.5 
Other ...................................................................................................... 29 
3.3 
Protocol deviation summaries................................................................................ 29 
3.4 
Groupings for analysis ........................................................................................... 30 
3.5 
Patient disposition .................................................................................................. 30 
3.6 
Study treatment ...................................................................................................... 30 
3.6.1 
Duration of study treatment exposure ................................................... 30 
3.6.2 
Cumulative dose and average daily dose .............................................. 31 
3.6.3 
Dose intensity and relative dose intensity ............................................. 31 
3.6.4 
Dose reductions, interruptions and delays ............................................ 32 
3.6.5 
Discontinuation of study treatment components ................................... 33 
3.7 
Concomitant and post treatment therapy ............................................................... 33 
3.8 
Efficacy evaluation ................................................................................................ 34 
3.8.1 
Primary efficacy .................................................................................... 35 
3.8.2 
Secondary efficacy analyses ................................................................. 40 
3.9 
Safety evaluation ................................................................................................... 47 
3.9.1 
Adverse events (AEs) ............................................................................ 47 
3.9.2 
Laboratory data ..................................................................................... 50 
3.9.3 
Vital signs.............................................................................................. 52 
3.9.4 
ECG ....................................................................................................... 53 
3.9.5 
Cardiac imaging (MUGA / ECHO) ...................................................... 54 
3.9.6 
Other safety data ................................................................................... 54 
 
 54 
 
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 56 
 
 57 
 
 
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 60 
 
 60 
 
 60 
 
 61 
 
 61 
 
 62 
 
 62 
 
 63 
 
 63 
 
 63 
 
 63 
 
 63 
 
 64 
3.14 
Interim analyses ..................................................................................................... 64 
3.14.1 
Primary Endpoint: PFS ......................................................................... 64 
3.14.2 
Key Secondary Endpoint: OS ............................................................... 65 
3.14.3 
Confidentiality of Interim OS results .................................................... 65 
 
 65 
 
 66 
 
 67 
3.16 
Sample size calculation .......................................................................................... 68 
3.17 
Power for analysis of key secondary variables ...................................................... 69 
 
 69 
 
 69 
4 
Details of the statistical analysis ........................................................................................ 70 
4.1 
Baseline comparability .......................................................................................... 70 
4.2 
Time-to-event analyses .......................................................................................... 70 
4.2.1 
Analysis of time-to-event data with ties ................................................ 70 
4.2.2 
Hazard ratio ........................................................................................... 70 
4.2.3 
Hypothesis and test statistic .................................................................. 71 
4.2.4 
Kaplan-Meier estimates ........................................................................ 71 
4.2.5 
Audit-based BIRC assessment of PFS .................................................. 71 
4.3 
Group sequential design used in Phase III studies ................................................. 72 
4.3.1 
Alpha-spending function ....................................................................... 73 
4.3.2 
Methodology ......................................................................................... 73 
4.3.3 
Calculation of stopping boundaries ....................................................... 74 


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4.4 
Duration of follow-up ............................................................................................ 74 
4.5 
Confidence intervals for response rate and clinical benefit rate ............................ 74 
5 
References ......................................................................................................................... 75 
Appendix 1 
CTC grades for laboratory values in Novartis Oncology ...................... 77 


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List of tables 
Document history – LEE011E2301 Statistical Analysis Plan (SAP). ........................................ 2 
Table 1-1 
Study objectives .................................................................................... 15 
Table 2-1 
Last contact date data sources ............................................................... 19 
Table 2-2 
Patient classification based on protocol deviations and non-
protocol deviation criteria ..................................................................... 21 
Table 2-3 
Schedule for tumor assessment and time windows ............................... 25 
Table 2-4 
Assessments considered for calculation of best percentage change 
for waterfall graphs ............................................................................... 27 
Table 3-1 
Planned dose intensity ........................................................................... 32 
Table 3-2 
Sources for overall lesion response ....................................................... 34 
Table 3-3 
Outcome and event/censor dates for PFS analysis ................................ 35 
Table 3-4 
ECOG Performance Scale ..................................................................... 43 
Table 3-5 
Time windows for ECOG PS assessments............................................ 43 
Table 3-6 
Time windows for patient reported outcomes ....................................... 44 
Table 3-7 
AESI groupings ..................................................................................... 50 
Table 3-8 
Clinically notable ECG values .............................................................. 53 
 
 60 
 
 64 
Table 3-11 
Timelines for interim and final analyses ............................................... 65 
Table 4-1 
Local versus central disease progression assessments .......................... 72 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 15 
 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BOR 
Best overall response 
CI 
Confidence Interval 
CBR 
Clinical benefit rate 
CR 
Complete response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Case retrieval strategy 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
ΔQTcF 
Change from baseline in QTcF 
DAR 
Dosage administration Record 
DI 
Dose Intensity 
DMC 
Data Monitoring Committee 
DOR  
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
FAS 
Full analysis set 
HER2 
Human epidermal growth factor receptor 2 
HR  
Hazard Ratio 
HRQoL  
Health-Related Quality of Life 
IRT 
Interactive Response Technology 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NMQ 
Novartis MedDRA queries 
NSAI 
Non-steroidal aromatase inhibitor  
ORR  
Overall response rate  
OS 
Overall survival  
PAS 
Pharmacokinetic analysis set 
PD 
Progressive disease 


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PDI 
Planned dose intensity 
PDS 
Programming Datasets Specifications 
PFS 
Progression-free survival 
PhRMA 
Pharmaceutical Research and Manufacturers of America 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PS 
Performance Status 
PT 
Preferred term 
QTcF 
QT interval corrected by Fridericia method 
RAP 
Report and Analysis Process 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SD 
Standard deviation 
SEC 
Safety Event Categories 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TA 
Tumor assessment 
TBIL  
Total Bilirubin 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, Figures, Listings 
UNK 
Unknown 
 


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1 
Introduction 
This document describes the detailed statistical methodology to be used for the Clinical Study 
Report (CSR) for the primary PFS analysis of study CLEE011E2301, a phase III, randomized, 
double-blind, placebo-controlled study of LEE011 (ribociclib) or placebo in combination with 
tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the 
treatment of premenopausal women with hormone receptor positive, HER2-negative, advanced 
breast cancer.  
The content of this SAP is based on protocol amendment 4 (clee011e2301-v04--protocol). All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock and unblinding of the study data. 
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in the Tables, Figures & Listings (TFL) shells and Programming Datasets 
Specifications (PDS), respectively. 
1.1 
Study Design 
This is a phase III randomized, double-blind, placebo-controlled global study comparing the 
combination of tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + LEE011 to 
tamoxifen or a NSAI (letrozole or anastrozole) + goserelin + placebo in premenopausal women 
with HR+, HER2-negative advanced breast cancer.  
Approximately 660 patients will be randomly assigned to one of the below treatment arms in 
1:1 ratio: 
a. [Tamoxifen or a NSAI (letrozole or anastrozole)] + goserelin + LEE011  
OR, 
b. [Tamoxifen or a NSAI (letrozole or anastrozole)] + goserelin + placebo. 
Randomization will be stratified by the presence of liver and/or lung metastases (yes versus no), 
prior chemotherapy for advanced disease (yes versus no), and endocrine combination partner 
(tamoxifen and goserelin versus NSAI (letrozole or anastrozole) and goserelin). 
Treatment with tamoxifen or NSAI in this study will be based on the patient’s prior (neo) 
adjuvant therapy for breast cancer as outlined in the Clinical Study Protocol. The choice of 
NSAI (letrozole or anastrozole) is left to the discretion of the investigator. Once assigned, 
changing the dose or type of endocrine therapy is not permitted. 
PFS, as assessed by the local radiologists/investigators and using RECIST 1.1 criteria will be 
the primary endpoint. PFS as assessed through audit-based blinded independent central review 
will be used for supportive evidence of the primary efficacy endpoint. 
An independent Data Monitoring Committee (DMC) will monitor unblinded safety and PK data 
during the trial. Separate DMC RAP documents specify the analyses to be performed for the 
DMC reviews.  
Overall survival is a key secondary endpoint in this study and will be analyzed provided the 
primary endpoint PFS is statistically significant. A Lan-DeMets alpha spending function with 
O’Brien Fleming type stopping boundary (as implemented in East 6.3) will be used to maintain 


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the overall type-I error rate for OS. The interim OS analyses will be performed by Novartis. 
Further details regarding the group sequential design are provided in Section 3.14.  
The study design is summarized in Figure 1-1. 
Figure 1-1 
Study design 
 
1.2 
Objectives 
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1. 
Table 1-1 
Study objectives 
Objective 
Endpoint 
Analysis 
Primary  
 
 
To determine whether treatment 
with tamoxifen or a NSAI + 
goserelin + LEE011 prolongs PFS 
compared to treatment with 
tamoxifen or a NSAI + goserelin + 
placebo in premenopausal women 
with HR+, HER2-negative 
advanced breast cancer 
PFS per local assessment and 
RECIST 1.1 
Section 3.8.1 
Key secondary 
 
 
To determine whether treatment 
with tamoxifen or a NSAI + 
goserelin + LEE011 prolongs OS 
compared to treatment with 
tamoxifen or a NSAI + goserelin + 
placebo in premenopausal women 
with HR+, HER2-negative 
advanced breast cancer. 
 
OS 
Section 3.8.2.1 
Other secondary 
 
 


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Objective 
Endpoint 
Analysis 
To evaluate the safety and 
tolerability of LEE011 in 
combination with tamoxifen + 
goserelin or a NSAI + goserelin. 
Frequency/ severity of adverse 
events, lab abnormalities 
Section 3.9 
To evaluate the two treatment 
arms with respect to response rate 
and clinical benefit rate (CBR). 
ORR as defined by RECIST 1.1. 
CBR, defined as percentage of 
patients with CR, PR per RECIST 
1.1 or SD lasting 24 weeks or 
longer 
Section 3.8.2.2 and 3.8.2.3 
To describe time to response 
(TTR) and duration of response 
(DOR) in each treatment arm.   
Time to response and duration of 
response per RECIST 1.1 
Section 3.8.2.4 and 3.8.2.5 
To evaluate the two treatment 
arms with respect to time to 
deterioration of ECOG PS. 
Time to definitive deterioration of 
the ECOG PS from baseline 
Section 3.8.2.6 
To evaluate patient reported 
outcomes for health-related quality 
of life in the two treatment arms. 
Time to 10% deterioration in the 
global health status/QOL scale 
score of the EORTC QLQ-C30 
Change from baseline in the global 
health status/QOL scale score of 
the EORTC QLQ-C30 
Section 3.8.2.7 


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2 
Definitions and general methodology 
2.1 
Definitions 
2.1.1 
Study drug and study treatment 
Study drug is defined as ribociclib or matching placebo. 
Study treatment is defined as ribociclib + (tamoxifen or a NSAI) + goserelin, or matching 
placebo + (tamoxifen or a NSAI) + goserelin. 
2.1.2 
Date of first administration of study drug 
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 DAR CRF. 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. 
2.1.3 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on the DAR CRF date. Similar definitions apply for 
the other components of study treatment. 
2.1.4 
Date of first administration 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 CRF. The 


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date of first administration of study treatment will also be referred to as the start of study 
treatment. 
2.1.5 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF. 
2.1.6 
Study day 
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 (i.e., tumor assessment, death, 
disease progression, tumor response, ECOG performance status, and patient reported outcomes 
(PRO)) is the date of randomization. In other words, all efficacy time-to-event variables (e.g. 
progression-free survival, overall survival, time to response) will be calculated from date of 
randomization. (Example: if randomization date is 15DEC2014, start of study drug is on 
18DEC2014, and the date of death is 28DEC2014 then the study day when the death occurred 
is 14). 
The study day will be displayed in data listings. 
2.1.7 
Baseline 
For efficacy evaluations, the last available assessment on or before the date of randomization 
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 endpoints (e.g. PFS, best overall response), a window of 7 days 
after the start of study treatment will be allowed, i.e. the baseline will also be considered valid 
if it occurs within 7 days of the 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. 


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2.1.8 
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 3.6.1). 
An AE started in the screening phase and ongoing in the on-treatment phase will not be 
considered an on-treatment AE unless it has worsened.   
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 2.1.4 and 2.1.5, respectively. 
2.1.9 
Last contact date 
For patients not known to have died at the analysis cut-off the last contact date will be derived 
using the last complete date among the following: 
 
Table 2-1 
Last contact date data sources  
 
 
Source data 
Conditions 
Date of Randomization  
 
No Condition 
Last date patient was known to be alive from 
Survival Follow-up page  
 
Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 
Start/End dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
Date of discontinuation/study phase completion 
from end of treatment or end of post-treatment 
follow-up disposition page 
No condition. 
Date of ECG assessment 
At least one non-missing parameter value 
Date of PRO assessment  
At least one non-missing answer to questionnaire 
Tumor (RECIST) assessment date 
For non-target lesion: non-missing lesion status 
For target lesion: non-missing lesion diameter 
For new lesion: “Is there a new lesion?” = yes 
Laboratory collection dates 
 
At least one non-missing parameter value  
 
 
Vital signs date 
At least one non-missing parameter value 


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Source data 
Conditions 
 
Performance Status date 
 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
Concomitant medication date 
Non-missing medication 
 
 
Body fluid/Tissue Collection/Results 
Non-missing result (positive/negative tumor cells) 
 
 
Cardiac imaging date 
Non-missing LVEF or overall interpretation 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. For patients 
who died, the last contact date is defined as the date of death. Partial date imputation is allowed 
for event (death)/censoring from the ‘Survival information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival.  
2.2 
Data included in the analysis 
The primary PFS endpoint will be carried out after approximately 329 PFS events have been 
documented based on local assessment, and up to 3 analyses for OS may be performed as 
described in Section 3.8.2.1. 
For each of the analyses, cutoff dates will be established and statistical analyses will be 
performed using all data collected in the database up to the data cutoff date. Any data collected 
beyond the cutoff date will not be included in the analysis and will not be used for any 
derivations. 
2.3 
Analysis sets 
2.3.1 
Full analysis set (FAS) 
The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment and stratum they were assigned 
to at randomization. The FAS will be the primary analysis set for efficacy analyses. 
2.3.2 
Safety set 
The Safety Set consists of all patients who received at least one dose of any component of study 
treatment. Patients will be analyzed according to the treatment actually received. Treatment 


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actually received refers to the treatment the patient was randomized to, unless the alternative 
treatment was received throughout the trial. 
2.3.3 
Per protocol set 
The Per-Protocol Set (PPS) includes the subset of the patients in the FAS without any major 
protocol deviation who took at least one dose of study treatment. Patients with any of the 
following protocol deviations will be excluded from the PPS. 
• Written informed consent not obtained; 
• Patient without HR+ and HER2- advanced breast cancer at baseline; 
• Patient is postmenopausal; 
• Patient received prior CDK4/6 inhibitor; 
• Baseline ECOG performance status>1; 
• Neither measurable disease nor predominantly lytic bone lesion at baseline; 
• Patient received any prior hormonal anti-cancer therapy for advanced breast cancer, 
except for ≤ 14 days of tamoxifen or a NSAI ± goserelin or ≤ 28 days of goserelin prior 
to randomization; 
• Patient received >1 line of chemotherapy for advanced breast cancer; 
• Patient received different treatment throughout the study than the one randomized to; 
• Inadequate documentation available to support patient eligibility; 
• Patient has inflammatory breast cancer; 
• Patient has CNS metastases. 
A sensitivity analysis of the primary endpoint (i.e., PFS) will be performed using PPS if the 
primary efficacy analysis is significant and the FAS and PPS differ. 
2.3.5 
Patient classification 
Patients may be excluded from the analysis sets defined above based on the protocol deviations 
entered in the database and/or on specific subject classification rules as defined in Table 2-2. 
Table 2-2 
Patient classification based on protocol deviations and non-protocol 
deviation criteria 
Analysis set 
Protocol deviations leading 
to exclusion 
Non-protocol deviation 
criteria leading to exclusion 
FAS  
No written informed consent 
NA 
Safety set 
No written informed consent 
No dose of study treatment 


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Per Protocol set 
Any major protocol deviation as 
listed in definition of per 
protocol set 
No dose of study treatment 
Withdrawal of informed consent 
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.   
Death events may be used in the analysis if captured from public records (registers), local law 
and patient informed consent permiting. 
 
 
2.4 
Concomitant therapies with specific impact on the analysis 
According to the study protocol, the following medications are prohibited during combined 
ribociclib, tamoxifen or a NSAI, and goserelin treatment in this study: 
• Strong inhibitors or inducers of CYP3A4/5  
• Strong inhibitors of CYP2D6 (that could affect tamoxifen exposure) 
• Substrates of CYP3A4/5 with a narrow therapeutic index 
• Medications with a known risk of QT prolongation 
• Warfarin and coumarin derivatives  
• Other investigational and antineoplastic therapies (with the exception of palliative 
radiotherapy) 
• Herbal medications/preparations 
These substances are listed in Table 14-1 in the study protocol. A corresponding list for 
programming purposes will be saved in a separate document. If there is an update to the list of 
prohibited medications (e.g., in a protocol amendment), the most up-to-date list shall be used 
for the Clinical Study Report. 
However, some patients may take these substances during the treatment period so these 
concomitant medications will be selected via programming and tabulated and listed in the 
Clinical Study Report. 
Treatment with the prohibited substances mentioned above will be identified in the database as 
protocol deviations.  
With the exception of palliative radiotherapy, administration of anti-neoplastic therapies (apart 
from study treatment) is not allowed during study treatment. Patients who take anti-neoplastic 
therapies after randomization but before end of treatment will be identified through data review. 
Tumor assessments (TAs) made after the start of anti-neoplastic therapies (whether on study 
treatment or afterwards) will not be included in the efficacy analyses based on best overall 
response (i.e. Overall Response Rate (ORR), Clinical Benefit Rate (CBR), time to response, 
and duration of response (Section 3.8.2.2 to 3.8.2.3). In addition, a sensitivity analysis will be 


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performed for the primary efficacy PFS analysis in which PFS will be censored at the last tumor 
assessment before the start of new anti-neoplastic therapy. Further details are provided in 
Section 3.8.1. Time to event analyses based on ECOG performance status and patient reported 
outcomes will not consider assessments after the start of new anti-neoplastic therapy. Further 
details are provided in Section 3.8.2.6 and 3.8.2.7. For these analyses, the following will not be 
considered as new antineoplastic therapies: (i) palliative radiotherapy; (ii) continuation of 
combination partner therapy alone after end of study treatment.  
2.5 
Implementation of RECIST 
Response and progression evaluation will be performed according to the Novartis RECIST 
guideline (as described in detail in Appendix 3 of the Clinical Study Protocol), which is based 
on the RECIST 1.1 guidelines (Eisenhauer et al 2009). The text below gives instructions and 
rules to provide details needed for programming. 
2.5.1 
Overall lesions response for patients with only non-measurable 
lesions at baseline 
Patients without measurable disease per RECIST 1.1 are eligible to enter the study if they have 
at least one predominantly lytic bone lesion. For patients with non-measurable lesions only at 
baseline, the overall lesion response will be based solely on non-target lesion response or an 
occurrence of a new lesion. Non-measurable lesions will be entered as non-target lesions. 
Therefore, the best overall response is determined from non-target lesion response and presence 
of new lesions (refer to Table 3-1 in Section 3.2.9 of RECIST Novartis guidelines as described 
in detail in Appendix 3 of the Clinical Study Protocol). 
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression, unless there is unequivocal progression 
of existing non-target lesions or a new lesion. 
2.5.2 
Disease progression 
Progressive disease should only be assigned if it is confirmed by an assessment method as per 
RECIST 1.1 guidelines (e.g. radiologic scan, photos for skin lesions, etc). If a new lesion is 
detected using an objective assessment method other than radiologic scan then it should also be 
entered on the ‘New lesion’ RECIST CRF with appropriate method. Discontinuation due to 
disease progression or death due to study indication, without corresponding supportive  data in 
the RECIST CRF (as defined above), will not be considered as progressive disease in the 
calculation of best overall response and in the analysis of PFS. 
2.5.3 
Best overall response (BOR) 
The best overall tumor response will be assessed per RECIST 1.1 criteria. The definitions and 
the details on the derivation are given in Appendix 3 of the Clinical Study Protocol. 
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e. 
any additional anti-neoplastic therapy or surgery) and within 30 days after the last 
administration of study treatment will be considered in the assessment of best overall response. 
Further anti-neoplastic therapies will be identified from the data collected on ‘Anti-neoplastic 


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therapies since discontinuation of study treatment’ CRFs. Palliative radiotherapy is the only 
setting of radiotherapy allowed during the study. Therefore, palliative radiotherapy will not be 
considered as an anti-neoplastic therapy for assessment of BOR. Continuation of combination 
partner therapy alone after end of study treatment will also not be considered as a new anti-
neoplastic therapy.  
The standard definition of a best overall response evaluation of ‘stable disease’, ‘disease 
progression’ or ‘unknown’ given in the Appendix 3 of the Clinical Study Protocol will be used 
for this study.  Best overall response for each patient is determined from the sequence of overall 
(lesion) responses (as reported by the investigator for local BOR, and as reported by BIRC for 
central BOR) according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR). 
• SD = at least one SD assessment (or better) > 6 weeks after randomization (and not 
qualifying for CR or PR). 
• Non-CR/non-PD = at least one non-CR/non-PD assessment (or better) > 6 weeks after 
randomization date (and not qualifying for CR). This applies only for patients with non-
measurable disease alone at baseline. 
• PD = progression ≤ 12 weeks after randomization (and not qualifying for CR, PR, SD or 
Non-CR/non-PD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD or 
Non-CR/Non-PD after more than 6 weeks or progression within the first 12 weeks). 
Patients with best overall response “unknown” will be summarized by reason for having 
unknown status. The following reasons will be used: 
• No valid post-baseline assessment  
• All post-baseline assessments have overall response UNK  
• New anti-neoplastic therapy started before first post-baseline assessment  
• SD too early (≤6 weeks after randomization)  
• PD too late (>12 weeks after randomization and not qualifying for CR, PR, SD or Non-
CR/Non-PD) 
Special (and rare) cases where BOR is unknown due to both early SD and late PD will be 
classified as “SD too early”. 
2.5.4 
Change in imaging modality 
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use or vice-
versa, regardless of the justification for the change) or a 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. However, a response from 


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the investigator or the central blinded reviewer 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.  
2.5.5 
Determination of missing adequate assessments 
The term ‘missing adequate assessment’ refers to assessments that are not done or for which 
the overall lesion response is ‘Unknown’. ‘Missing adequate assessment’ will also be referred 
to as ‘missing assessment’. 
As detailed in Section 3.2.10 and in Appendix 3 of the Clinical Study Protocol, the 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 assessments is censored at the last 
adequate tumor assessment.  
An exact rule to determine whether there are no, one or two missing TAs is therefore needed. 
This rule is based on the interval between the last adequate tumor assessment (LATA) date and 
the event date. The scheduled date of tumor assessments (in weeks from randomization), 
protocol specified window for tumor assessments, and the thresholds for LATA to belong to a 
visit can be found in the following table. 
Table 2-3 
Schedule for tumor assessment and time windows 
Assessment 
schedule 
Scheduled date 
– 1 week 
Scheduled date 
(weeks from 
randomization) 
Scheduled date 
+1 week 
Threshold* 
Every 8 
weeks 
for the 
first 18 
months 
Baseline 
0 
0 
0 
0 
C3D1 
7 
8 
9 
12 
C5D1 
15 
16 
17 
20 
C7D1 
23 
24 
25 
28 
C9D1 
31 
32 
33 
36 
C11D1 
39 
40 
41 
44 
C13D1 
47 
48 
49 
52 
C15D1 
55 
56 
57 
60 
C17D1 
63 
64 
65 
68 
C19D1 
71 
72 
73 
78 
Every 
12 
weeks 
after 18 
months 
C22D1 
83 
84 
85 
90 
C25D1 
95 
96 
97 
102 
C28D1 
107 
108 
109 
114 
C31D1 
119 
120 
121 
126 
* The mid-point between current and next visit (except for baseline) and the upper limit for LATA to 
be matched to a certain scheduled assessment, e.g. if LATA is at week 13, this is after threshold 
for C3D1 and before that for C5D1, so the matching scheduled assessment is C5D1. 


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To calculate the number of missing tumor assessments, the LATA before an event is matched 
with a scheduled tumor assessment using the time window in Table 2-3 (essentially whichever 
scheduled assessment it is closest to). Two thresholds, D1 and D2 are calculated for that 
scheduled assessment based on the protocol-specified schedule and windows 
• An event after LATA+D1 will be considered as having >=1 missing assessment 
• An event after LATA+D2 will be considered as having >=2 missing assessments 
Since there is a change of schedule for tumor assessments at 18 months, D1 and D2 are 
defined differently depending on when LATA happens. 
Rule 1: if LATA happens within 60 weeks from randomization (the matched scheduled tumor 
assessment is C15D1 or before) 
• D1=8+2=10 weeks 
• D2=2*8+2=18 weeks 
Rule 2: if LATA happens after 60 weeks but within 68 weeks from randomization (the 
matched scheduled tumor assessment is C17D1) 
• D1=8+2=10 weeks 
• D2=8+12+2=22 weeks 
Rule 3: if LATA happens after 68 weeks from randomization (the matched scheduled tumor 
assessment is C19D1 or later) 
• D1=12+2=14 weeks 
D2=2*12+2=26 weeks.   
Therefore, using the D2 definition above, the censoring of an event occurring after ≥2 missing 
TAs (in the primary PFS analysis) can be refined as follows: if the distance between the last 
adequate TA date and the PFS event date is larger than D2 then the patient will be censored and 
the censoring reason will be ‘Event documented after two or more missing tumor assessments’. 
The same definition of D2 will be used to determine the PFS censoring reason. If the distance 
between the last adequate tumor assessment date and the earliest of the following dates: 
1. Analysis cut-off date 
2. Date of consent withdrawal 
3. Date of loss to follow-up 
is less than or equal to D2 then the censoring reason will be 1. ‘Ongoing without event’, 2. 
‘Withdrew consent’, or 3. ‘Lost to follow-up’, respectively. However, if this distance is larger 
than D2 then the censoring reason will be ‘Adequate assessment no longer available’. If an 
event is documented after two missing assessments, then the censoring reason will be ‘Event 
documented after two or more missing tumor assessments’. 
2.5.6 
No baseline tumor assessments 
As specified in Table 3-2 in Section 3.2.10 of the Appendix 3 of the Clinical Study Protocol, 
since the timing of disease progression cannot be determined for patients with missing baseline 
tumor assessment, these patients are censored in the PFS analysis at the date of randomization. 


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This rule however only applies to the disease progression component of the PFS assessment, 
and not to the survival component.  
Patients without baseline tumor assessments who die within D2 distance (see Section 2.5.5 for 
definition) of randomization will be counted as having an event in the primary analysis of PFS 
at the date of death (Note: all deaths will be counted in the overall survival analysis regardless 
of presence or absence of the baseline tumor assessment). 
These patients will be excluded from the PPS for the analysis of PFS as defined in Section 2.3 
2.5.7 
Construction of waterfall graphs 
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of all target lesions for each patient. 
Only patients with measurable disease at baseline will be included in the waterfall graphs. 
Special consideration is needed for assessments where the target lesion response is CR, PR or 
SD, but the appearance of a new lesion or a worsening of non-target lesions results in an overall 
lesion response of PD. As a conservative approach, such assessments will not be considered for 
display as bars in the graph, since the percentage change in the sum of diameters of target lesions 
reflects the non-PD target lesion response, but the overall lesion response is PD. A patient with 
only such assessments will be represented by a special symbol (e.g.  ) in the waterfall graph. 
Assessments with “unknown” target lesion response and assessments with unknown overall 
response will be excluded from the waterfall plots. Patients without any valid assessments will 
be completely excluded from the graphs. 
The total number of patients displayed in the graph will be shown and this number will be used 
as the denominator for calculating the percentages of patients with tumor shrinkage and tumor 
growth. Footnote will explain the reason for excluding some patients (due to absence of any 
valid assessment). 
All possible assessment scenarios are described in Table 2-4. 
Table 2-4 
Assessments considered for calculation of best percentage change 
for waterfall graphs 
Case 
Target response 
Overall lesion 
response 
Calculate % change from baseline 
in sum of diameters? 
1 
UNK 
Any 
No, exclude assessment 
2 
Any 
UNK 
No, exclude assessment 
3 
CR/PR/SD 
PD 
No, flag assessment with  
4 
PD 
PD 
Yes 
5 
CR/PR/SD 
CR/PR/SD 
Yes 
 


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3 
Statistical methods used in reporting 
3.1 
Enrollment status 
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The reasons for screen failure will also be summarized. 
3.2 
Background and demographic characteristics 
The FAS will be used for all baseline disease characteristics and demographic summaries and 
data listings. 
3.2.1 
Basic demographic and background data 
Demographic and background disease characteristics data will be listed in detail. Qualitative 
data (e.g. race, ECOG performance status, etc.) will be summarized by means of contingency 
tables by treatment arm and quantitative data (e.g. age, body weight, etc) will be summarized 
by appropriate descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) by treatment arm. 
Discrepancies between randomization stratification information (obtained from the Interactive 
Response Technology (IRT) system) and stratum information based on data collected on CRFs 
will be tabulated and listed. 
Unless otherwise specified, stratified analyses and analyses “by stratum” will be based on IRT 
stratification data, while data for other subgroup analyses and model covariates will be based 
on CRF data. 
3.2.2 
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, histological grade, stage at initial diagnosis, 
time since initial diagnosis, 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, disease-free interval (DFI) for non-de novo patients, and a categorization of 
prior (neo-)adjuvant endocrine therapy (ET) as outlined below: 
• De novo patients will be identified as those with no date of first recurrence/progression or 
the first recurrence/progression is within 90 days of initial diagnosis without prior 
antineoplastic medication (other than the short period of hormonal therapy for advanced 
breast cancer permitted by the protocol). 
• DFI for non-de novo patients will be calculated as the time from initial diagnosis to first 
recurrence/progression and categorized as ≤12 months and >12 months. 
• Patients will be grouped as follows based on prior (neo-)adjuvant ET: 
• No prior (neo-)adjuvant endocrine therapy 
• Progression while on or within 12 months of end of (neo-)adjuvant ET 
• Progression > 12 months after end of (neo-)adjuvant ET. 
Time since initial diagnosis  will be summarized in months. A month is defined as 
365.25/12=30.4375 days. 


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3.2.3 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions, will be 
summarized and listed. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by primary system organ class and 
preferred term. Medical history/current medical conditions are coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA) terminology available at the time of 
the analyses. The MedDRA version used for reporting will be specified in the CSR and as a 
footnote in the applicable tables/listings. 
3.2.4 
Prior anti-neoplastic therapy 
The number and percentage of patients recording any prior anti-neoplastic medications, 
radiotherapy or surgery (biopsy and non-biopsy separately) will be summarized by treatment 
arm both separately and in a combined fashion. 
• Prior anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, 
hormonal therapy etc), and also by lowest ATC class, preferred term and treatment. The 
total number of regimens along with the type (e.g. hormonal therapy), setting (e.g. 
adjuvant), best response and time from last treatment to progression for the last therapy 
will be summarized by treatment arm. 
• Hormonal therapy (tamoxifen/letrozole/anastrozole) for advanced breast cancer 
received for ≤ 14 days with or without goserelin, or treatment with goserelin for ≤ 28 
days prior to randomization, as permitted by the study protocol, will be summarized 
separately. 
• Hormonal therapies in (neo-)adjuvant setting will also be summarized, including time 
from last dose of (neo-)adjuvant hormonal therapy to randomization. 
• For radiotherapy, the setting (e.g. adjuvant, palliative) for the last therapy will be 
summarized. 
• For surgery (excluding biopsies), the time since last surgery will be summarized by 
treatment arm. 
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
3.2.5 
Other 
All data collected at baseline, including source of patient referral, child bearing potential and 
, will be listed. 
3.3 
Protocol deviation summaries 
The number and percentage of patients in the FAS with any protocol deviation will be tabulated 
by deviation category (as specified in the Study Specification Document) and by treatment arm. 
Protocol deviations leading to the exclusion from the per protocol set will be tabulated 
separately by treatment arm.  
All protocol deviations, as well as protocol deviations leading to exclusion from the per protocol 
set, will be listed. 


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3.4 
Groupings for analysis 
The number and percentage of patients in each analysis set (definitions are provided in Section 
2.3) will be summarized by treatment arm and randomization stratum.  
3.5 
Patient disposition 
Patient disposition for all randomized patients will be summarized based on the FAS. There 
will be one combined by-treatment summary showing: 
1. Number (%) of patients treated/untreated 
2. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of treatment’ page) 
3. Number (%) of patients who discontinued study treatment (based on the ‘End of 
Treatment’ page) 
4. Reasons for study treatment discontinuation (based on ‘End of Treatment’ page) 
5. Number (%) of patients who entered the post-treatment evaluations (based on ‘End of 
Treatment’ page) 
6. Number (%) of patients who discontinued from the post-treatment evaluations (based 
on ‘End of post treatment follow up disposition’ page) 
7. Reasons for discontinuation from the post-treatment evaluations phase (based on ‘End 
of post treatment follow up disposition’ page) 
8. Number (%) of patients who entered survival follow-up. 
In a separate summary, the reasons for patients not completing the screening phase will be 
presented based on the “Screening Phase Disposition” CRF. 
3.6 
Study treatment 
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. The number of patients with dose 
reductions/interruptions, and the reasons, will be summarized and listed. Details of the 
derivations and summaries are provided in the following sections. 
The safety set will be used for all summaries and listings of study treatment. 
3.6.1 
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 any single component of study treatment will be calculated as 
Duration of exposure (days) = (last date of exposure to study treatment component) – (date of 
first administration of study treatment component) + 1. 
The last date of exposure is defined as follows for the study treatment components: 
• For ribociclib/placebo, tamoxifen, anastrozole, and letrozole: the last date of exposure is 
defined as the date of last administration of the corresponding medication; 


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• For goserelin, the last date of exposure is defined as the date of last administration of 
goserelin + 27 days.  
• If a patient died or was lost to follow-up within date of last administration + 27 days, 
then the last date of exposure is the date of death or last contact date, respectively. 
This 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 and exposure to 
each treatment component will be summarized by treatment arm. In addition, the duration of 
exposure will be categorized into time intervals (e.g. <3 months; 3-<6 months; 6-<9 months, 
etc); frequency counts and percentages will be presented for the number of patients in each 
interval. 
3.6.2 
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 by 
treatment arm for each component of study treatment. Patients with no exposure to the study 
treatment component will be excluded from the corresponding summary. 
3.6.3 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure to each study treatment 
component is defined as follows:  
For tamoxifen, letrozole, and anastrozole, DI is defined as 
DI (mg/day) = Cumulative dose (mg) / duration of exposure to study treatment component 
(days). 
For goserelin, DI is defined as 
DI (mg/28 days) = Cumulative dose (mg) / {[(date of last administration of goserelin + 27) – 
(date of first administration of goserelin) + 1] / 28}, 
to account for the goserelin dosing schedule in the DI computation. 
For ribociclib/placebo, DI is defined as 
DI (mg/day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib/placebo 
(days), 
where adjusted duration of exposure (days) to ribociclib/placebo represents the number of 
ribociclib/placebo dosing days a patient would be expected to have received per protocol, given 
their duration of exposure to ribociclib/placebo as defined in Section 3.6.1. Since 
ribociclib/Placebo follows a 3 weeks on, 1 week off schedule, the adjusted duration of exposure 
to ribociclib/placebo is the duration of exposure to ribociclib/placebo minus the planned off 
days. The adjusted duration of exposure to ribociclib/placebo is therefore 21 x (# completed 28 
day cycles) + min(21, duration of last incomplete cycle). 


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For example, if the duration of exposure to ribociclib/placebo is 66 (corresponding to two cycles 
and 10 days), then the adjusted duration of exposure to ribociclib/placebo is 21*2+10=52. If the 
duration of exposure to ribociclib/placebo is 108 days (corresponding to three cycles and 24 
days), then the adjusted duration of exposure is 21*3+21=84 days. 
Specifically, let D1 represent the duration of exposure to ribociclib/placebo as defined in 
Section 3.6.1. Then the adjusted duration of exposure is defined as  
D=21*[D1/28]+min(21,D1-28*[D1/28]) days,  
where [x] stands for the integer part of x. In this equation [D1/28] is the number of completed 
cycles, and D1-28*[D1/28] is the additional number of days in the last, incomplete cycle (if 
any). For example, if D1=30 then [D1/28]=1, D1-28*[D1/28]=2, and D=23. If D1=7 then D=7; 
if D1=22 then D=21; if D1=28 then D=21, etc. 
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 each study treatment component is displayed in Table 
3-1. Note that DI will also be calculated and reported in the units displayed in Table 3-1, 
whereas duration of exposure itself will be summarized in months. 
Table 3-1 
Planned dose intensity 
Medication 
PDI (dose unit/unit of time) 
Ribociclib/placebo 
600 mg/day 
Tamoxifen 
20 mg/day 
Letrozole 
2.5 mg/day 
Anastrozole 
1 mg/day 
Goserelin 
3.6 mg/28 days 
Relative dose intensity (RDI) is defined as: 
RDI = DI (dosing unit / unit of time)  / PDI (dosing unit / unit of time).   
DI and RDI will be summarized separately for each of the study treatment components. 
3.6.4 
Dose reductions, interruptions and delays 
The number and percentage of patients with dose reductions, interruptions or delays, and the 
reasons, will be summarized by treatment arm as outlined below.  
Interruption: An interruption is defined as a 0mg dose given on one or more days during the 
period where (for ribociclib/placebo only) 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 600 mg – 0mg (dose break) -0mg (dose interruption) – 0 mg (dose permanently discontinued) 
the 0mg (dose interruption) will not be counted as a dose interruption. Interruptions will be 
summarized for each component of study treatment. 
Delay: A special case of an interruption is one that, for ribociclib/placebo, occurs at the start of 
a new cycle, after a planned rest period. Such instances will be identified as a subset of the 
interruptions (specifically those occurring directly after a planned dose break) and will be 
summarized separately as dose delays. 


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Reduction: A dose reduction for ribociclib/placebo is defined as a decrease from the previous 
non-zero dose to another non-zero dose less than the protocol-planned dose, even if this 
decrease has been directly preceded by an interruption.  For example, in the sequence 600mg 
– 0mg – 400mg, the 400mg dose will be counted as a reduction.  
If due to dosing error, a patient took a dose during the dosing break with a dose that is lower 
than the previous dose, this will not be considered as a dose reduction. For example, a patient 
took 600 mg from day 1-21, then mistakenly took 200 mg per day on day 22-28, which is 
supposed to be a dosing break, then resumed 600 mg dosing on day 29. This will not be 
considered as a dose reduction. 
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. 
In this study, dose reductions for letrozole, anastrozole, tamoxifen or goserelin are not permitted 
and will not be summarized, however all dosing data will be listed. 
3.6.5 
Discontinuation of study treatment components 
The reasons for discontinuation of each study treatment component will be summarized by 
treatment arm, based on the information on the component-specific DAR CRFs (i.e. using the 
“Reason Dose Permanently Discontinued” field on the applicable DAR CRF for patients who 
have the “dose permanently discontinued” box checked).  
Partial discontinuation: Partial discontinuations and their reasons will also be summarized for 
ribociclib/placebo and goserelin (separately). Partial discontinuation refers to discontinuation 
of ribociclib/placebo or goserelin, respectively, while continuing on study treatment. 
• For ribociclib/placebo, partial discontinuation is defined as the  event when the last non-
zero dose of ribociclib/placebo is more than 21 days before the last non-zero dose of study 
treatment, with the permanent discontinuation box checked in the ribociclib/placebo DAR 
page; 
• For goserelin, partial discontinuation is defined as the last non-zero dose of goserelin plus 
27 days being more than 21 days before the last non-zero dose of study treatment, with the 
permanent discontinuation box checked on the goserelin DAR page. 
3.7 
Concomitant and post treatment therapy 
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.  
Concomitant medications will be summarized by lowest ATC class, preferred term and 
treatment arm. These summaries will include:  


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1. medications starting on or after the start of study treatment but no later than 30 days 
after last dose of study treatment, and  
2. medications starting prior to the start of study treatment and continuing after the start 
of study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to 
the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing.  
The safety set will be used for all concomitant medication tables and listings. 
Concomitant medications that have the potential to impact some specific analyses (e.g. PK, 
efficacy or safety analyses) will be identified prior to database lock. Separate summaries of 
these concomitant medications will be produced using the appropriate analysis set (e.g. FAS 
for those potentially affecting efficacy). 
• Strong inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow 
therapeutic window, medications with a known risk of QT prolongation and other 
prohibited medications described in Section 2.4 will be identified. They will be tabulated 
by ATC class and preferred term. 
• Any anti-neoplastic therapy administered concomitantly with study treatment will be 
listed based on their identification through the protocol deviation process. 
Post treatment anti-cancer therapy 
Anti-neoplastic therapies after discontinuation of study drug will be listed and tabulated by ATC 
class, preferred term and treatment arm by means of frequency counts and percentages using 
the FAS. In addition, 1st and 2nd new anti-neoplastic medication regimens after discontinuation 
of study treatment will be summarized by medication type, e.g. hormonal therapy, 
chemotherapy, etc. The medication type will be determined by clinical review. 
 
 
 
 
3.8 
Efficacy evaluation 
The efficacy endpoints based on the tumor assessments will be derived according to the 
RECIST guideline version 1.1 (see Section 2.5 and Appendix 3 of the Clinical Study Protocol 
for details). The tumor endpoint derivation is based on the sequence of overall lesion responses 
at each assessment/time point. However, the overall lesion response at a given assessment/time 
point may be provided from different sources as illustrated in Table 3-2. 
Table 3-2 
Sources for overall lesion response 
Source 1 
Investigator (local radiology) reported overall lesion response 
Source 2 
Novartis-calculated overall lesion response based on raw (i.e. individual 
lesion) measurements from investigator (local radiology) 
Source 3 
Final BIRC-reported overall lesion response 


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The primary efficacy analysis will be based on the investigator/local radiology review. The 
investigator reported overall lesion response at each assessment/time point (Source 1 in Table 
3-2) will be used to derive the efficacy endpoints.  
The overall response at each assessment will also be calculated using the raw lesion 
measurements (Source 2 in Table 3-2). The calculated responses will be listed along with the 
responses given by the investigator. As a sensitivity analysis, PFS based on calculated overall 
lesion response (Source 2 in Table 3-2) will also be summarized. 
Tumor assessment data based on BIRC assessment (Source 3) will be used for selected 
supportive efficacy analyses. The BIRC comprises of two independent radiologists and an 
adjudicator. The BIRC-reported overall lesion response data will be used to derive the BIRC-
based endpoints. Data from independent readers will be listed together with the adjudication. . 
Differences in overall responses between local radiology (Source 1) and central radiology 
(Source 3) will be listed. 
3.8.1 
Primary efficacy 
PFS based on local radiology assessment is the primary efficacy variable in this study. PFS is 
defined as the time from the date of randomization to the date of the first documented disease 
progression or death due to any cause. If a patient has not progressed or died at the analysis 
cutoff date, PFS will be censored at the time of the last adequate tumor assessment before the 
cut-off date. Definitions and further details on PFS can be found in Appendix 3 of the study 
protocol. 
Discontinuation due to disease progression (collected on the ‘End of treatment’ and ‘End of 
post treatment follow up’ disposition page) without supporting objective evidence (as defined 
in Section 2.5.2) satisfying progression criteria per RECIST will not be considered disease 
progression for PFS derivation. 
3.8.1.1 
Primary analysis 
The primary analysis of PFS will be based on the local radiological assessments (Source 1 in 
Table 3-2). The analysis will be performed on the FAS and will use the default censoring and 
event date options from Table 3-2 of study protocol Appendix 3 i.e. event/censoring rules will 
be based on options A(1), B(1), C1(1), C2(1), D(1), E(1), and F(1) (summarized in Table 3-3). 
In particular, PFS will be censored at the last adequate tumor assessment if a patient didn’t have 
an event or the event occurred after two or more missing tumor assessments (see Section 2.5.5). 
In the primary analysis in this study PFS will not be censored if a new antineoplastic therapy is 
started; instead, an ITT approach will be used and this new antineoplastic therapy will be 
ignored for the purposes of PFS derivation (and tumor assessments will continue), i.e. option 
F(1) in Table 3-2 of protocol Appendix 3 will be used. A sensitivity analysis will be performed 
censoring PFS at the last adequate tumor assessment prior to start of new antineoplastic therapy, 
i.e. using option F(2).  Discontinuation of study treatment (for any reason) will not be 
considered as a reason for censoring. 
Table 3-3 
Outcome and event/censor dates for PFS analysis 
Situation 
Date 
Outcome 


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No baseline assessment 
Date of randomization* 
Censored 
Progression or death at or before 
next scheduled assessment 
Date of progression (or death) 
Progressed 
 
Progression or death after exactly 
one missing assessment 
Date of progression (or death) 
Progressed 
 
Progression or death after two or 
more missing assessments 
Date of last adequate 
assessment prior to missed 
assessments  
Censored 
 
No progression (or death) 
Date of last adequate 
assessment  
Censored 
 
New anticancer therapy given prior 
to protocol defined progression  
Ignore the new anticancer 
therapy and follow situations 
above  
As per above situations 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
Ignore clinical progression and 
follow situations above  
 
As per above situations 
* The rare exception to this is if the patient dies no more than D2 days (see Section 2.5.5 for 
definition) after randomization, in which case this is a PFS event at the date of death 
3.8.1.2 
Hypothesis and test statistic 
The primary efficacy analysis will be the comparison of PFS between the two treatment arms 
using a stratified (strata based on IRT data) log-rank test at one-sided 2.5% level of significance.  
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested to address the primary efficacy objective: 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (Tamoxifen or a NSAI+goserelin+ribociclib arm vs. tamoxifen 
or a NSAI+goserelin + placebo arm) of PFS.  
3.8.1.3 
Kaplan-Meier estimates 
The survival distribution of PFS will be estimated using the Kaplan-Meier method. The results 
will be plotted graphically (Kaplan-Meier curves) by treatment arm. The plots will display the 
number of patients at risk at equidistant time points. The median, 25th and 75th percentiles for 
PFS for each treatment arm will be provided with associated 95% confidence intervals. The 
survival probabilities at 2-month intervals, and the associated 95% confidence intervals, will be 
summarized by treatment arm. Kaplan-Meier estimates will be obtained using PROC 
LEFETEST with method=KM option in SAS. The loglog option available within PROC 
LIFETEST will be used to compute the confidence intervals. 
3.8.1.4 
Hazard Ratio 
The PFS hazard ratio with two-sided 95% confidence interval will be estimated using the 
stratified Cox proportional hazards model. In this analysis the baseline hazard function will be 
allowed to vary across strata. SAS PHREG procedure with ties=EXACT option will be used to 
carry out this analysis in which the model statement will include treatment arm variable as the 


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only covariate and the STRATA statement will include the stratum information as obtained via 
IRT. 
3.8.1.5 
Sensitivity and supportive analyses of the primary endpoint PFS 
NSAI/tamoxifen subgroup analyses 
In addition to the primary analysis in all patients, the treatment effect in terms of PFS for  
1. tamoxifen + goserelin + ribociclib vs. tamoxifen + goserelin + placebo, and 
2. NSAI + goserelin + ribociclib vs. NSAI + goserelin + placebo, 
where tamoxifen/NSAI are identified based on CRF data, will be estimated using separate 
unstratified Cox regression models. Estimated hazard ratios with corresponding 95% CIs will 
be presented for each subgroup. Survival distribution of PFS will be estimated using Kaplan-
Meier methodology within each subgroup. 
Audit-based BIRC assessment of PFS 
PFS assessed by Blinded Independent Review Committee (BIRC) will be used as a supportive 
analysis of the primary endpoint. 
For studies with PFS based on local radiology assessment as the primary endpoint, PFS assessed 
centrally has generally been used as a secondary or supportive analysis of the treatment effect 
observed in the primary efficacy analysis. Although 100% central review of scans has been 
performed in many trials, there is a growing body of evidence that an audit based approach for 
central evaluation is sufficient (Zhang et al, 2012, FDA ODAC 2012). 
An audit (sample) based approach will therefore be implemented for the BIRC assessment of 
PFS, whereby all assessments for a randomly selected subset of randomized patients will be 
assessed by BIRC. An independent random sampling process, implemented by the third party 
IRT vendor, will select approximately 40% of randomized patients. This random allocation will 
be stratified by randomized treatment arm and the strata used for the randomization of patients 
to treatment arms.  
The distribution of PFS based on the audit BIRC sample will be estimated using the Kaplan-
Meier method. The median along with two-sided 95% confidence interval (CI) will be presented 
by treatment group. A Kaplan-Meier figure will also be displayed. A stratified Cox regression 
will be used to estimate the hazard ratio (HR), along with two-sided 95% CI based on the audit 
BIRC sample. 
In order to determine whether a 100% BIRC review should be conducted, two additional 
methods will be used to summarize the data from the sample-based BIRC assessment.  
1. NCI method: The NCI (National Cancer Institute) method (Dodd et al. 2011) uses an 
auxiliary variable estimator of the log-hazard ratio that combines information from 
patient-level investigator assessments from all patients (in the FAS) and the BIRC 
assessment of patients randomly selected for central review (see Section 4.2.5 for 
methodology details). This estimate and its one-sided 95% CI will be provided. The NCI 
method is used for the audit sample size determination (see Section 3.16) and summary of 
treatment effect for the supportive BIRC assessment. 


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2. PhRMA method: The data from the BIRC assessment generated following the sampling 
scheme as above will also be summarized using the method proposed by Amit et al. 2011, 
referred to as the PhRMA (Pharmaceutical Research and Manufacturers of America) 
method, based on the early discrepancy rate (EDR) and late discrepancy rate (LDR). 
The EDR quantifies the frequency with which the investigator declares progression early 
relative to BIRC within each arm as a proportion of the total number of investigator 
assessed PDs. The LDR quantifies the frequency that the investigator declares progression 
later than BIRC as a proportion of the total number of discrepancies within the arm (see 
Section 4.2.5 for further details). If the distribution of discrepancies is similar between the 
arms this suggests the absence of evaluation bias favoring a particular arm. With this 
approach, the differential discordance (DD) of the early discrepancy rate (EDR) and late 
discrepancy rate (LDR) between the two arms will be estimated as the rate on the 
ribociclib arm minus the rate on the placebo arm. The EDR and LDR results will also be 
summarized by treatment arm. 
The following thresholds based on the NCI and PhRMA methods will be used to define the 
trigger for a full BIRC review: 
• If the upper-bound of the one-sided 95% confidence interval for BIRC-based log-hazard 
ratio exceeds zero (i.e. HR>1) based on the NCI  method 
and/or 
• If ≥ 15% differential discordance is observed in EDR or LDR based on the PhRMA 
method. 
A full BIRC review will only be considered if the primary endpoint is statistically significant. 
In the event of a full BIRC read of all patients’ imaging data, all analyses based on BIRC 
assessment will be repeated including all randomized patients, with the exception of the 
auxiliary variable estimate (NCI method) described above. 
Sensitivity analyses and additional supportive analyses 
As a sensitivity analysis to assess the impact of stratification, the two treatment groups will be 
compared using an unstratified log-rank test. The hazard ratio together with associated 95% 
confidence interval obtained using the unstratified Cox regression model will also be presented. 
The primary efficacy analyses; i.e. the stratified log-rank test, Kaplan-Meier estimates, estimate 
of the median PFS along with 95% confidence interval, and hazard ratio obtained using the Cox 
proportional hazards model, will be repeated (as appropriate) based on the data obtained: 
1. Using the investigator/local assessments (Source 1 in Table 3-2) on the PPS and using 
the same conventions as for the primary analysis if the primary analysis is found to be 
statistically significant and if the PPS/FAS are different. 
2. Using investigator/local assessment (Source 1 in Table 3-2) on the FAS and taking the 
event whenever it occurs - even after two or more missing tumor assessments. The 
following options from Table 3-2 in Section 3.2.10 of Study Protocol Appendix 3 will 
be used: A(1), B(1), C1(1), C2(3), D(1), E(1) and F(1). In the summary table, this 
approach is referred as ‘Actual event PFS analysis’ 


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3. Using investigator/local assessment (Source 1 in Table 3-2) on the FAS and backdating 
events occurring after missing tumor assessments. The following options from Table 3-
2 in Section 3.2.10 of Study Protocol Appendix 3 will be used: A(1), B(1), C1(2), C2(2), 
D(1), E(1), and F(1). In the summary tables, this approach is referred as ‘Backdating 
PFS analysis’. 
4. Using investigator/local assessment (Source 1 in Table 3-2) on the FAS and censoring 
PFS at the last adequate tumor assessment before the start of any new antineoplastic 
therapy (excluding palliative radiotherapy and continuation of combination partner 
therapy alone after end of study treatment). 
A stratified multivariate Cox regression model will be fitted to evaluate the effect of other 
baseline demographic or disease characteristic on the estimated hazard ratio. This model will 
include treatment arm and the following key prognostic factors: ECOG performance status (0 
vs. ≥1), bone only lesion at baseline (yes or no), age (<40 vs ≥40 years old), and prior 
(neo-)adjuvant hormonal therapy usage (no; yes – progression while on or within 12 months 
of end of (neo-)adjuvant ET; yes – progression > 12 months after end of (neo-)adjuvant ET). 
In additional, stratified multivariate Cox models will be fitted including treatment arm and 
each of these factors individually, including treatment by factor interaction, to explore the 
relationship between each factor and treatment. 
Further supportive analyses will include: 
• Stratified Cox regression using derived local radiology assessment (source 2 in Table 3-2). 
No p-value will be presented. 
• Number of patients and number of events by treatment arm within each stratum and for 
each level of each stratification factor will be presented along with the hazard ratio for 
treatment effect obtained using unstratified Cox proportional hazards regression models 
with corresponding confidence intervals. No p-values will be presented for thee analyses. 
K-M plots of survival distributions will also be presented. 
• If there is a high rate of discrepancy between the strata classifications constructed using 
the eCRF data and those obtained from the IRT, a sensitivity analysis will be performed in 
which a stratified Cox regression model will be used to estimate the treatment hazard ratio 
and the associated 95% confidence interval based on the CRF-derived strata. No other 
inferential statistics will be provided.   
• Number of patients with a PFS event and number of patients censored for the PFS analysis 
will be summarized. In addition, a summary of reasons for PFS censoring will be provided 
by treatment arm based on the reasons defined in Section 2.5.5. These summaries on 
censoring reasons will be produced for PFS by investigator radiology and BIRC review. 
• Comparison of PFS event type/censor between local radiology review and BIRC review 
• 
 
 
 
 
• If more than 5% of the patients are found to have been force randomized, a sensitivity 
analysis using local radiology assessments (Source 1 in Table 3-2) will be performed on 


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all randomized patients with the force randomized patients assigned to the alternative 
treatment group. 
3.8.2 
Secondary efficacy analyses 
The secondary efficacy objectives in this study are to  
• compare the two treatment arms with respect to overall survival  
• evaluate the two treatment arms with respect to overall response rate and clinical benefit 
rate; 
• describe time to response and duration of response in each treatment arm; 
• evaluate the two treatment arms with respect to time to deterioration of ECOG 
Performance Status; 
• evaluate patient reported outcomes for health-related quality of life in the two treatment 
arms. 
OS is the key secondary endpoint. A hierarchical testing strategy, where OS is to be statistically 
evaluated and interpreted only if the primary efficacy endpoint PFS is statistically significant 
favoring the treatment arm, will be used to control the overall type-I error rate. 
The analysis of all secondary efficacy endpoints will be performed based on the FAS. 
3.8.2.1 
Key secondary objective: overall survival 
Comparing the overall survival (OS) between ribociclib+tamoxifen/NSAI+goserelin and 
placebo+tamoxifen/NSAI+goserelin is the key secondary objective in this study. OS is defined 
as the time from date of randomization to date of death due to any cause. A cut-off date will be 
established for each analysis of OS. If a patient is not known to have died by the date of analysis 
cut-off, then OS will be censored at the last contact date (see Section 2.1.9). 
The analysis of OS will be based on the FAS. If the primary analysis of PFS is significant, the 
distribution of OS will be compared between the two treatment arms using a stratified log-rank 
test (strata based on IRT data) at one-sided 2.5% level of significance.  
Up to 3 analyses may be performed for OS: (1) at the time of the primary analysis for PFS, at 
which point a total of 123 (49%) deaths are expected; (2) after approximately 189 (75%) deaths 
have been documented; and (3) a final analysis for OS after approximately 252 deaths. The type 
I error probability for OS tests will be controlled by using a Lan-DeMets (O’Brien- Fleming) 
alpha spending function at the one-sided α=0.025 level (see Section 3.14.2 for further details). 
The distribution function of OS will be estimated using the Kaplan-Meier method and displayed 
for each treatment arm and stratum. The median OS along with 95% confidence intervals will 
be presented by treatment arm, along with the proportion of patients alive at selected time points 
and the associated 95% confidence intervals. The stratified Cox regression model, where the 
baseline hazard function is allowed to vary across strata, will be used to estimate the hazard 
ratio (HR) of OS, along with 95% confidence interval. Strata information will be obtained from 
the IRT. 
 


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Survival status, reason for censoring and death cause will be listed. Patients not known to have 
died will be censored for ‘Loss to follow-up’ if the time between their last contact date and the 
analysis cut-off date is longer than 12 + 2 weeks = 98 days (i.e. the planned interval between 
two OS follow-up visits plus the 1 week window on both sides).  
Handling missing month/day in date of death 
For rare cases when either day is missing or both month and day are missing for the date of 
death, the follow imputation rules will be implemented: 
- If only day is missing, then impute max [(1 mmm-yyyy), min (last contact date +1, 
cutoff date)].  
- If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date 
+1, cutoff date)].  
3.8.2.2 
Overall response rate 
ORR is defined as the proportion of patients with best overall response of confirmed complete 
response (CR) or confirmed partial response (PR) according to RECIST 1.1 (see Appendix 3 of 
the study protocol). ORR will be calculated based on the FAS using investigators’ review of 
tumor assessment data. Patients with only non-measurable disease at baseline will be part of the 
analysis and will be included in the numerator only if a complete response was observed. ORR 
will be presented by treatment arm along with standard Wald asymptotic (i.e. normal 
approximation) 95% confidence intervals. The Cochran-Mantel Haenszel chi-square test (strata 
based on IRT data) will be used to compare the two treatment arms with respect to the ORR at 
a one-sided 2.5% level of significance.  
As sensitivity analysis, ORR will be calculated and summarized including only patients with 
measurable disease at baseline. 
As a supportive analysis, ORR will also be summarized based on the BIRC review of tumor 
data. However, no p-value will be presented.  
Clinical benefit rate 
CBR is defined as the proportion of patients with a best overall response of confirmed CR or 
PR, or SD lasting 24 weeks or longer, according to RECIST 1.1 criteria. A patient will be 
considered to have SD for 24 weeks or longer if a SD response is recorded at 24-1=23 weeks 
or later from randomization, allowing for the ±1 week visit window for tumor assessments. 
Patients with only non-measurable disease at baseline will be part of the analysis and will be 


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included in the numerator only if they achieve a complete response or have a ‘Non-CR/Non-
PD’ response 23 weeks or more after randomization. CBR will be calculated using the FAS 
based on the investigators’ tumor assessments. CBR will be summarized for the two treatment 
arms using descriptive statistics. The Cochran-Mantel-Haenszel test (strata based on IRT data) 
at one sided 2.5% level of significance will be used to compare the two treatment arms with 
respect to CBR.  
As a sensitivity analysis, the above analyses will be repeated including only patients with 
measurable disease at baseline. 
As a supportive analysis, CBR based on BIRC data will be summarized for the two treatment 
arms using descriptive statistics but no p-value. 
3.8.2.3 
Time to response 
Time to response (CR or PR) is the time from date of randomization to first documented 
response (CR or PR, which must be confirmed subsequently) according to RECIST 1.1. All 
patients in the FAS will be included in the time to response calculation. Patients who did not 
achieve a confirmed PR or CR will be censored at: 
• the maximum follow-up time (i.e. FPFV to LPLV used for the analysis) for patients 
who had a PFS event (i.e. either progressed or died due to any cause); 
• the last adequate tumor assessment date for all other patients. 
Time to response data will be listed and summarized by treatment arm. The distribution of time 
to response will be estimated using the Kaplan-Meier method and the median time to response 
will be presented along with 95% confidence interval only if a sufficient number of responses 
is observed. A descriptive summary of time to response for the responders will also be presented. 
No inferential analysis that compares time to response between the two treatment arms will be 
performed. 
3.8.2.4 
Duration of response  
DoR applies only to patients whose best overall response was CR or PR. The start date is the 
date of first documented response (CR or PR, which must be confirmed subsequently) and the 
end date is the date of event defined as the first documented progression or death due to 
underlying cancer. The start date will be determined using the time the response was first 
determined and not using the time the response was confirmed. If a patient has not had an event, 
duration is censored at the date of last adequate tumor assessment, using the same censoring 
rules described for primary PFS analysis. DoR will be summarized by treatment arm. The 
distribution of duration of response will be estimated using the Kaplan-Meier method and the 
median response duration will be presented along with 95% confidence interval only if a 
sufficient number of responses is observed. No inferential analysis that compares the DoR 
between the two treatment arms will be performed. 
3.8.2.5 
ECOG performance status 
The ECOG PS scale (Table 3-4) will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active): 


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Table 3-4 
ECOG Performance Scale 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
The following intervals will be used to group the ECOG PS data over time. Day in columns 2 
and 3 is defined as date of ECOG PS assessment date – randomization date + 1. The 
correspondence with Day in column 1 assumes that a patient is treated on the day of 
randomization; however the definition of Day in columns 2 and 3 still applies if this is not the 
case, i.e. randomization date is taken as the reference for the windows. 
Table 3-5 
Time windows for ECOG PS assessments 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
 
Day 1 (if not available use 
screening) 
Cycle 1 Day 15 
15 
Day 2 to day 21  
Cycle 2 Day 1 
29 
Day 22 to day 42  
Cycle 3 Day 1 
57 
Day 43 to day 63  
Cycle 3 Day 15 
71 
Day 64 to day 77 
Cycle 4 Day 1 
85 
Day 78 to day 98  
Cycle k Day 1 (k≥5) 
d=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the end 
of treatment visit 
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 worst of the 2 assessments will be used. 
Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point.  
An analysis of time to definitive deterioration of performance status will be performed. The 
time to definitive deterioration is calculated from the date of randomization. Deterioration is 
defined as an increase in ECOG PS by at least one category from the baseline score or death 
due to any cause. Deterioration is considered definitive if no return to baseline or better in 
ECOG PS is observed subsequent to the deterioration during the treatment period.  
If a definitive deterioration is observed after two or more missing assessments (using an 
analogous rule to that defined for PFS in Section 2.5.5, based on the windows specified above), 


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time to deterioration will be censored at the date of the last ECOG PS assessment prior to the 
deterioration. 
Patients receiving any further anti-neoplastic therapy before definitive deterioration will be 
censored at the date of their last assessment before the start date of the therapy. Patients that 
have not deteriorated as of the cutoff date will be censored at the date of their last assessment 
before the cutoff. 
Kaplan-Meier estimates will be constructed for each treatment arm. The median, 25th and 75th 
percentiles for time to definitive deterioration for each treatment group will be obtained along 
with 95% confidence intervals. 
A stratified log-rank test at one-sided 2.5% level of significance will be used to test the 
difference in time to definitive deterioration of performance status between treatment arms. A 
(stratified) Cox proportional hazards model will be used to estimate the hazard ratio (with 95% 
confidence interval). 
3.8.2.6 
Patient reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) and breast cancer specific questionnaire 
(EORTC QLQ-BR23, version 1.0) 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 PRO instruments are planned to be administered during screening and every 8 weeks after 
randomization in the first 18 months, and every 12 weeks thereafter until the end of treatment. 
PRO assessments 
 will continue to be collected during the 
efficacy follow-up after the end of treatment. 
The following time based intervals will be used to group the PRO data over time. Day is defined 
as date of PRO assessment date – randomization date + 1.  
Table 3-6 
Time windows for patient reported outcomes 
 
Time Interval 
Baseline 
 
Last assessment before or on date of randomization 
 
Day 1 of Cycle 3, 5, 
7, 9 until cycle 19 
+/- 4 weeks centered around the planned assessment date (except for 
the first and last windows): 
i.e. days 2 to 85 for Cycle 3 Day 1 
      days 86 to 141 for Cycle 5 Day 1   
      days t-27 to t+28 for Cycle k Day 1 (k= 7, 9, ..., 17), where t=(k-
1)*28+1 is the target day of the assessment  
      day 478 to 547 for Cycle 19 Day 1 
Day 1 of Cycle 22, 
25, 28, … 
+/- 6 weeks centered around the planned assessment date: 
i.e. days 548 to 631 for Cycle 22 Day 1 


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      days 632 to 715 for Cycle 25 Day 1 
      days t-41 to t+42 for Cycle k Day 1 (k= 28, 31,...), where t=(k-
1)*28+1 is the target day of the assessment 
End of treatment 
At the end of treatment visit 
Efficacy follow-up 
 
At each of the efficacy follow-up visits 
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. If 2 assessments within a time window are equidistant 
from the target date, then the assessment obtained prior to target date will be used. 
The FAS will be used for all PRO summaries and listings. 
EORTC-QLQ and EQ-5D-5L 
The global health status/global QoL scale score of the EORTC QLQ-C30 is identified as a 
primary PRO variable of interest. The physical functioning, emotional functioning and social 
functioning sub-scale scores of the EORTC QLQ-C30, the breast cancer symptoms scale of the 
EORTC QLQ-BR23, and the visual analog scale (VAS) of the EQ-5D-5L are identified as 
secondary PRO variables of interest. High scores in the EORTC QLQ-C30 and QLQ-BR23 
represent 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.  Higher scores in the EQ-5D-5L also correspond to better health states.     
The number of patients completing QoL questionnaires and the number of patients 
missing/expected to have QoL assessments will be summarized by treatment arm for scheduled 
assessment time points (the number of ongoing patients will be used as denominator). 
Furthermore, the amount and the pattern of missing data may be explored by treatment arm and 
over time using summary statistics. The following categories will be used to describe whether 
the questionnaire was completed at a specific time point: 
- yes, fully completed 
- yes, partly completed 
- no. 
Scoring of raw data and methods for handling of missing items or missing assessments will be 
handled according to scoring manuals for each respective patient questionnaire (Fayers et al 
2001, Rabin 2011). 
A time-to-event approach will be considered in the analysis of the time to definitive 10% 
deterioration in the primary and the secondary PRO variables of interest.  
Definitive 10% deterioration is defined as a worsening in score by at least 10% compared to 
baseline, with no later improvement above this threshold observed during the treatment period, 
or death due to any cause. Time to deterioration is the number of days between the date of 
randomization and the date of the assessment at which deterioration is seen. If a patient has not 
had an event prior to analysis cut-off, end of treatment, start of new anti-neoplastic therapy, lost 
to follow-up, or withdrawal of consent, the time to deterioration will be censored at the date of 


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the last evaluation before the earliest of these times. Only assessments collected while the 
patient is on treatment and on or before the end of treatment visit will be included in the PRO 
time to deterioration analysis. 
If deterioration is observed after two or more missing assessments, time to deterioration will be 
censored at the date of the last assessment prior to the deterioration. The rules for calculating 
number of missing assessments are the same as those for tumor assessments (see Section 2.5.5) 
Time to 10% deterioration in the global health status/QOL scale, and secondary PRO scales of 
interest as listed above, will be compared between the two treatment arms using a stratified log-
rank test (strata based on IRT data) at one-sided 2.5% level of significance. The survival 
distributions will be presented descriptively using Kaplan-Meier curves. Summary statistics 
from the Kaplan-Meier distributions will be determined, including the median time to 10% 
deterioration and the proportions of patients without 10% deterioration at 2-monthly intervals. 
Both point estimates and 95% CIs will be presented. A stratified Cox regression model will be 
used to estimate the hazard ratio (HR) of time to deterioration, along with 95% confidence 
interval. 
Change from baseline in all sub-scales obtained from EORTC QLQ-C30 and the breast 
symptoms score of QLQ-BR23, and the VAS of EQ-5D-5L will be analyzed using a linear 
mixed effects model for longitudinal data to assess the treatment effect over time including 
terms for treatment, stratification factors, time of visit (in weeks counting from the time of 
randomization to the time of a particular post baseline measurement), treatment by time of visit 
interaction, and baseline score. Time will be considered as a continuous variable in this analysis. 
The data for selected time points will also be fitted using a linear model including treatment 
stratification factors, and baseline value as covariates. The differences in least square means 
between treatment and control group, and the corresponding 2-sided 95% CI at selected time 
points will be presented. 
For the mixed effects model, patients with baseline and at least one non-missing post-baseline 
assessments will be included. This analysis will only include assessments up to the time point 
where there are at least 50 patients on each of the treatments. Data collected under treatment 
(i.e. up to the EOT assessment) will be included. As a first approach, an unstructured correlation 
matrix will be used to model the correlation within patients. The structure of the correlation 
matrix will be investigated and simplified using likelihood ratio test if appropriate. If PRO is 
found not to follow a linear trend, the time variable might be considered as a categorical variable 
instead of continuous in the model. 
Descriptive statistics (n, mean, median, SD, min, max) will be used to summarize the individual 
item and subscale scores from the EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L at each 
scheduled assessment time point. Additionally, change from baseline in the subscale scores at 
the time of each assessment will be summarized. Patients with an evaluable baseline score and 
at least one evaluable post baseline score during the treatment period will be included in the 
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3.9 
Safety evaluation 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory/ECG values that fall outside of pre-determined ranges. Other safety data 
(e.g. vital signs and special tests) will be considered as appropriate. 
All safety outputs will use the safety set. The safety summary tables will include only ‘on-
treatment’ events/assessments, i.e. those collected on or after the first date of study treatment 
and collected no later than 30 days after the date of last study treatment administration. The 
AEs started before the first dose but worsening during the treatment period are also considered 
as ‘on-treatment’ events. All safety events/assessments will be listed and those collected outside 
of the on-treatment window will be flagged. 
3.9.1 
Adverse events (AEs) 
3.9.1.1 
Coding of AEs 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
3.9.1.2 
Grading of AEs 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.3. 


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The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE v4.0.3 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. 
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will not be 
used in this project; if an AE results in death it will be documented in the outcome (“fatal”). 
Information on deaths will also be collected on the ‘Death’ CRF.  
3.9.1.3 
General rules for AE Reporting 
AE summaries will include all AEs starting on or after study Day 1 (i.e. on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last administration 
of study treatment (see Section 2.1.5). All AEs will be listed. AEs starting prior to study Day 1 
and AEs starting later than 30 days after the last treatment date will be flagged in the listings. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, having at least one AE in each 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. 
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 sort order for 
the preferred term will be based on their frequency in the ribociclib arm. 
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. 
3.9.1.4 
AE summaries 
The following adverse event summaries will be produced:  
• Summary of deaths and adverse events 
• AEs, irrespective of causality, by primary system organ class, preferred term and 
maximum grade 
• AEs with suspected relationship to study treatment by primary system organ class, 
preferred term and maximum grade 
• Most common grade 3-4 adverse events, irrespective of causality, by preferred term 
and maximum grade (greater than x% in either arm) 
• Adverse events, irrespective of causality, by primary system organ class and 
maximum grade 
• Adverse events, irrespective of causality, by preferred term and maximum grade 


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• Adverse events with suspected relationship to study treatment by preferred term and 
maximum grade  
• Grade 3 or 4 AEs, irrespective of causality, by primary system organ class, preferred 
term and maximum grade 
• Grade 3 or 4 AEs with suspected study treatment relationship by primary system organ 
class, preferred term and maximum grade 
• On treatment deaths, by preferred term 
• All Deaths(on-treatment + post-treatment), by primary system organ class and 
preferred term 
• Serious AEs, irrespective of causality, by primary system organ class, preferred term 
and maximum grade 
• Serious AEs with suspected relationship to study treatment, by primary system organ 
class, preferred term and maximum grade 
• AEs leading to discontinuation, irrespective of causality, by primary system organ 
class, preferred term and maximum grade 
• AEs requiring dose adjustment , irrespective of causality, by primary system organ 
class, preferred term and maximum grade 
• AEs requiring treatment interruption, irrespective of causality, by primary system 
organ class, preferred term and maximum grade 
• AEs requiring additional therapy, irrespective of causality, by primary system organ 
class, preferred term and maximum grade 
• Non-serious AEs (at least x% incidence rate in either treatment arm) by primary 
system organ class and preferred term. 
• Serious and non-serious adverse events with number of occurrences (an occurrence is 
defined as >1 day between start and prior end date of record of same preferred term) 
• On-treatment deaths and SAEs with fatal outcome, by SOC and PT 
AEs of special interest will also be summarized. See Section 3.9.1.5 for the grouping details. 
3.9.1.5 
Grouping of AEs of special interest 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to ribociclib. 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 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 by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, etc.).  
 


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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 3-7 provides the latest groupings at the time of the finalization of the 
SAP, from the CRS dated 13Dec2016. The most up-to-date version of the CRS will be used at 
the time of the analysis. 
Table 3-7 
AESI groupings 
AESI grouping 
MedDRA category 
Anemia 
SMQ 
Diarrhea 
SMQ 
Hepatobiliary toxicity 
SMQ 
Infections 
SMQ and SOC 
Leukopenia 
HLT 
Nausea, emesis 
HLT 
Neutropenia 
HLT and PT 
Pneumonitis, interstitial lung disease  
SMQ 
Pulmonary embolism 
SMQ and HLT 
QTc prolongation 
SMQ 
Renal impairment 
SMQ 
Reproductive toxicity 
SMQ 
Thrombocytopenia 
SMQ 
3.9.2 
Laboratory data 
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected no later than 30 
days after the last administration of study treatment. All laboratory assessments will be listed 
and those collected later than 30 days after the last treatment date will be flagged in the listings. 
Laboratory data will be classified (by biostatistics/statistical reporting) into CTC grades 
according to the NCI CTCAE v4.0.3. The calculation of laboratory CTC grades will be based 
on the observed laboratory values only; clinical assessments will not be taken into account. The 
criteria to assign CTC grades 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. 
The following summaries will be produced for the laboratory data (by laboratory parameter): 
• Number and percentage of patients with each CTC grade as their worst post-baseline 
value (regardless of the baseline status). Each patient will be counted only for the 
worst grade observed post baseline. 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value 
will be produced for hematology and biochemistry laboratory parameters with CTC 
grades. 


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• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges. 
• Number and percentage of patients meeting categorical liver function test criteria, 
including ALT, AST and ALT/AST (>3x, 5x, 8x, 10x, 20x ULN), Total Bilirubin 
(>1x, 2x ULN), ALP (>1.5x, 2x, 3x, 5x, 8x, 10x ULN), combined categories of 
ALT/AST and total bilirubin (e.g., ALT/AST>3x ULN & total bilirubin > ULN) as 
well as potential Hy’s Law criteria (ALT or AST > 3 x ULN and TBIL > 2 x ULN and 
ALP < 2 x ULN). For the combined categories, the assessments need not be 
concurrent, i.e. patients are counted based on their most extreme value for each 
parameter (highest in the case of ALT, AST and TBIL; lowest in the case of ALP). 
• Box plots of laboratory values by scheduled time point and treatment arm. 
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. 
Time to first occurrence of grade 2 or worse laboratory toxicity and time to first occurrence of 
grade 3 or worse laboratory toxicity will be performed for (i) neutropenia and (ii) ALT/AST.  
Median time to first occurrence and 95% CI will be provided based on the Kaplan-Meier 
method. In addition, Kaplan-Meier plots will be generated. 
Time to first occurrence of grade X or worse laboratory toxicity is defined as the time from the 
start of treatment to the start date of the first incidence of grade X or worse laboratory toxicity, 
i.e. time in days is calculated as (start date of first occurrence) – (date of first dose of study 
treatment) +1. A patient will be censored if: 
• The patient did not report any post-baseline grade X or worse event on or before the 
analysis cut-off date. 
• The patient discontinued treatment without reporting any grade X or worse event up to 30 
days after study treatment discontinuation. 
• The patient died without reporting any grade X or worse event. 
• The patient received a new anticancer therapy before reporting any grade X or worse 
event.  
The censoring date will be the earliest of the following dates: end of treatment + 30 days, 
analysis cut-off, new anti-cancer therapy start date, death date and last non-missing 
assessment for the lab parameter. Note that patients who have grade X or worse toxicity at 
baseline or missing baseline evaluation will be excluded from this analysis.  
In addition, the median time to first occurrence for the subset of patients who experienced the 
event of interest will be calculated. Simple descriptive statistics, median, min and max as well 
as 25th percentile and 75th percentile, will be presented. 
Duration of grade X or worse laboratory toxicity may also be summarized. Duration of grade 
X or worse event is calculated as: 
(Date when the grade of the event decreases to below X) – (date of onset of grade X or 
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For patients experiencing any grade X or worse event, the duration of the first such event will 
be summarized using the Kaplan-Meier method. Median duration and 95% CI will be presented. 
In addition, Kaplan-Meier plots will be generated.  
A patient will be censored for the duration of grade X or worse event, if: 
• The patient dies without reporting  a decrease to below grade X 
• The patient receives a new anticancer therapy before reporting a decrease to below grade 
X 
• The patient discontinues from the study treatment without reporting a decrease to below 
grade X up to 30 days after study treatment discontinuation 
• The patient is still ongoing at the analysis cut-off date without reporting a decrease to 
below grade X 
The censoring date is the earliest of the following dates: end of treatment + 30 days, analysis 
cut-off, new anti-cancer therapy start date, death date and last non-missing assessment for the 
lab parameter. 
Urinalysis 
The following parameter will be summarized using shift table to compare baseline to the worst-
post baseline values: urine bilirubin dipstick, urine blood dipstick, urine glucose dipstick, urine 
ketones dipstick, urine leukocyte dipstick, and urine nitrate dipstick. For all these parameters, 
both negative and trace are considered as normal and the more pluses the worse. The urine pH 
dipstick will be summarized using shift table with low/normal/high classifications based on 
laboratory reference ranges. 
3.9.3 
Vital signs 
Vital signs assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height, weight, body temperature, heart rate, and 
systolic and diastolic blood pressure. 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable elevated values 
• Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline. 
• Body temperature:  ≥ 39.1°C 
• Heart 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 
• Body temperature: ≤ 35°C 
• Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm 
The following summaries will be produced for each vital sign parameter: 


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• Summary statistic for change from baseline to the worst post-baseline value (in both 
directions, i.e. from baseline to highest post baseline and from baseline to lowest post 
baseline value). 
• Number and percentage of patients with at least one post-baseline vital sign 
abnormality (in both directions, i.e. both elevated and below normal values). 
In addition, the following two listings will be produced by treatment arm: 
• Patients with clinically notable vital sign abnormalities. 
• All vital sign assessments will be listed by patient and vital sign parameter. 
In both listings, the clinically notable values will be flagged and also the assessments collected 
later than 30 days after the last treatment date will be flagged. 
3.9.4 
ECG 
All analyses of ECG data will be based on the average of all available replicate ECGs assessed 
at each time point for each patient. For unscheduled assessments, 15-minute windows will be 
applied to group assessments for averaging. 
ECG data will be summarized by presenting summary statistics of the raw data and change from 
baseline by treatment arm and time point. The following parameters will be assessed: QT, QTcF, 
QTcB, PR, and QRS intervals in msec, heart rate (bpm), and the overall interpretation if 
clinically significant abnormalities are present.  
The number and percentage of patients with notable abnormalities will be summarized. 
Summary statistics and shift tables will be presented. Individual listings will be provided by 
subject.  
Table 3-8 
Clinically notable ECG values 
ECG parameter (unit)  
Clinically notable criteria  
QT, QTcF, QTcB (ms)  
New > 450  
 
New > 480  
 
New > 500  
 
Increase from Baseline > 30  
 
Increase from Baseline > 60  
PR duration (ms) 
Increase > 25% from baseline and to PR duration > 200  
New > 200 
QRS duration (ms) 
Increase > 25% from baseline and to QRS duration > 110 
New > 110  
Heart Rate (bpm)  
< 50 and decrease from Baseline of > 25%  
> 100 and increase from Baseline of > 25%  
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 average of the last  replicate ECG measurements taken 


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on or before treatment start date. The percentage of patients having notable ECG interval values is 
based on the number of patients at risk for the change with a value at baseline and post-baseline. 
Time to grade 2 or worse QT prolongation will be analyzed using the Kaplan-Meier method 
and the median time to grade 2 or worse QT prolongation will be presented along with a 95% 
confidence interval if there are sufficient numbers of events for each treatment group. 
In addition, the median time to event for the subset of patients who experienced grade 2 or 
worse QT prolongation will be calculated. Simple descriptive statistics, median, min and max 
as well as 25th percentile and 75th percentile, will be presented. 
Note that patients who have grade 2 or worse toxicity at baseline or missing baseline evaluation 
will be excluded from these analyses. 
ECG by dose group will also be explored as described in Section 3.10.4.3. 
3.9.5 
Cardiac imaging (MUGA / ECHO) 
Shift tables comparing baseline to worst post-baseline cardiac imaging (MUGA or ECHO) 
overall interpretation will be provided. Percentages will be based on all patients in the Safety 
set. 
Note: If there is any change in the methodology used throughout the study compared to baseline, 
the post-baseline values for which the methodology differs from baseline will be discarded in 
the tables presenting comparisons to baseline. 
Descriptive statistics of the left ventricular ejection fraction (LVEF) at baseline, worst post-
baseline value and change from baseline to worst post-baseline value will be provided.  
A listing of patients with newly occurring clinically significant abnormality will be produced 
by treatment arm. 
3.9.6 
Other safety data 
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate. 
All assessments collected later than 30 days after the last treatment date will be flagged in the 
listings. 
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration. 
 


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3.14 
Interim analyses 
3.14.1 
Primary Endpoint: PFS 
No interim analyses are planned for PFS. The primary endpoint PFS will be assessed after 
approximately 329 PFS events have been documented. 


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3.14.2 
Key Secondary Endpoint: OS 
Overall survival will be compared between the two treatment groups, provided the primary 
endpoint PFS is statistically significant favoring the test treatment arm (tamoxifen or a NSAI + 
goserelin + ribociclib). A hierarchical testing procedure will be adopted in this study and the 
OS analyses will be performed only if the primary efficacy endpoint PFS is statistically 
significant.  A maximum of three analyses are planned for OS: at the time of the primary 
analysis for PFS (provided PFS is significant), at which point a total of 123 deaths are expected, 
after 189 events have been documented, and a final analysis for OS when 252 deaths are 
expected (expected 40 months from date of first patient to be randomized).  
An  α-spending function according  to  Lan-DeMets (O’Brien-Fleming), (as implemented in 
East 5.4) along with the testing strategy outlined below will be used to maintain the overall type 
I error probability (Lan and DeMets 1983). This guarantees the protection of the 2.5% overall 
level of significance across the two hypotheses and the repeated testing of the OS hypotheses 
in the interim and the final analysis (Glimm 2010). The trial allows for the stopping of the study 
for a superior OS result, provided the primary endpoint PFS has already been shown to be 
statistically significant favoring the test treatment arm (tamoxifen or a NSAI + goserelin + 
ribociclib). Further, the exact nominal p-values that will need to be observed to declare 
statistical significance at the time of these analyses for OS will depend on the number of OS 
events that have been observed at the time of these analyses and the α for OS already spent at 
the time of earlier analyses. 
The operating characteristics for OS are shown in Table 3-11 considering the hierarchical 
testing strategy of PFS and OS. The probabilities shown in Table 3-11 are conditional on PFS 
being statistically significant. 
Table 3-11 
Timelines for interim and final analyses 
Months after 
randomization of the 
first  patient 
 
PFS  
events 
Cumulative Power 
(%)  
against a hazard 
ratio of 0.67 
 
OS  
events 
Cumulative Conditional 
Power (%) 
against hazard ratio of 
0.7 
22 
329 (100%) 
95 
123 (49%) 
15 
30 
-- 
-- 
189 (75%) 
54 
40 
-- 
-- 
252(100%) 
80 
Statistical significance of OS will only be declared if significance for primary PFS analysis has 
been declared. 
3.14.3 
Confidentiality of Interim OS results 
At the time of primary PFS analysis, both PFS and interim OS analysis will be performed by 
the Sponsor’s clinical team. Investigators and patients will remain blinded to study treatment 
and all patients will continue to be followed for OS until the final OS analysis (or earlier if OS 
reaches statistical significance at any of the interim analyses). 


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3.16 
Sample size calculation 
The assumption of median PFS of 9 months in the control arm (tamoxifen/NSAI + goserelin) 
for sample size calculation is based on the meta analysis of 4 trials in premenopausal advanced 
breast cancer treated with combination of tamoxifen and luteinizing hormone-releasing 
hormone agonist (Klijn 2001) and the results of the letrozole study in breast cancer patients 
(Mouridsen 2003). It is expected that the addition of ribociclib will result in 33% reduction in 
the hazard rate (corresponding to an increase in median PFS to 13.4 months assuming PFS has 
an exponential model assumption).  
If the true hazard ratio is 0.67 (under alternative hypothesis), a total of  329 PFS events provide 
95% power at a one-sided overall 2.5% level of significance to reject the null hypothesis (hazard 
ratio=1) using a log-rank test. Considering a recruitment period of approximately 18 months at 
a uniform rate of 33 patients/month, 600 patients will need to be randomized to the two 
treatment arms in a 1:1 ratio. Assuming about 10% patients will be lost to follow-up for PFS, a 
total of 660 patients will need to be randomized. Given the above assumptions, it is estimated 
that the 329th PFS event will be observed at approximately 22 months from the date of first 
patient randomized in the study. The sample size calculation was conducted with software 
package East 6.3.  
It is expected that both the endocrine treatment types (tamoxifen and NSAI) will have an 
adequate number of patients randomized for the respective subgroup analyses. However, this 
will be monitored closely in a blinded fashion and the protocol may be amended for further 
randomization in a given group if enrollment is found to be slow. 
Audit size calculation for BIRC assessment of PFS 
The audit size of the sample-based BIRC assessment will be 40% of all randomized patients. 
Based on the audit size calculation approach proposed by Dodd et al (2011), assuming 
investigator and BIRC assessments are similar and the estimated log of investigator-based HR 
is -0.40 (i.e. HR=0.67), the audit size of 40% will ensure that the upper bound of a one-sided 
95% CI for BIRC-based log-hazard ratio has 86% probability of being below zero (i.e. HR < 1) 
if the correlation between investigator assessment and BIRC assessment is 0.7 (the estimated 


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correlation based on data from the BELLE-2 [CBKM120F2302] study in metastatic breast 
cancer). 
3.17 
Power for analysis of key secondary variables 
OS will be compared between the two treatment arms, provided that the primary endpoint, PFS, 
is statistically significant.  Based on available data (Klijn 2001, Jonat 1995) the median OS in 
control arm is expected to be around 33 months. It is hypothesized that test treatment arm 
(LEE011 + tamoxifen or a NSAI + goserelin) will result in a 30% reduction in the hazard rate 
for OS (corresponding to an increase in median survival to 47 months under the exponential 
model assumption).  If the true hazard ratio is 0.7 (under alternative hypothesis), a total of 252 
deaths need to be observed to have  80% power at a one-sided overall 2.5% level of significance 
to reject the null hypotheses (hazard ratio = 1) using a log-rank test and a 3-look group 
sequential design. Based on the same number of patients that are planned to be enrolled in this 
study to detect the primary endpoint, it is estimated that these 252 deaths will be observed at 
approximately 40 months from the date of first patient to be randomized. Therefore the 
estimated time for the final OS evaluation will be 18 months after the primary analysis of the 
PFS endpoint has been conducted. The power calculation was conducted with software package 
East 6.3. 


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4 
Details of the statistical analysis 
4.1 
Baseline comparability 
Appropriate descriptive summary statistics of baseline variables (see Section 3.2) will be 
provided as in-text tables in the core CSR and also in Section 14 in the post-text tables. The 
summaries will be grouped by treatment arms, but no p-values will be provided.  
4.2 
Time-to-event analyses 
The following sections present a general methodology to be used to analyze time-to-event 
variables, e.g.: 
• Progression-free survival 
• Overall survival 
• Time to definitive deterioration of the ECOG score by one category of the score from 
baseline 
• Time to response: defined as the time between date of randomization until first 
documented response (CR or PR) according to RECIST 
• Time to definitive deterioration of PRO scores (eg, global health status/QoL, physical 
functioning, emotional functioning, social functioning scales of the EORTC QLQ-
C30, total score of breast cancer symptoms scale of the EORTC QLQ-BR23, and the 
VAS of the EQ-5D-5L)                                                                                                                         
4.2.1 
Analysis of time-to-event data with ties 
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model.  
4.2.2 
Hazard ratio 
The hazard ratio as a measure of treatment effect will be derived from the Cox proportional 
hazards model using SAS procedure PHREG with TIES=EXACT option in the MODEL 
statement. The stratified unadjusted Cox model will be used (where the baseline hazard function 
is allowed to vary across strata) for the primary analysis, i.e. the MODEL statement will include 
only the treatment arm variable as a covariate and the STRATA statement will include 
stratification variable(s). 
Hazard ratio with two-sided 95% confidence interval will be based on Wald test. 


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4.2.3 
Hypothesis and test statistic 
The primary efficacy analysis will be the comparison of the distribution of PFS between the 
two treatment arms using a stratified log-rank test at one-sided 2.5% level of significance.  
Assuming proportional hazards model for PFS, the following statistical hypothesis will be 
tested to address the primary efficacy objective 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (Tamoxifen or a NSAI+goserelin+ribociclib arm vs. tamoxifen 
or a NSAI+goserelin + placebo arm) of PFS.. 
The stratified log-rank test (strata based on IRT data) will be implemented as follows: For each 
of the K=8 strata, the LIFETEST procedure will be run with the STRATA statement including 
only the treatment variable. The TIME statement will include the survival time and a (right) 
censoring variable.  The rank statistic Sk and the corresponding variance var(Sk) ( k=1, 2) will 
be estimated from this analysis. 
The final test statistics will then be reconstructed using the formula:  
Z=[S1+ ... + SK]/√[var(S1) + ...+ var (SK)]. One-sided p-value will be computed using this Z 
statistic. Note: Under the null hypothesis, the asymptotic distribution of the test statistic Z is 
approximately normal (and correspondingly, Z2 is approximately distributed as chi-square with 
one degree of freedom). 
4.2.4 
Kaplan-Meier estimates 
The survival function in each treatment arm will be estimated using the Kaplan-Meier (product-
limit) method as implemented in PROC LIFETEST with METHOD=KM option. The PROC 
LIFETEST statement will use the option CONFTYPE=LOGLOG. 
Median survival for each treatment group will be obtained along with 95% confidence intervals 
calculated from PROC LIFETEST output using the method of [Brookmeyer and Crowley 1982]. 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific time 
points will be summarized. Median survival for each treatment arm will be obtained along with 
95% confidence intervals calculated from PROC LIFETEST output using the method of 
[Brookmeyer and Crowley 1982].  Kaplan-Meier estimates with 95% confidence intervals at 
specific time points will be summarized. The standard error of the Kaplan-Meier estimate will 
be calculated using Greenwood’s formula [Collett 1994]. 
4.2.5 
Audit-based BIRC assessment of PFS 
NCI method 
The auxiliary variable estimator of the NCI audit-based method (Dodd et al. 2011) has the form 
𝜃𝜃෨𝐶𝐶= 𝜃𝜃෠𝐶𝐶𝐶𝐶+ 𝜆𝜆̂൫𝜃𝜃෠𝐿𝐿𝐴𝐴̅ −𝜃𝜃෠𝐿𝐿𝐿𝐿൯, 
where 𝜃𝜃෠𝐶𝐶𝐶𝐶, 𝜃𝜃෠𝐿𝐿𝐴𝐴̅ and 𝜃𝜃෠𝐿𝐿𝐿𝐿 are estimators of the log-hazard ratio based on the central assessment 
in the audited subset of patients, the local assessment in the nonaudited subset of patients, and 
the local assessment in the audited subset, respectively. 𝜆𝜆̂ is defined as 𝜌𝜌ො√𝛿𝛿(1 −𝛿𝛿)√(𝑉𝑉෠𝐶𝐶𝐶𝐶/𝑉𝑉෠𝐿𝐿),  


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where 𝑉𝑉෠𝐶𝐶𝐶𝐶 and 𝑉𝑉෠𝐿𝐿 are variance estimators of  𝜃𝜃෠𝐶𝐶𝐶𝐶 and 𝜃𝜃෠𝐿𝐿 (the estimator of log-HR based on the 
local assessment in all patients) respectively, 𝛿𝛿 is the proportion of patients in the audited subset, 
and 𝜌𝜌ො is an estimator of the correlation between 𝜃𝜃෠𝐿𝐿𝐿𝐿 and 𝜃𝜃෠𝐶𝐶𝐶𝐶. For the latter, a bootstrap 
approach will be used:  
• Within the audited subset of size m, m patients will be sampled with replacement. Using 
this sample of m patients, the log-hazard ratio will be estimated based on the local and 
central assessments separately;  
• This procedure will be repeated 10 000 times, giving rise to 10 000 pairs (local and 
central) of estimates of the log-HR;  
• The sample correlation coefficient between these pairs of estimates will be used for 𝜌𝜌ො. 
The log-hazard ratio estimates contributing to the auxiliary variable estimate and corresponding 
variance estimates will be based on stratified Cox proportional hazards models, with 
stratification based on the randomization stratification factors. The upper bound of a 95% CI 
for 𝜃𝜃𝐶𝐶 will be calculated assuming asymptotic normality of 𝜃𝜃෨𝐶𝐶 and using the variance estimator 
for 𝜃𝜃෨𝐶𝐶 provided in Dodd et al., 2011, i.e. 𝑉𝑉෠𝐶𝐶𝐶𝐶{1 − 𝜌𝜌ො2(1 −𝛿𝛿)}. 
PhRMA method 
The early discrepancy rate (EDR) and late discrepancy rate (LDR) will be calculated using the 
equations below together with information in Table 4-1. 
EDR = (b + a3)/(a + b); 
LDR = (c + a2)/(b + c + a2 + a3). 
Table 4-1 
Local versus central disease progression assessments 
 
Central 
Local 
PD 
No PD 
PD 
a = a1 + a2 + a3 
b 
No PD 
c 
d 
a1: number of agreements on timing and occurrence of PD 
a2: number of times local PD declared later than central PD 
a3: number of times local PD declared earlier than central PD  
The timing of local and central response assessments will be considered to agree if they occur 
within ±7 days of each other, aligned with the protocol-specified window for tumor assessments. 
4.3 
Group sequential design used in Phase III studies 
The statistical methodology for the interim OS analyses will be based on group sequential 
methodology with efficacy stopping boundaries defined by type I error spending functions. 
Since the exact number of events available for interim and final analyses cannot be predicted 
exactly in the clinical trial setting, the group sequential design will be implemented using the α 
spending function approach. This approach is flexible in dealing with any deviations from the 
targeted event totals, or unexpected changes to the plan. 


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If the exact number of events observed at the interim and final analyses deviates from the target 
numbers described in the protocol, the actual critical boundaries will be derived using the pre-
specified error spending functions and the actual numbers of events observed.  
• At interim analyses, information fractions will be computed as the ratio of the number 
of events observed at the considered interim analysis relative to the number targeted 
for the final analysis, as described in the sample size section of the protocol.  
• At the final analysis, the critical value will be calculated using the exact number of 
observed events at the final cut-off date, considering the α-levels spent at interim 
analyses and considering the actual correlation among the test statistics, in order to 
achieve a cumulative type I error smaller than the desired significance level (i.e. 
smaller than 2.5% for a one-sided test).   
4.3.1 
Alpha-spending function 
The stopping boundaries to be used for the efficacy test will be calculated using the α-spending 
function approach described in Lan and DeMets (Lan and DeMets, 1983). The spending 
function for one-sided test has the following functional form: 
 
This function generates stopping boundaries that closely resemble the O’Brien-Fleming 
boundaries (O’Brien and Fleming, 1979). 
4.3.2 
Methodology 
A maximum of three analyses are planned for OS: at the time of the primary analysis for PFS 
(provided PFS is significant), at which point a total of 123 deaths are expected, after 189 events 
have been documented, and a final analysis for OS when 252 deaths are expected (expected 40 
months from date of first patient to be randomized).  
If the exact number of events observed at the interim and final analyses deviates from numbers 
defined in the protocol, the actual critical boundaries to be used at each of the interim analyses 
will be recalculated and will be derived from the pre-specified error spending functions using 
the actual number of events observed and assuming the final events number is the number 
derived in the sample size section of the protocol. The critical value for the final analysis will 
be calculated using the exact number of observed events at the cut-off date, and considering the 
α-levels spent at interim analyses, in order to achieve a cumulative type I error smaller than 
2.5%. 
It is recognized that circumstances (that are either internal or external to the trial) may require 
changes in the scheduling of the interim analyses. In case an additional unscheduled interim 
analysis is requested (e.g. the DMC might request this analysis if the study duration is much 
longer than expected) the procedure to calculate stopping boundaries needs to be adapted 
accordingly. An adaptation is also required if the interim analysis is skipped, e.g. is not 
considered necessary anymore. Both scenarios can be implemented without inflating the type-
I error, thanks to the error spending approach used for the group sequential design. The 
calculation of stopping boundaries needs to be adapted accordingly. 
)
/
(
2
2
)
(
2
/
t
Z
t
α
α
Φ
−
=


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4.3.3 
Calculation of stopping boundaries 
At the interim and the final analysis the critical boundaries for the group sequential test 
(stratified log-rank test) will be derived from the predefined spending functions. The 
calculations will be performed with East 6.3 software. 
4.4 
Duration of follow-up 
Study follow-up will be summarized using the following methods:  
• Summary of duration between randomization and cut-off date, and follow-up times for 
PFS/OS, which are defined as follows: 
• Randomization (recruitment) period = (Date of last patient randomized - Date of first 
patient randomized + 1) / 30.4375 (months 
• Duration between randomization and data cut-off date = (Cut-off date – Date of 
randomization + 1) / 30.4375 (months). This item will be summarized overall. 
• Follow-up time = (Date of event or censoring – Date of randomization + 1) / 30.4375 
(months) regardless of censoring. Date of censoring is defined as the last adequate 
tumor assessment date for PFS or last contact date for OS. This item will be 
summarized by treatment arm. 
All summaries will be reported in months. The calculations for PFS will be based on local 
assessment. Date of censoring is the same as defined for the PFS and OS analysis. 
The time from PFS and OS censoring date to data cut-off date will be summarized by time 
intervals in months: <3, 3 - < 6, 6 - < 12, 12 - < 18, 18 - <24 and by 12 month intervals thereafter 
if necessary. The gap time is calculated as ([analysis cut-off date] - [censoring date] + 
1)/30.4375. 
4.5 
Confidence intervals for response rate and clinical benefit rate 
Response rate and clinical benefit rate will be summarized as percentages with 95% confidence 
intervals. A standard Wald asymptotic confidence interval, i.e., normal approximation, 
(implemented using SAS procedure FREQ for one-way tables) will be calculated. 


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Appendix 1 
CTC grades for laboratory values in Novartis Oncology 
 


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