Clinical trial NCT02422615
Conditions: Advanced Breast Cancer
Keywords: HR-positive HER2-negative Advanced breast cancer LEE011 ribociclib fulvestrant faslodex CDK CDK4 CDK6 CDK4/6 CDK4/6 inhibitor Phase III ER-positive PR-positive Postmenopausal Men Breast Neoplasms Breast Diseases Neoplasms Neoplasms by Site Antineoplastic Agents Antineoplastic Agents, Hormonal Estrogen Receptor Antagonists Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Therapeutic Use
Sponsor: Novartis Pharmaceuticals
Start date: 2015-06-09; Completion date: 2023-01-11
Enrollment: 726 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main aim of this study was to evaluate the efficacy and safety of adding ribociclib to fulvestrant in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer.

Detailed description:
This study was a randomized, phase III, double-blind, placebo-controlled international trial aimed at determining the efficacy and safety of treatment with fulvestrant in combination with ribociclib compared to fulvestrant with placebo in men and postmenopausal women diagnosed with HR+, HER2-negative advanced breast cancer. The study comprised four phases: screening (up to 28 days), randomized treatment, post-treatment disease progression follow-up, and post-treatment survival follow-up.

Enrolled participants were randomly assigned to receive either fulvestrant+ribociclib or fulvestrant+placebo in a ratio of 2:1. The randomization process was stratified based on the presence of liver and/or lung metastases (yes versus no) and prior endocrine therapy. Treatment was administered until disease progression, occurrence of unacceptable toxicity, or discontinuation from the study treatment for other reasons.

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.

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

A protocol amendment 4 (dated 29-Jan-2020) allowed for unblinding of study participants, and those still receiving placebo had the option to switch to the ribociclib arm. The decision for crossover was made at the investigator's discretion and required patient consent.

Arms: arm 1: Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment. arm 2: Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.

Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.
Interventions: intervention 1: Ribociclib intervention 2: Fulvestrant intervention 3: Placebo
Intervention descriptions: intervention 1: Ribociclib capsules were administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. intervention 2: Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15. intervention 3: Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle.

Protocol documents:
Prot_002.pdf: 
Clinical Development
LEE011 (ribociclib)
Protocol CLEE011F2301 / NCT02422615 
MONALEESA-3: A randomized double-blind, placebo-
controlled study of ribociclib in combination with 
fulvestrant for the treatment of men and postmenopausal 
women with hormone receptor positive, HER2-negative, 
advanced breast cancer who have received no or only one 
line of prior endocrine treatment
Document type
Amended Protocol Version (Clean)
EUDRACT number
2015-000617-43
Version number
04 (Amended Protocol)
Development phase
III
Document status
Final
Release date
29-Jan-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version (17-Nov-2014)


Novartis
Confidential
Page 2
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................12
Amendment 4 (29-Jan-2020).............................................................................................14
Amendment 3 (06-Aug-2018)...........................................................................................18
Amendment 2 (28-Jul-2016) .............................................................................................21
Amendment 1 ....................................................................................................................24
Protocol summary:.............................................................................................................29
1
Background........................................................................................................................34
1.1
Overview of disease pathogenesis and current treatment......................................34
1.1.1
Epidemiology........................................................................................34
1.1.2
Available therapeutic options in ER+, HER2-negative breast 
cancer ....................................................................................................34
1.1.3
Role of the CDK4/6 pathway in breast cancer......................................35
1.2
Introduction to investigational treatment(s) and other study treatment(s).............36
1.2.1
Overview of ribociclib ..........................................................................36
1.2.2
Overview of fulvestrant.........................................................................42
1.2.3
Overview of ribociclib in combination with fulvestrant.......................44
2
Rationale............................................................................................................................45
2.1
Study rationale and purpose...................................................................................45
2.2
Rationale for the study design ...............................................................................46
2.3
Rationale for dose and regimen selection..............................................................46
2.4
Rationale for choice of combination drugs............................................................47
2.5
Rationale for choice of comparator drugs .............................................................47
2.6
Risks and benefits..................................................................................................48
2.6.1
Potential benefits to clinical trial participants.......................................48
2.6.2
Potential risks to clinical trial participants............................................48
3
Objectives and endpoints...................................................................................................48
4
Study design ......................................................................................................................51
4.1
Description of study design ...................................................................................51
4.1.1
Screening phase.....................................................................................53
4.1.2
Treatment phase ....................................................................................53


Novartis
Confidential
Page 3
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
4.1.3
Safety follow-up....................................................................................54
4.1.4
Efficacy follow-up ................................................................................54
4.1.5
Survival follow-up ................................................................................54
4.2
Timing of interim analyses and design adaptations...............................................54
4.3
Definition of end of the study................................................................................55
4.4
Early study termination..........................................................................................55
5
Population..........................................................................................................................56
5.1
Patient population..................................................................................................56
5.2
Inclusion criteria ....................................................................................................56
5.3
Exclusion criteria...................................................................................................58
6
Treatment...........................................................................................................................60
6.1
Study treatment......................................................................................................60
6.1.1
Dosing regimen.....................................................................................61
6.1.2
Guidelines for continuation of treatment ..............................................63
6.1.3
Ancillary treatments..............................................................................63
6.1.4
Rescue medication ................................................................................63
6.1.5
Treatment duration................................................................................63
6.2
Dose escalation guidelines.....................................................................................63
6.3
Patient numbering, treatment assignment or randomization .................................64
6.3.1
Patient numbering .................................................................................64
6.3.2
Treatment assignment or randomization...............................................64
6.3.3
Treatment blinding................................................................................65
6.4
Study drug preparation and dispensation...............................................................65
6.4.1
Study drug packaging and labeling.......................................................66
6.4.2
Drug supply and storage........................................................................66
6.4.3
Study drug compliance and accountability ...........................................66
6.4.4
Disposal and destruction .......................................................................67
6.5
Dose modifications................................................................................................67
6.5.1
Dose modification and dose delay ........................................................67
6.5.2
Follow-up for toxicities.........................................................................75
6.5.3
Anticipated risks and safety concerns of the study drug.......................75
6.6
Concomitant medications ......................................................................................75
6.6.1
Permitted concomitant therapy .............................................................75
6.6.2
Concomitant therapy requiring caution.................................................76
6.6.3
Prohibited concomitant therapy ............................................................77
6.6.4
Drugs with QT prolongation.................................................................78


Novartis
Confidential
Page 4
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
7
Visit schedule and assessments .........................................................................................78
7.1
Study flow and visit schedule................................................................................78
7.1.1
Screening...............................................................................................91
7.1.2
Treatment period...................................................................................92
7.1.3
Discontinuation of Study Treatment .....................................................92
7.1.4
Withdrawal of Consent .........................................................................94
7.1.5
Follow up for Safety Evaluations..........................................................95
7.1.6
Efficacy follow-up ................................................................................95
7.1.7
Survival follow-up ................................................................................95
7.1.8
Lost to follow-up...................................................................................95
7.1.9
End of post-treatment follow-up...........................................................96
7.2
Assessment types...................................................................................................96
7.2.1
Efficacy assessments.............................................................................96
7.2.2
Safety and tolerability assessments.....................................................101
7.2.3
Pharmacokinetics ................................................................................106
109
112
7.2.6
Patient reported outcomes...................................................................113
8
Safety monitoring and reporting......................................................................................116
8.1
Adverse events.....................................................................................................116
8.1.1
Definitions and reporting ....................................................................116
8.1.2
Laboratory test abnormalities..............................................................117
8.2
Serious adverse events.........................................................................................118
8.2.1
Definitions...........................................................................................118
8.2.2
Reporting.............................................................................................118
8.3
Emergency unblinding of treatment assignment .................................................119
8.4
Pregnancies..........................................................................................................119
8.5
Warnings and precautions....................................................................................120
8.6
Data monitoring committee.................................................................................120
8.7
Steering committee..............................................................................................120
9
Data collection and management.....................................................................................120
9.1
Data confidentiality .............................................................................................120
9.2
Site monitoring ....................................................................................................121
9.3
Data collection.....................................................................................................121
9.4
Database management and quality control..........................................................122
10 Statistical methods and data analysis ..............................................................................123


Novartis
Confidential
Page 5
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.1
Analysis sets ........................................................................................................123
10.1.1
Full analysis set...................................................................................123
10.1.2
Safety set .............................................................................................123
10.1.3
Per-protocol set ...................................................................................123
10.1.4
Pharmacokinetic analysis set...............................................................123
10.1.5
Cross-over analysis set........................................................................124
10.2
Patient demographics/other baseline characteristics ...........................................124
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................124
10.4
Primary objective.................................................................................................124
10.4.1
Variable...............................................................................................125
10.4.2
Statistical hypothesis, model, and method of analysis........................125
10.4.3
Handling of missing values/censoring/discontinuations.....................125
10.4.4
Supportive analyses.............................................................................125
10.5
Secondary objectives ...........................................................................................126
10.5.1
Overall Survival ..................................................................................127
10.5.2
Other secondary efficacy objectives ...................................................128
10.5.3
Safety objectives .................................................................................129
10.5.4
Pharmacokinetics ................................................................................131
10.5.5
Patient-reported outcomes...................................................................131
132
132
134
 
134
135
10.7
Interim analysis....................................................................................................135
10.7.1
Progression free survival.....................................................................135
10.7.2
Overall survival (OS)..........................................................................135
10.8
Sample size calculation........................................................................................136
11 Ethical considerations and administrative procedures ....................................................139
11.1
Regulatory and ethical compliance......................................................................139
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................139
11.3
Informed consent procedures...............................................................................139
11.4
Discontinuation of the study................................................................................139
11.5
Publication of study protocol and results.............................................................140
11.6
Study documentation, record keeping and retention of documents.....................140


Novartis
Confidential
Page 6
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
11.7
Confidentiality of study documents and patient records .....................................141
11.8
Audits and inspections.........................................................................................141
11.9
Financial disclosures............................................................................................141
12 Protocol adherence ..........................................................................................................141
12.1
Amendments to the protocol................................................................................141
13 References (available upon request)................................................................................142
14 Appendices ......................................................................................................................148
14.1
Appendix 1 - Concomitant medications ..............................................................148
14.2
Appendix 2 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....152
14.2.22
Time to treatment failure.....................................................................166
167
14.2.24
Duration of response ...........................................................................167
14.3
Appendix 3 - Bone Marrow Reserve in Adults ...................................................178
14.4
Appendix 4 - Patient reported outcomes .............................................................179
List of figures
Figure 1-1
Regulation of cell cycle checkpoint control..........................................35
Figure 2-1
Ribociclib plus fulvestrant in ER+ breast cancer xenograft models.....46
Figure 4-1
Study Design .........................................................................................52
Figure 14-1
EORTC QLQ-C30 ..............................................................................179
Figure 14-2
EQ-5D-5L ...........................................................................................181
Figure 14-3
Brief Pain Inventory-Short Form ........................................................184
List of tables
Table 1-1
Serious adverse events with a suspected causal relationship with 
ribociclib single agent ...........................................................................40
Table 1-2
Adverse events suspected to be study drug related in 
[CLEE011X2108] .................................................................................44
Table 3-1
Objectives and related endpoints ..........................................................49
Table 6-1
Dose and treatment schedule.................................................................61
Table 6-2
Packaging and labeling .........................................................................66
Table 6-3
Dose modification guidelines................................................................68
Table 6-4
Ribociclib/Placebo dose adjustment and management 
recommendations for hematological adverse reactions (CTC AE 
v4.03) ....................................................................................................68


Novartis
Confidential
Page 7
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table 6-5
Ribociclib/placebo dose adjustment and management 
recommendation for hepatic toxicities (CTC AE v4.03) ......................69
Table 6-6
Ribociclib/placebo dose adjustment and management 
recommendation for QTcF prolongation (CTC AE v4.03)...................72
Table 6-7
Ribociclib/placebo dose adjustment and management 
recommendation for ILD/pneumonitis (CTCAE v4.03).......................73
Table 6-8
Ribociclib/placebo dose adjustment and management 
recommendation for all other adverse reactions ...................................74
Table 7-1a
Visit evaluation schedule- Patients that, after protocol amendment 
4, continue with their originally randomized study treatment ..............80
Table 7-1b
Visit evaluation schedule – Cross over treatment phase for patients 
who cross over from placebo to LEE011 after protocol amendment 
4.............................................................................................................87
Table 7-2
Imaging collection plan.........................................................................98
Table 7-3
ECOG performance status...................................................................101
Table 7-4
Central clinical laboratory parameters collection plan........................102
Table 7-5a
Local ECG collection plan..................................................................104
Table 7-5b
Local ECG collection plan – for crossover patients............................105
Table 7-6
Sparse pharmacokinetic blood collection log .....................................108
Table 7-7
Trough pharmacokinetic blood collection log ....................................108
110
110
Table 7-9
Patient reported outcomes collection plan ..........................................114
Table 10-1
Estimated timelines for interim and final analyses .............................136
Table 10-2
Probability of Study Outcomes under various true Hazard Ratios .....137
Table 14-1
List of prohibited medications during study drug treatment...............148
Table 14-2
List of medications to be used with caution during study drug 
treatment..............................................................................................150
Table 14-3
Response criteria for target lesions .....................................................159
Table 14-4
Response criteria for non-target lesions..............................................161
Table 14-5
Overall lesion response at each assessment ........................................162
Table 14-6
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................170
Table 14-7
Options for event dates used in PFS, TTP, duration of response........171


Novartis
Confidential
Page 8
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
List of abbreviations
AE
Adverse Event
(e)PRO
(electronic) Patient Reported Outcomes
AI
Aromatase Inhibitors
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
AV
Atrioventricular
BC
Breast Cancer
BCRP
Breast cancer resistance protein
BIRC
Blinded independent review committee
BPI-SF
Brief Pain Inventory – Short Form
BSEP
Bile salt export pump
BUN
Blood Urea Nitrogen
CABG
Coronary artery bypass graft
CBR
Clinical Benefit Ratio
CCND1
Cyclin D1
CDK4/6
Cyclin-Dependent Kinases 4 and 6
Cmax
Peak blood concentration
Cmin
Minimum concentration
CNS
Central nervous system
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DOR 
Duration of Response
DS&E
Drug Safety and Epidemiology
E2F
Group of transcription factors that plays a major role during the G1/S transition of the cell 
cycle
EBV
Epstein Barr Virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group


Novartis
Confidential
Page 9
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
EDC
Electronic Data Capture
EORTC QLQ-
C30
European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire
EOT
End of Treatment
EQ-5D
EuroQol 5 Dimension questionnaire
ER
Estrogen Receptor
ERT
EResearch Technology
ET
Endocrine therapy
EU
European Union
FMO3
Flavin-containing monooxygenase 3
FAS
Full Analysis Set
FFPE
Formalin-Fixed, Paraffin-Embedded
FIH
First-in-human
FISH
Fluorescence in situ hybridization
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
HDL
High Density Lipoprotein
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HPV
Human Papilloma Virus
HR
Hazard ratio
HR+
Hormone Receptor Positive
HSV
Herpes Simplex Virus
i.v.
intravenous(ly)
IB
Investigator Brochure
IC50
Inhibitory Concentration, where 50% inhibition is observed
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
Intrauterine device
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LKM
Liver-kidney microsome antibodies
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
LVEF
Left Ventricular Ejection Fraction


Novartis
Confidential
Page 10
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MATE1
Multidrug and toxin exclusion protein-1
MBC
Metastatic Breast Cancer
MHC
Major histocompatibility complex
MI
Myocardial infarction
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition
NASH
Non-alcoholic steato-hepatitis
NCCN
National comprehensive cancer network
NCI
National Cancer Institute
NSAI
Nonsteroidal Aromatase Inhibitors
NSCLC
Non-Small Cell Lung Cancer
OCT2
Organic cation transporter 2
ORR 
Overall Response Rate
OS
Overall survival
p16
Product of the CDKN2A gene; a cyclin-dependent kinase inhibitor
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics
PFS
Progression free survival
P-gP
Permeability-glycoprotein
PgR
Progesterone receptor
PHI
Protected Health Information
PhRMA
Pharmaceutical Research and Manufacturers of America
PK
Pharmacokinetics
p.o.
per os/by mouth/orally
PPS
Per Protocol Set 
pRb
Retinoblastoma Protein
PS
Performance Status
PT
Prothrombin time
QD
Quaque Die (every day)
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia)
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RBC
Red Blood Cells
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RoW
Rest of the World
R Value
ALT/ALP in x ULN
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Stable disease
SEC
Safety Event Categories
SERM
Selective ER Modulators
S-ICF
Study ICF
SISH
Silver enhanced in situ hybridization


Novartis
Confidential
Page 11
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
SLA
Soluble liver antigen antibodies
SMA
Smooth muscle antibodies soluble
SMT
Novartis Safety Management Team
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
Tmax
The time at which the maximum observed concentration (Cmax) occurs
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time).
TBIL
Total Bilirubin
TdP
Torsades de Pointe
TTR 
Time to Response 
ULN
Upper Limit of Normal
WBC
White blood cell count


Novartis
Confidential
Page 12
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of 
the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. treatment 
group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new 
drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated placebo 
and active treatment controls (when applicable). This also includes approved drugs used 
outside of their indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study treatments administered 
as concomitant background therapy required or allowed by the protocol when used in 
within approved indication/dosage
Medication 
number
A unique identifier on the label of each study treatment package which is linked to one of 
the treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study procedures that was not 
included in the investigational treatment
Subject Number
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples.
Premature 
patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all study 
treatment administration and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments are planned, unless the patient 
will be followed for progression and/or survival
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.


Novartis
Confidential
Page 13
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Study treatment 
discontinuation
Point/time when a patient permanently discontinues study treatment for any reason
Supportive 
treatment
Refers to any treatment required by the exposure to a study treatment, e.g. premedication 
of vitamin supplementation and corticosteroid for pemetrexed disodium.
Treatment group
A treatment group defines the dose and regimen or the combination, and may consist of 1 
or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected using 
specified assessments at specified time points
Withdrawal of 
Study Consent 
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of personal 
data


Novartis
Confidential
Page 14
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Amendment 4 (29-Jan-2020)
Amendment rationale
Study CLEE011F2301 was initiated in June 2015 and completed enrollment on June 2016. 727
patients were randomized. 
The study met its primary endpoint of progression-free survival (PFS) at the time of the primary 
analysis in January 2018, demonstrating a statistically significant improvement in PFS in 
patients receiving ribociclib plus fulvestrant compared to patients receiving placebo plus 
fulvestrant with hazard ratio of 0.593 (95% CI: 0.480, 0.732) at one-sided 2.5 level of 
significance (p = 4.10×10-7). Results of this trial led to the approval of KISQALI (Ribociclib, 
LEE011) for supplement indication and new indications in HR-positive, HER2-negative 
advanced or metastatic breast cancer in the United States in July 2018 and the positive opinion 
from CHMP in November 2018.
The study met its secondary endpoint of overall survival (OS) at the time of the second OS 
interim analysis in July 2019. As all the planned inferential analyses for this study are now 
completed, all study participants will be unblinded for knowledge of their treatment allocation. 
 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 Jan 8th, 2020, there are still 117 patients ongoing on study treatment.
The purpose of this amendment is to:
i.
Allow unblinding of all patients and investigators in order to know patient’s current 
treatment allocation.
ii.
Allow for patients currently receiving placebo the opportunity to transition to 
investigational treatment (LEE011) per investigator discretion.
iii.
Specify that central safety ECG assessments can cease and ECG assessments should be 
performed locally and update the frequency of safety ECG assessments.
iv.
Update the visit evaluation schedule for patients on placebo transitioning to 
investigational treatment (LEE011).
v.
Specify that patient reported outcome (PRO) measures should no longer be collected.
vii.
Update of the protocol requirements for consistency with the most recent IB version 14 
information:
1. Update the dose adjustment and management recommendation table to include 
information on Interstitial Lung Disease (ILD)/pneumonitis.
2. Minor update to the Guidance for other Adverse Reactions to include Toxic 
Epidermal Necrolysis (TEN).
3. Update the adjustment of starting dose in special populations (hepatic impairment and 
renal impairment).


Novartis
Confidential
Page 15
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
4. Update the list of prohibited medications during study treatment and medications to 
be used with caution during study treatment.
viii.
Minor editorial changes, typographical error corrections, and alignment to the most 
recent program standard language as described in the list of changes below.
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 do 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 font for deletions and underlined for insertions.
The changes 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 4.3 End of Study and 6.1 Definition of Study and Study Treatment sections were 
updated to note that the study will be unblinded and patients will have the opportunity to 
transition from placebo to investigational treatment (LEE011).

Figure 4-1 Study Design has been updated to reflect the transition from placebo to 
investigational treatment (LEE011). 

Section 6.3.2 Treatment assignment and 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 6.3.3 Treatment unblinding was updated to clarify that the study will be 
unblinded.

Section 6.5.1.2.3 Added Toxic Epidermal Necrolysis (TEN) to the guidance for all other 
Adverse Reactions.

Section 6.5.1.2.4 Adjustment of starting dose in patients with hepatic impairment and 
renal impairment has been updated based on new information from pharmacokinetic 
analysis.

Table 6-5 Dose adjustement recommendations for hepatic toxicities was updated as per 
latest Program Standard Language.

Table 6.6 Additional follow-up for QTcF prolongation: wording related to PK assessment 
was removed.

Table 6-7 added to include dose adjustment and management recommendations on 
Interstitial Lung Disease (ILD)/pneumonitis. 

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 clarify study assessments.

Table 7-1b was added to clarify assessments for cross-over patients.


Novartis
Confidential
Page 16
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Section 7.2.1.3 has been updated to clarify that radiology review from the blinded 
independent review committee has been completed.

Section 7.2.2.5.6 Hepatic Safety Markers: was updated to clarify hepatic safety markers
will no longer be collected.

Section 7.2.2.6.1 Cardiac Assessments was updated to clarify that all ECGs will be 
performed locally and the schedule of assessments was updated for all patients.

Section 7.2.3 PK was updated to clarify that no additional PK should be collected from 
any patient also including cross-over 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 will be unblinded.

Section 9.3 and 9.4 Data collection parameters have been udpated with latest changes.

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 secondary objective (OS) was met, 
 
 and no further formal analyses of OS are planned.

Section 10.5.3 Incorporate safety summaries for the cross-over analysis set.

Section 10.7.2 was updated to clarify that further analysis will be descriptive. 

Section 14 Appendices:

Appendix 1: Concomitant medication tables for prohibited medications and 
medications to be used with caution updated

Table 14.1: List of prohibited concomitant medications during study drug 
treatment.

Table 14.2: List of medications to be used with caution during study drug 
treatment.


Novartis
Confidential
Page 17
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.


Novartis
Confidential
Page 18
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Amendment 3 (06-Aug-2018)
Amendment rationale
Study CLEE011F2301 was initiated in June 2015 and completed enrollment on June 2016. 727
patients were randomized. The study met its primary endpoint of progression-free survival (PFS) 
at the time of the primary analysis in January 2018. Results of this trial led to the approval of 
KISQALI (Ribociclib, LEE011) for expanded and new indications in HR-positive, HER2-
negative advanced or metastatic breast cancer in the United States.
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), 
CLEE011F2301 
(MONALEESA-3) 
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 QTcF prolongation.
(ii) Update the prohibited concomitant medications based on drug-drug interaction and co-
medication considerations.
(iii)The study has met the 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)Imaging tumor assessments- As the radiology review from the blinded independent review 
is completed, note added on stopping the transmission of images to CRO.
(v) 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 any interaction with 
the investigator; paper PRO utilization, when ePRO technical issues occur.
(vi)Update the withdrawal of consent language to align with the new Global Data Protection 
Requirements. 
(vii)
Minor additional updates, as summarized below.
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.
All the changes made to the protocol due to this amendment are incorporated in the following 
sections:


Novartis
Confidential
Page 19
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

List of abbreviations and glossary of terms updated

Sections 6.1.1.1: General dosing guidelines information updated

Table 6-6:  Potential risk of QT prolongation has been observed in patients treated with 
ribociclib. Therefore updates to dose adjustment have been added, dose reduction is 
recommended after the first event of QTc prolongation >480ms. 

Section 6.6.1: Permitted concomitant therapy section updated.

Section 6.6.1.2: Hematopoietic growth factors information updated.

Section 6.6.1.4: Use of antiemetic medications: New section to explain use of antiemetic 
medications according to NCCN guidelines added.

Section 6.6.2: Concomitant therapy requiring caution: Information on concomitant therapy 
requiring caution updated.

Section 6.6.3: Prohibited concomitant therapy: Information on prohibited concomitant 
therapy updated.

Section 6.6.4: Drugs with QT prolongation- Co-administration of drugs with known risk 
of torsade’s pointes TdP further clarified.

Section 7.1.4: Withdrawal of consent wording revised to align with new Global Data 
Protection Requirements.

Section 7.2.1.1: Imaging tumor assessments- As the radiology review from the blinded 
independent review is completed, note added on 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 and paper PRO implementation, when ePRO technical 
issues occur. 

Efficacy Assessments Update: Section Efficacy Assessments, Section 4.1.4, Section 
7.2.1.1, Section 7.16, Table 7-1 updated for sections 7.2.1, 7.2.6.1, 7.2.6.2, 7.2.6.3, 
Updated  Table 7-2, Updated Table 7-9 for the timing of PRO assessments.. 

Table 7-2: Note added on stopping the transmission of images to CRO for patients’ 
radiological and photography.

Section 13: New References added.

Minor updates: Sections 6.4.2, Table 6-4, Table 6-5, Section 7.1.3

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.


Novartis
Confidential
Page 20
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.


Novartis
Confidential
Page 21
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Amendment 2 (28-Jul-2016)
Amendment rationale 
Study CLEE011F2301 was initiated in June 2015 and enrollment has been completed on June 
14th. 727 patients have been randomized in the study.
The purpose of this amendment is to:
(i). Eliminate the originally planned futility interim analysis:
Since the start of Study CLEE011F2301, 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 CLEE011F2301 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) Eliminate the originally planned efficacy interim analysis and add the requirement of 
minimum amount of information from 1st line patients in the primary end point final analysis:
The primary objective of the study is to compare investigator assessed PFS in the overall 
population (both 1st line and 2nd line). If the primary analysis is statistically significant, 
treatment effect will be evaluated in 1st line and 2nd line patients separately. Based on the 
estimated median PFS and proportion of patients in 1st line and 2nd line respectively, it is 
expected that the accumulation of events in 1st line will be slower than 2nd line patients . By 
the projected efficacy interim analysis, there may not be enough events from 1st line patients 
to support the treatment effect in this sub population. Hence the originally planned efficacy 
interim analysis is eliminated. In addition, to ensure enough information coming from the 1st 
line patients, a requirement of minimum  amount of events coming from 1st line patients in the 
final analysis is added.
(iii). 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 study is being amended to change the central 
assessment of PFS from a full read to an audit based approach. Consequently, blinded 
independent review committee (BIRC) based PFS will no longer be a secondary endpoint but 
will be considered supportive of the primary analysis.
Additional changes in the protocol amendment
(i). Clinical pharmacokinetic data has been updated as new data is available
(ii). Clarifications have been provided on the following study procedures:

Schedule of the EOT visit


Novartis
Confidential
Page 22
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Palliative radiotherapy, previously only allowed for bone pain relief, is permitted 
provided it is not delivered to a target lesion

The use of the randomization date as the reference for the tumor assessement schedule
(iii) To better evaluate treatment effect on ORR, a sensitivity analysis of ORR is added for 
patients with measurable disease at baseline. 
(iv) The PK analysis was updated to only summarize PK concentrations by time point 
considering that PK parameters will not be estimable due to the sparse PK sampling 
schedule. PK data collected from this study may be used in population PK analysis of 
ribociclib using non-linear mixed effect modeling and would be reported in a separate 
report.
(v). The protocol appendix 2 has been updated to reflect the new Novartis guidance on the 
implementation of RECIST 1.1
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 underline for insertions.

Summary section of the protocol has been updated to maintain consistency within the 
main body of the protocol

Section 1.2.1.2.3 has been updated to add new pharmacokinetic data on ribociclib

Section 3, Table 3-1 secondary 
 objectives and endpoints have been 
updated
 

to clarify the pharmacokinetic endpoint

Section 4.1.2 has been updated to clarify when an end of treatment (EOT) visit must be 
performed

Section 4.2 and Section 4.3 have been updated to remove the 1st and 2nd interim analyses 
(respectively futility and efficacy analysis) for the primary endpoint PFS

Section 6.5.1.3 has been updated to clarify that all QTcF grade values refer to the average 
of triplicate measurements 

Section 6.6.1.3 has been updated to remove the requirement of palliative radiation solely 
for bone pain
 
 

Section 7.2.1.1 has been updated 


Novartis
Confidential
Page 23
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

to reflect the change to the audit based stratefy for the BIRC assessment

to clarify that the randomization is the reference date for the planning of the tumor 
assessment schedule.

Section 7.2.1.3 has been added to describe the describe the audit-based central assessment

Section 8.6 has been updated to reflect the removal of the 1st and 2nd interim analyses 
(respectively futility and efficacy analysis) for the primary endpoint PFS

Section 10, 10.5.1, 10.7.1 has been updated to reflect the removal of the 1st and 2nd
interim analyses (respectively futility and efficacy analysis) for the primary endpoint PFS

Section 10.4.4 has been updated to describe the supportive analysis of PFS using audit 
based BIRC assessment

Section 10.5 has been updated to remove reference to the BIRC based PFS as secondary 
endpoint

Section 10.5.2.1 has been removed to reflect the removal of the PFS as assess by the BIRC 
as a secondary endpoint

Section 10.5.2.2 has been updated to add a sensitivity analysis for Overall Response Rate 
(ORR)

Section 10.5.4 has been updated to reflect the change in the analysis of PK data 

Section 10.7.2 to reflect the removal of one OS interim analysis at the originally planned 
PFS efficacy interim analysis

Section 10.8 has been updated

to reflect the removal of one OS interim analysis at the originally planned PFS 
efficacy interim analysis

to add the requirement of minimum amount of information coming from 1st line 
patients in final analysis.

to add sample size calculation for audit size of sample-based BIRC assessment of 
PFS.

Section 13: new protocol references have been added

Appendix 2 has been updated to reflect the new Novartis guidance on the implementation 
of RECIST 1.1

In addition to above, changes to typographical errors where applicable have been made.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


Novartis
Confidential
Page 24
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Amendment 1
Amendment rationale
Study CLEE011F2301 was initiated in June 2015 and enrollment is currently ongoing.
As of February 17th 2016, 351 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 ribociclib 
clinical trials, and better characterize the QTc and liver side effects, including:

Management of QTcF prolongation: 
Potential risk of QT prolongation has been observed in patients treated with ribociclib. 
Updates to inclusion and exclusion criteria, ECG monitoring (triplicates) and dose
modification guidelines for QTcF prolongation have been made. 

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 with bilirubin increase) in 
patients treated with ribociclib. 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.
 

Management of dose modification based on local laboratory results:
Clarification was provided that, in case of safety emergency, local laboratories results can 
be used to evaluate the need for potential study treatment dose modifications.
(ii).Modification of the study population and eligibility criteria:
Following interaction with Health Authorities, men are eligible to be included in the 
study.
(iii)Additional changes

Revision of the screening visit window changed within 21 days to within 28 days of 
randomization

Whole body bone scan window has been changed from within 28 days to within 42 
days of randomization

Removal of the requirement for a central radiology assessment by medical oncologist: 
Medical oncologist review has been replaced by a standard blinded independent 
review committee (BIRC) review assessment. 

List of prohibited concomitant medications has been updated based on recently 
released 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.


Novartis
Confidential
Page 25
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
 
 

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.

Update of the protocol requirements for consistency with the most recent IB
information:

New information is provided on the safety pharmacology and toxicology

Update clinical trial information with the most recent data

Minor editorial changes, typographical error corrections, additional clarifications to 
address investigators’ questions and alignment to the most recent program standard 
language as described in the list of changes below.
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 Addition of disease information regarding the men population 

Section 1.1.2 Addition of most recent information on available therapeutic options

Section 1.2 Addition of language to refer to most recent version of the ribociclib 
investigator brochure

Section 2.3 and 2.5 have been updated to incorporated most updated trials information
 

Section 4 and Figure 4-1 have been updated to incorporate men population and screening 
visit window of 28 days into the study design

Section 4.1 Advanced/ metastatic terms have been included to add clarity to the patient 
population in the stratification criterion

Section 5.1 Patient population has been updated to reflect the inclusion of men in the 
study.

Section 5.2 Inclusion Criteria has been updated:


Novartis
Confidential
Page 26
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

#1) Addition of male population and male contraception information

#2) to clarify that ovarian radiation or treatment with a luteinizing hormone-releasing 
hormone agonist (LH-RHa) are not allowed for induction of ovarian suppression in 
this study.

#3) and 4) to clarify that diagnosis of breast cancer should be based on recent biopsy

#6) to clarify the definition of curative therapy per protocol. Advanced/ metastatic 
terms have been included to add clarity to the patient population. The terms relapse 
and progressed have been corrected accordingly to the treatment setting.

#8) phosphorus assessment has been removed from screening visit.

Section 5.3 Exclusion Criteria have been updated:

#12) to clarify that squamous cell carcinoma refers to squamous skin cancer. 

#17). and #18):

To clarify the exclusion criteria for patients with clinically significant, 
uncontrolled heart disease and/or cardiac repolarization abnormality and for 
patients currently receiving prohibitied medications.

To clarify that resting heart rate should be <90 bpm 

Section 6.1 has been updated with timing recommendation on dosing schedule and meal 
conditions

Section 6.5.1.2: 

To add clarity on fulvestrant dosing interruption

To add clarity on the use of local laboratories results for dose modifications.

To add clarity on dose modification guidelines

Section 6.5: Table 6-5 and Table 6-6

Section 6.5.1.2 wording has been modified to clarify to the dosing 
recommendations and requirements 

Dose modifications have been updated to clarify actions to be taken for 
hematologic toxicities, QTcF prolongation and all other toxicities, as well as 
providing new guidelines for hepatic toxicities. 

Renal toxicity wording has been moved from section 6.5.1.3.2 to the safety section 
6.5.1.3.1 for clarity.

“Placebo” has been added in the table wording and baseline value has been 
modified to baseline grade based on CTCAE.

Section 6.6.2.1 and 6.6.3: the use of corticosteroids therapy has been added to allow the 
topical and short term use per protocol. Chronic use remain prohibited due to the potential 
for drug- drug-interaction.

Section 6.6.2 immunosuppressant therapies have been added in the medications to use 
with caution due to their higher risk of infections. 

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:


Novartis
Confidential
Page 27
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Modification to the screening window change within 21 days to within 28 days of 
randomization. 

Modification to the visit windows schedule to include a ±3 days visit windows for all 
visits including PK visits

To add clarity that physical exam assessment will not be repeated at Cycle 1 Day 1 
when done in the timeframe -7 to -1 at the screening visit
 

Revision to the whole body bone scan requirement window: change from 28 to  
within 42 days or 6 weeks prior to randomization.

Section 7.1.1 screening: 

clarification that screening assessments to be performed at -7 to -1 should be repeated 
in the case where randomization visit is delayed more than 7 days from cycle 1 day 1. 

clarification on inform consent form process for patients who rescreen

Section 7.1.3 

Clarity added by the addition of the word “reasonable” 

update to the study treatment discontinuation language in the case of AEs. 

Section 7.2.1.1 

Revision of window regarding whole body bone scan: change from within 28 days to 
within 42 days of randomization

Updated to remove the medical oncologist review of central images.

Section 7.2.2: Thyroid monitoring has been removed as is not longer mandatory based on 
recent study results.

Section 7.2.2.5: 

clarification on the use of local laboratories results 

Table 4 - addition of the hepatic safety markers assessments 

Section 7.2.2.5.6: addition of the hepatic safety markers section

Section 7.2.2.6.1 and Table 7-5: 

Electrocardiogram (ECG) was updated with the use of triplicate for each collection 
time points 

Clarity was added on the unscheduled ECG management

Section 7.2.3.1: clarification to PK sampling when no study drug has been taken
 
 
. 
 
 

Section 7.2.6 Table 7-9 has been updated to reflect the 28 days screening visit window 

Section 8: implementation of new Serious Adverse Event (SAE) reporting instructions


Novartis
Confidential
Page 28
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Section 8.4: addition of pregnancies recommendations for female partner of any male 
participants

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.

Modification to the table removing CYP2D6 since is it not applicable to the study 
treatment . 

In addition to above, changes to typographical errors where applicable have been made.
Review requirements by IRB/IEC and Heath 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.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


Novartis
Confidential
Page 29
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Protocol summary:
Title
A randomized double-blind, placebo-controlled study of ribociclib in combination 
with fulvestrant for the treatment of men and postmenopausal women with 
hormone receptor positive, HER2-negative, advanced breast cancer who have 
received no or only one line of prior endocrine treatment
Brief title
Study assessing the efficacy and safety of ribociclib plus fulvestrant in men and 
postmenopausal women with advanced breast cancer having been treated with no 
or only one prior endocrine therapy.
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 a significant number of patients are 
expected to have, or to develop, resistance to endocrine therapies that have been 
given in the adjuvant or first line metastatic setting. CDK4/6 pathway alterations 
appear to play a key role in the development of this resistance. The rationale for 
assessing the efficacy of ribociclib, a CDK4/6 inhibitor, in combination with the 
hormonal agent fulvestrant, in a randomized Phase III study is therefore based 
upon the role of the CDK4/6 pathway in HR+ breast cancer and the potential 
synergy when combined with hormonal agents such as fulvestrant.
The purpose of this study is to determine whether treatment with ribociclib plus 
fulvestrant will result in an improved progression free survival compared to 
fulvestrant and placebo in men and postmenopausal women with HR+, HER2-
negative advanced breast cancer who have received no or only one prior 
endocrine treatment for advanced disease.
Primary Objective(s) 
The primary objective is to compare progression free survival (PFS) between 
ribociclib in combination with fulvestrant to placebo in combination with fulvestrant 
among men and postmenopausal women with HR+, HER2-negative advanced 
breast cancer who received no or only one prior endocrine treatment for advanced 
disease.
Secondary Objectives
●
To compare the two treament arms with respect to overall survival
●
To evaluate the two treatment arms with respect to overall response rate, 
clinical benefit rate, time to response and duration of response as assessed by 
tumor evaluation (RECIST 1.1) every 8 or 12 weeks.
●
To evaluate the two treatment arms with respect to time to deterioration of 
ECOG performance status by assessing the performance status at each cycle.
●
To evaluate the safety and tolerability of ribociclib in combination with 
fulvestrant by assessing the frequency/severity of adverse events (AEs) and of 
laboratory abnormalities on a continuous basis throughout the study.
●
To evaluate patient reported outcomes every 8 or 12 weeks for health-related 
quality of life (QOL) in the two treatment arms based on the global health 
status/QOL scale of the EORTC QLQ-C30 questionnaire.
●
To characterize the pharmacokinetics (PK) of ribociclib (and relevant 
metabolites such as LEQ803) at Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 
15, when given in combination with fulvestrant by compiling summary statistics for 
PK parameters at steady state.


Novartis
Confidential
Page 30
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Study design
This is a randomized, phase III, double-blind, global trial comparing the 
combination of fulvestrant + ribociclib to fulvestrant + placebo in men and 
postmenopausal women with HR+, HER2-negative advanced breast cancer. The 
study will consist of a 28-day screening phase, of a treatment phase, and of a post-
treatment phase which includes safety, efficacy, and survival follow up.
Patients will be randomly assigned to either fulvestrant+ribociclib or 
fulvestrant+placebo in a 2:1 ratio. Randomization will be stratified by the following 
factors:
●
Lung or liver metastases (yes versus no)
●
Previous endocrine therapy
Population
The study will include 660 men and postmenopausal women with HR+ HER2-
negative advanced breast cancer who received no or only one prior endocrine 
therapy. 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 and full listing of inclusion criteria.
●
Patient is an adult ≥ 18 years old at the time of informed consent and has 
signed informed consent before any trial related activities and according to local 
guidelines
●
Patient is a man or a postmenopausal woman
●
Patient has a histologically and/or cytologically confirmed diagnosis of 
estrogen-receptor positive and/or progesterone receptor positive breast cancer
●
Patient has HER2-negative breast cancer
●
Patient must have either:
●
Measurable disease, i.e., at least one measurable lesion as per RECIST 
1.1.
OR
●
If no measurable disease is present, then at least one predominantly lytic 
bone lesion must be present
●
Patient has advanced (loco regionally recurrent not amenable to resection or 
radiation therapy with curative intent or metastatic) breast cancer.
Patients may be :
●
newly diagnosed advanced/metastatic breast cancer, treatment naïve
●
relapsed with documented evidence of relapse more than 12 months from 
completion of (neo)adjuvant endocrine therapy with no treatment for 
advanced/metastatic disease
●
relapsed with documented evidence of relapse on or within 12 months 
from completion of (neo)adjuvant endocrine therapy with no treatment for 
advanced/metastatic disease
●
relapsed with documented evidence of relapse more than 12 months from 
completion of (neo)adjuvant endocrine therapy and then subsequently 
progressed with documented evidence of progression after one line of 
endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for 
advanced/metastatic disease
●
newly diagnosed advanced/ metastatic breast cancer, that progressed 
with documented evidence of progression after one line of endocrine therapy 
(with either an antiestrogen or an aromatase inhibitor)
●
Patient has an Eastern Cooperative Oncology Group (ECOG) performance 
status 0 or 1
●
Patient has adequate bone marrow and organ function


Novartis
Confidential
Page 31
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Exclusion criteria
Refer to Section 5.3 for details on and full listing of exclusion criteria.
●
Patient with symptomatic visceral disease
●
Patient has received prior treatment with chemotherapy (except for 
neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor
●
Patients with Child pugh score B or C
●
Patient with inflammatory breast cancer at screening or concurrent malignancy 
or malignancy within 3 years of randomization
●
Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality including any of the following:
●
History of angina pectoris, symptomatic pericarditis, coronary artery 
bypass graft (CABG) or myocardial infarction 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)
●
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

Concomitant medication(s) with a known risk to prolong the QT 
interval and/or known to cause Torsades de Pointe that cannot be
discontinued or replaced by safe alternative medication (e.g. within 5 
half-lives or 7 days prior to starting study drug) 

Inability to determine the QTcF interval

Clinically significant cardiac arrhythmias including but not limited to (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)
●
Systolic Blood Pressure (SBP) >160 or <90 mmHg
●
Bradycardia (heart rate < 50 bpm at rest), by ECG (mean of triplicate) and
pulse.

Tachycardia (heart rate > 90 bpm at rest), by ECG (mean of triplicate) and 
pulse.
●
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 screening ECG (mean of triplicate ECGs).
●
Patient has not recovered from all toxicities related to prior anticancer therapies 
to NCI CTCAE version 4.03 Grade ≤1
●
Patient has received radiotherapy ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to randomization
●
Patients with central nervous system (CNS) involvement unless they meet ALL 
of the following criteria:
●
At least 4 weeks from prior therapy completion (including radiation and/or 
surgery) to starting the study treatment
●
Clinically stable CNS tumor at the time of screening and not receiving 
steroids and/or enzyme inducing anti-epileptic medications for brain metastases
●
Patient has any other concurrent severe and/or uncontrolled medical condition 
that would, in the investigator’s judgment, cause unacceptable safety risks, 
contraindicate patient participation in the clinical study or compromise compliance 
with the protocol.
●
Patient is currently receiving any of the following substances and cannot be 
discontinued 7 days prior to start the treatment:
●
Known strong inducers or inhibitors of CYP3A4/5.
●
Medications that have a narrow therapeutic window and are 
predominantly metabolized through CYP3A4/5.


Novartis
Confidential
Page 32
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
●
Herbal preparations/medications, dietary supplements (except vitamins)
Investigational and 
reference therapy
For this study, the term “investigational drug” refers to Novartis study drug 
ribociclib. Fulvestrant is also being used in this study. Study treatment in this study 
refers to the combination of drugs in each of the study arms and includes 
ribociclib/placebo and fulvestrant.
Patients will be randomly assigned to one of the below treatment arms in a 2:1 
ratio:
●
Experimental arm (Arm A): fulvestrant + ribociclib
OR
●
Control arm (Arm B): fulvestrant + placebo
Study 
treatment
Pharmaceutical form 
and route of 
administration
Frequency and/or Regimen
Fulvestrant
Two 5ml injections for 
i.m. administration
Dosed every 28 days (Cycle n Day 
1) with 1 additional dose on Day 
15 of Cycle 1
Ribociclib/ 
placebo
Capsule for oral use
Once daily; days 1 to 21 in a 28-
day Cycle
Efficacy assessments
●
CT/ MRI every 8 weeks for 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, or subject/guardian decision
●
Brain CT or MRI as clinically indicated if brain lesion at screening
●
Whole body scan as clinically indicated
●
Bone X-ray, CT or MRI (if bone lesion at screening) every 8 weeks for the first 
18 months, then every 12 weeks until 36 months, and thereafter as clinically 
indicated.
●
Skin color photography (if skin lesions at screening) every 8 weeks during the 
first 18 months, then every 12 weeks until 36 months, and thereafter as clinically 
indicated.
●
CT/ MRI for any disease outside of the chest, abdomen, pelvis (if lesion 
identified at screening) every 8 weeks for the first 18 months, then every 12 weeks 
until 36 months, and thereafter 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), hepatic safety markers, and urinalysis
Other assessments
Pharmacokinetic: PK blood samples will be collected for analysis of ribociclib (and 
metabolites) plasma concentrations 
Biomarkers: Tumor and blood samples will be collected for biomarker 
assessments. Tumor tissue will be used to assess molecular alterations of several 
genes shown to be associated with HR+ breast cancer and the CDK4/6 pathway. 
Collection of blood for circulating tumor DNA (ctDNA) analysis will allow additional 
serial monitoring of mutations in genes that are relevant to HR+ breast cancer and 
CDK4/6.
In addition exploratory liver biomarkers (e.g. microRNA-122, HMGB1) will be 
evaluated to explore potential mechanisms underlying hepatic toxicity.
GWAS/HLA genotyping will be performed for potential association with safety 
endpoints.
Patient-reported outcomes: Patient questionnaires (EORTC-QLQ-C30, EQ-5D-
5L, BPI-SF) will be collected to assess health-related quality-of-life, health status, 


Novartis
Confidential
Page 33
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
functioning, disease symptoms, side effects, and cancer-related pain.
Following protocol amendment 4, no further ePRO, PK data, central ECG 
 
will be collected.
Data analysis
The primary objective for this study is to determine whether treatment with 
fulvestrant + ribociclib prolongs PFS compared to treatment with fulvestrant + 
placebo in men and postmenopausal 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.
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 (HR) of OS, along with 95% confidence interval. 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.
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 includes all 
patients who received at least one dose of study medication defined as fulvestrant, 
or ribociclib/placebo and had at least one post-baseline safety assessment. 
Patients will be analyzed according to treatment actually received.
One of the secondary objectives of the study is to determine whether treatment 
with fulvestrant + ribociclib prolongs overall survival (OS) compared to treatment 
with fulvestrant + placebo. OS will be hierarchically tested (provided the primary 
PFS analysis is statistically significant), in the following way. The first potential 
time point for OS analysis will be at the time of the primary PFS  analysis at which 
time approximately 161 deaths are expected. If OS is not statistically significant at 
this stage, the 2nd OS analysis is planned  after approximately 263 deaths are 
expected. If OS is not statistically significant at this stage, the final  OS analysis will 
be planned after approximately 351 deaths.
Key words
HR-positive, HER2-negative, advanced breast cancer, ribociclib, fulvestrant, 
CDK4/6, Phase III, ER-positive, PR-positive, postmenopausal, men, metastatic 
breast cancer 


Novartis
Confidential
Page 34
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
1
Background
1.1
Overview of disease pathogenesis and current treatment
1.1.1
Epidemiology
An estimated 231,840 new cases of invasive breast cancer are expected to be diagnosed among 
women in the US during 2015; excluding cancers of the skin, breast cancer is the most 
frequently diagnosed cancer in women. An estimated 40,730 breast cancer deaths (40,290 
women) are expected in 2015. Breast cancer ranks second as a cause of cancer death in women 
after lung cancer (Cancer facts & figures 2015). Breast cancer in men is a less frequent disease 
than women and makes up < 1% of all cases of breast cancers; its treatment is based on the 
guidelines for female breast cancer (Foerster 2014, Agrawal 2007, Patten 2013). Subtypes of 
BC are classified by the presence of estrogen receptor (ER), progesterone receptor (PgR), 
human epidermal growth factor receptor 2 (HER2) antigen as well as by distinct gene 
expression profiles (Perou et al 2000; Sotiriou and Pusztai 2009) and other features for 
prognostic and treatment purposes. Seventy percent of invasive breast cancers in women > 45 
years of age, express ER and/or PgR, but not HER2, and are termed hormone receptor positive 
(HR+, HER2-negative) (Huang 2005).
1.1.2
Available therapeutic options in ER+, HER2-negative breast cancer
Estrogen deprivation therapy is the core treatment modality in patients with HR+ advanced BC.
Endocrine therapy options for postmenopausal women with ER+ advanced breast cancer 
(locally advanced, recurrent, or metastatic breast cancer) include selective ER modulators 
(SERM; for example, tamoxifen), ER antagonists (for example fulvestrant), selective 
nonsteroidal aromatase inhibitors (NSAI; anastrozole and letrozole) and steroidal aromatase 
inhibitors (exemestane). Blocking estrogen signaling with tamoxifen has been the main 
treatment approach for ER+ breast cancer for over 35 years. In postmenopausal women, 
aromatase inhibitors (AI) reduce peripheral estrogen synthesis by blocking the conversion of 
androgens to estrogens in non-ovarian tissues; synthesis in these tissues is the primary source 
of estrogens in postmenopausal women. AIs are generally used as the first line of therapy for 
women with HR+ breast cancer (Beslija 2009; NCCN 2.2015). Fulvestrant is a pure ER 
antagonist approved at the dose of 500mg for the treatment of postmenopausal HR+ BC women 
previously treated with antiestrogen (Di Leo 2010; Di Leo 2014). Recently, the phase 2 FIRST 
trial (Robertson 2014) showed that the use of fulvestrant in first line setting significantly 
prolonged PFS as compared to anastrozole (median TTP 23.4 months versus 13.1 months (HR 
0.66; 95% CI:0.47, 0.92; p=0.01)) and extends OS (54.1 months versus 48.4 months (HR 0.70; 
95% CI: 0.5, 0.98; p=0.04)) (Ellis 2015). The combination of targeted and endocrine therapies 
has also been evaluated: everolimus, an mTOR inhibitor, combined with exemestane showed 
synergistic inhibition of the tumor proliferation and is approved for postmenopausal women 
with advanced hormone receptor-positive, HER2- negative breast cancer (advanced HR+ BC) 
in combination with exemestane after failure of treatment with letrozole or anastrozole (Baselga 
2012); recently, palbociclib, a CDK4/6i, has been approved in combination with letrozole for 
the treatment of postmenopausal women with estrogen receptor (ER)-positive, human 
epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial 


Novartis
Confidential
Page 35
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
endocrine-based therapy for their metastatic disease based on the results of the phase 2 Paloma-
1 study. The addition of palbocicib to letrozole significantly prolonged PFS as compared to 
letrozole alone (median PFS 20.2 months versus 10.2 months (HR 0.49; 95% CI:0.32, 0.75; 
p=0.0004)) (Finn 2015). 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. 
(Cristofanilli M 2015, Turner 2015) 
1.1.3
Role of the CDK4/6 pathway in breast cancer
Studies of ER+ breast cancer cell lines indicate that estrogens and antiestrogens act on sensitive 
populations of cells in early to mid-G1 phase (Leung 1987). G1/S transition is under the control 
of cyclin dependent kinases (CDKs) which are activated by specific complex formation with 
regulatory cyclins. CDK4 and CDK6 are activated by binding to D-type cyclins and act early 
in G1 phase (Sherr 1999; Musgrove et al 2011). A primary target of CDK4/6 activation in G1 
phase is the retinoblastoma protein (pRb), which mediates G1 arrest through sequestration of 
transcriptional factors of the E2F-DP family. Phosphorylation of pRb and other members of the 
pocket protein family (p107 and p130) by active cyclin-CDK complexes leads to release of E2F 
and DP and subsequent transcription of genes requisite for entry into the S-phase (Weinberg 
1995). D-type cyclins play an essential role in the recognition of extracellular growth stimuli 
and initiation of G1 to S transit (Roussel 1995; Sherr 1995).
Figure 1-1
Regulation of cell cycle checkpoint control
Adapted from (Lange and Yee 2011)Dysregulation of cell cycle checkpoints is common in 
cancer and aberrations in the cyclin/CDK/pRb pathway are frequently observed in breast cancer. 


Novartis
Confidential
Page 36
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Such aberrations include amplification of cyclin D1 and CDK4 along with loss of CDKN2A 
which encodes p16INK4a, an endogenous CDK inhibitor, all of which lead to activation of the 
cyclin/CDK/pRb pathway (Holm et al 2012; The Cancer Genome Atlas Network 2012; 
Beroukhim et al 2010). An upstream role for cyclin D1 has also been suggested by recent reports 
describing direct physical interactions between cyclin D1 and the ER, leading to recruitment of 
steroid receptor coactivators and activation of ER-dependent transcription. This occurs in the 
absence of hormone and is independent of D cyclin association with CDK4 (Neuman 1997; 
Zwijsen 1997; Zwijsen 1998; McMahon 1999). Furthermore, recent preclinical data suggest 
that despite estrogen deprivation, ERα retains genomic activity and drives a CDK4/E2F 
dependent transcriptional program (Miller 2011).
Previously published data have suggested that CDK4/6 inhibition may play a key role in the 
treatment of subsets of breast cancers. Loss of pRb has been observed in 10-30% of breast 
cancer patients (Knudsen and Knudsen 2008), however, this is more commonly seen in ER-
negative patients, as evaluated using a gene signature of pRb loss (Ertel et al 2010). Patients 
with HR+ breast cancer exhibiting a gene expression signature of pRb 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 CDK/pRb/E2F axis 
promotes endocrine resistance, and treatment with a CDK4/6 inhibitor or knockdown of CDK4 
expression would be expected to abrogate endocrine-resistant cell proliferation (Caldon 2006).
In vitro data generated from 47 human breast cancer cell lines demonstrated preferential 
sensitivity to CDK4/6 inhibitors in ER+ cell lines (Finn et al 2009; O’Brien et al 2014). Tumor 
growth inhibition by CDK4/6 inhibitors has been demonstrated in vivo in preclinical models of 
endocrine-resistant breast cancer by palbociclib (PD 0332991) (Miller 2011; Thangavel 2011) 
and in mouse xenograft models of HR+ breast cancer by ribociclib in combination with letrozole 
or fulvestrant (O’Brien et al 2014). Clinically, palbociclib combined with letrozole showed a 
benefit prolonging the progression free survival (PFS) in postmenopausal women with 
ER+/HER2-negative advanced BC (Finn et al 2015) and has recently received accelerated 
approval based on PFS by the FDA.
In conclusion, targeting the CDK/pRb/E2F pathway via a CDK4/6 inhibitor such as ribociclib 
in combination with endocrine treatment has the potential to have a positive influence on breast 
cancer progression.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
This study includes ribociclib and fulvestrant as treatments.
1.2.1
Overview of ribociclib
Ribociclib (LEE011) is an orally bioavailable and highly selective small molecule inhibitor of 
the CDK4/cyclin-D1 and CDK6/ cyclin-D3 enzyme complexes with IC50’s of 0.01 and 0.039 
μM in biochemical assays, respectively. Refer to LEE011 (ribociclib) [Investigator Brochure] 
for details.


Novartis
Confidential
Page 37
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
1.2.1.1
Nonclinical experience
1.2.1.1.1 Nonclinical pharmacology of ribociclib
In Jeko-1 mantle cell lymphoma (MCL) cells that overexpress cyclin D1 as a result of the 
t(11;14) chromosomal translocation, ribociclib 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, ribociclib demonstrates dose-dependent target inhibition in the tumors. Ribociclib 
doses that induce >75% inhibition of pRb phosphorylation in this model are associated with 
complete tumor regression (see LEE011 (ribociclib) [Investigator Brochure]). Ribociclib 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 ribociclib requires the presence of functional pRb. Refer to LEE011 (ribociclib) 
[Investigator Brochure] for more details.
A panel of human breast cancer cell lines was treated with increasing doses of ribociclib and 
dose-dependent inhibition of proliferation was observed across the panel with enhanced activity 
against ER+ breast cancer cell lines with IC50 < 1µM being observed for most ER+ breast 
cancer lines (Novartis internal data, LEE011 (ribociclib) [Investigator Brochure Figure 4-3]). 
Ribociclib as a single agent has been shown to have activity in preclinical models of ER+ breast 
cancer (Novartis internal data). In vivo studies of ribociclib in combination with endocrine 
therapy have demonstrated increased anti-tumor activity of the combination for letrozole, 
fulvestrant and tamoxifen compared to single agent ribociclib activity([Investigator Brochure];
O’Brien et al. 2014;) which support the proposed combination.
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. 


Novartis
Confidential
Page 38
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Generally all changes demonstrated either reversibility or a clear tendency towards reversibility.
In the rat, there was no evidence of teratogenicity however ribociclib was embryofetotoxic. 
Data from a rabbit embryofetal development study, shows that ribociclib is teratogenic in the 
rabbit in the absence of maternal toxicity.
1.2.1.1.3 Nonclinical pharmacokinetics and metabolism of ribociclib
The pharmacokinetics (PK) of ribociclib was investigated in mouse, rat, dog and monkey. 
Ribociclib 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%) andcynomolgus 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 ribociclib 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.
In vitro, ribociclib was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 
CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. Ribociclib may inhibit
CYP3A4 under therapeutic conditions. No induction of CYP1A2, CYP2B6 or CYP3A4 was 
observed. The in vitro inhibitory potency of ribociclib 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 ribociclib is dominated by oxidative metabolism mainly via 
CYP3A4 with a minor contribution by flavin-containing monooxygenase 3 (FMO3). The 
elimination of ribociclib may be affected by co-administered drugs that inhibit or induce 
CYP3A4. Although ribociclib 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 ribociclib.
1.2.1.2
Clinical experience
Ribociclib 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 


Novartis
Confidential
Page 39
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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. Ribociclib 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 (ribociclib) [Investigator Brochure].
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 LEE011 (ribociclib) [Investigator Brochure] for more details.
Ribociclib is being evaluated in a combination with fulvestrant and BKM120 (buparlisib) in an 
ongoing study [CLEE011X2108] as detailed in Section 1.2.3.
The combination of ribociclib (600 mg) with letrozole (2.5 mg once daily) is being evaluated 
in an ongoing study [CLEE011A2301]; as of 12-Feb-2015, the study has enrolled 668 patients.
The safety of 664 patients was reviewed at the most recent DMC on 07-Oct-2015, with the 
recommendation to continue the study unchanged.
1.2.1.2.1 Clinical safety of ribociclib
Single agent therapy:
As of 15-Jun-2015, 157 patients have been treated with single agent ribociclib in the first-in-
human (FIH) phase I study; 85 patients have been treated in the initial dose escalation part for 
the 3 weeks 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 ribociclib and, 7 patients were 
enrolled in the liquid formulation cohort.
Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
ribociclib 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); adverse events (AEs) (7 [5%] patients); death (2 
[1.5%] patients); withdrawal of consent (3 [2%] patient); and loss to follow up (1 [1%] patient).
The most frequently reported AEs (≥10%), regardless of grade, causality and ribociclib 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 


Novartis
Confidential
Page 40
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 ribociclib 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 1-1 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 ribociclib refer to the LEE011 (ribociclib) 
[Investigator Brochure].
Table 1-1
Serious adverse events with a suspected causal relationship with 
ribociclib single agent
Serious suspected adverse events which have occurred with ribociclib (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
Events in italic font indicate those events which are newly included since the previous edition 
of the reference safety information.
Refer to LEE011 (ribociclib) [Investigators Brochure] for more details.
1.2.1.2.2 Clinical efficacy of ribociclib
Preliminary anti-tumor activity of ribociclib from an ongoing Phase I trial [CLEE011X2101]
was assessed across all dose levels (50 mg – 1200 mg). Out of 114 evaluable subjects as of 24-
Apr-2014, 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 (ribociclib) 
[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, 


Novartis
Confidential
Page 41
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 ribociclib 
[Investigators Brochure] for more details.
1.2.1.2.3 Clinical pharmacokinetics of ribociclib
The pharmacokinetics of ribociclib 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 ribociclib, peak plasma concentrations 
(Cmax) are achieved at approximately 1-4 hours post-dose. Ribociclib 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 
ng*h/mL).
At this dose, inter-patient variability in Cmax and AUC is 62% and 66%, 
respectively, as assessed by geometric 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. Refer to the LEE011 (ribociclib) 
[Investigators Brochure] for more details.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 ribociclib (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 ribociclib 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 ribociclib, 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. Refer to the LEE011 (ribociclib) 
[Investigators Brochure] for more details.
A DDI study with ritonavir (a strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 
inducer) was conducted in 48 healthy subjects [CLEE011A2101]. Compared to ribociclib alone, 
ritonavir (100 mg bid for 14 days) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-
fold, respectively, following a single oral dose of 400 mg ribociclib. Cmax and AUClast for 


Novartis
Confidential
Page 42
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
LEQ803 decreased by 96% and 98%, respectively. These results demonstrated that concurrent 
use of strong CYP3A4 inhibitors may markedly increase ribociclib exposure and are prohibited.
Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib Cmax 
and AUCinf by 81% and 89%, respectively, following a single oral dose of 600 mg ribociclib. 
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 ribociclib 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 
ribociclib (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 ribociclib (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 ribociclib on 
caffeine was minimal, with Cmax decreased by approximately 10% and AUCinf increased 
slightly by 20%. Based on these data, ribociclib (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. Ribociclib (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 (ribociclib) [Investigators Brochure] for more details.
1.2.2
Overview of fulvestrant
Fulvestrant is a unique estrogen receptor down regulator with no known agonist effects (Addo 
et al 2002). Fulvestrant’s mechanism of action is distinct from other endocrine agents (Wakeling 
et al 2000); it binds, blocks and, unlike tamoxifen or other SERMs, degrades the estrogen 
receptor, completely inhibiting estrogen receptor signaling. As a result, there is less chance of 
the estrogen receptor being activated by alternative pathways that are believed to cause 
resistance (e.g. growth factor-mediated mechanisms) (Nicholson et al 2005).
Fulvestrant (FASLODEX®) is a first in class endocrine agent that was approved at the dose of 
500mg for the treatment of postmenopausal women with HR+ advanced BC who have failed 
on prior anti-estrogen therapy. This approval was based on data from the CONFIRM study 
which demonstrated that 500 mg of fulvestrant showed better progression free survival 
compared to 250 mg for postmenopausal women with estrogen receptor–positive advanced 
breast cancer who experienced progression after prior endocrine therapy (Di Leo 2010; Di Leo 
2014). More specifically, in that trial, subgroup analysis showed that PFS was prolonged in 
patients who had recurred or relapsed during anti-estrogen therapy (median PFS 8.6 vs. 5.8 
months; HR 0.76; 95% CI: 0.62-0.94; p=0.013) or during AI therapy although not reaching 
statistical significance for the latter (median PFS 5.4 vs. 4.1 months; HR 0.85; 95% CI: 0.67-
1.08; p=0.195) (FASLODEX® prescribing information). Median OS was 26.4 months for 
fulvestrant 500 mg and 22.3 months for 250 mg (HR 0.81; 95% CI 0.69–0.96; p=0.02) (DiLeo 
2014).
Fulvestrant has also been investigated as a first-line therapy in the phase II, randomized FIRST 
study (Fulvestrant First-Line Study Comparing Endocrine Treatments) where fulvestrant 500 


Novartis
Confidential
Page 43
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
mg was compared to anastrozole in postmenopausal women with HR+ advanced breast cancer 
who received no prior endocrine therapy. When 79.5% of patients had discontinued study 
treatment, the median TTP for fulvestrant was 23.4 months versus 13.1 months for anastrozole 
(HR 0.66; 95% CI:0.47, 0.92; p=0.01). The best overall response to subsequent therapy and
clinical benefit rate for subsequent endocrine therapy were similar (Robertson 2012). Recent 
median OS data, with analyses conducted at 66.8% maturity showed 54.1 months for fulvestrant 
and 48.4 months for anastrozole (HR 0.70; 95% CI 0.5-0.98; p=0.041) (Ellis et al 2015, 
Robertson SABCS abstract 2014). Fulvestrant at the dose of 250 mg has also demonstrated 
efficacy similar to tamoxifen in the first line setting of HR+ breast cancer tumors (78% of the 
study population in a preplanned subset analysis) where median TTP was 8.2 months for 
fulvestrant and 8.3 months for tamoxifen (HR 1.10; 95% CI: 0.89- 1.36; p=0.39) (Howell 2004). 
The difference in these TTPs for fulvestrant may be attributed to the higher dose of 500 mg 
since findings from clinical, biological studies and PK modeling suggested that fulvestrant at 
an increased dose could further increase the clinical efficacy (Robertson 2004). FALCON
(Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer; 
clinicaltrials.gov identifier: NCT01602380) is a randomized phase III study comparing 
fulvestrant (500 mg) with anastrozole for postmenopausal women who have not previously 
been treated with any hormonal therapy in the metastatic setting. This study has completed 
enrollment in September 2014 and results are still pending.
Clinical safety of fulvestrant
The most common clinically significant adverse reactions occurring in ≥5% of patients
receiving fulvestrant 500 mg were: injection site pain, nausea, bone pain, arthralgia, headache, 
back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal 
pain, cough, dyspnea and constipation. Please refer to the local SmPC for pooled safety data for 
fulvestrant 500 mg data.
1.2.2.1
Clinical pharmacokinetics of fulvestrant
Fulvestrant is slowly absorbed after administration of 500 mg intramuscularly (long-acting 
formulation). Maximum plasma concentrations are reached after about 5 days. Steady-state is 
achieved within the first month of dosing, if an additional dose is given 2 weeks after the initial 
dose. At steady-state there is more than a 2-fold difference between mean Cmax and Cmin. 
After intramuscular administration, the exposure is approximately dose proportional in the dose 
range of 50 to 500 mg. Fulvestrant is subject to extensive and rapid distribution and is 
eliminated mainly by metabolism. The major route of excretion is via the feces with less than 
1% being excreted in the urine. Fulvestrant has a high clearance, suggesting that it is a drug 
with high extraction ratio. The terminal half-life after intramuscular administration is governed 
by the absorption rate and was estimated to be 40-50 days.
Increased exposure to fulvestrant was observed in patients with moderate hepatic impairment 
(Child-Pugh class B). Fulvestrant has not been administered to patients with severe hepatic 
impairment (Child-Pugh class C) (FASLODEX® prescribing information). Therefore, patients 
with Child-Pugh class B and C will not be enrolled. No dose reductions for fulvestrant will be 
allowed in study CLEE011F2301.


Novartis
Confidential
Page 44
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
1.2.3
Overview of ribociclib in combination with fulvestrant
Ribociclib and fulvestrant have the following toxicities in common: nausea, fatigue, vomiting, 
decreased appetite, constipation, dyspnea, cough, AST increase, headache, and back pain. 
These overlapping adverse events are expected to be tolerable and manageable.
In addition, there are no known drug interactions with fulvestrant. In vitro studies showed no 
relevant inhibition of the major CYP enzymes, including CYP1A2, 2C9, 2C19, 2D6 or 3A4 by 
fulvestrant. The lack of inhibition of CYP3A4 was confirmed in an in vivo interaction study 
with midazolam. In addition, interaction studies with rifampicin (strong CYP3A4 inducer) and 
ketoconazole (strong 
CYP3A4 inhibitor) demonstrated no effect on fulvestrant 
pharmacokinetics (FASLODEX® prescribing information). Therefore, a drug-drug interaction 
(DDI) involving fulvestrant and ribociclib is unlikely to occur.
The combination of ribociclib and fulvestrant is currently being explored in study 
[CLEE011X2108]. This is an open-label Phase Ib/II study in postmenopausal women with 
locally advanced or metastatic HR+/HER2- BC. The phase Ib dose escalation includes triple 
combination arms of ribociclib + BKM120 (pan-PI3K) + fulvestrant and ribociclib + 
BYL719(PI3K-alpha) + fulvestrant and a dose confirmation arm with ribociclib + fulvestrant.
As of 05-Jun-2015 , a total of 13 patients have been treated with the combination of ribociclib
(600 mg daily on Day 1-21 of each 28-day cycle)  and fulvestrant (500 mg every 28 days with 
1 additional dose on Day 15 of Cycle 1) in study [CLEE011X2108]. 
Seven patients 
discontinued treatment, 1 adverse event was the reason for end of treatment and in the other 6 
patient due to progressive disease. All patients have completed the first 28 days cycle. Of these 
7 evaluable patients, there were no dose adjustments, interruptions or dose limiting toxicities. 
Grade 2/3 neutropenia was observed in 6 of the 7 patients. As of 04-Feb-2015, 5 patients are 
continuing to be treated with this combination, and 6 out of 7 patients have been exposed to the 
combination for more than 140 days. One patient met the dose limiting toxicity criteria wih a 
Grade 3 pulmonary embolism on Cycle 1. One patient discontinued after being hospitalized 
during Cycle 7 for Grade 4 atrial fibrillation, which was a serious adverse event and was 
suspected to be treatment related. Another patient discontinued at Cycle 5 due to progressive 
disease.
Table 1-2 contains the adverse events presented in more than 2 patients treated with the 
combination of ribociclib plus fulvestrant in [CLEE011X2108] and suspected to be study drug 
related.
Table 1-2
Adverse events suspected to be study drug related in 
[CLEE011X2108]
Table below is update with data including a cutoff incidence of more than 15%
All grades
Grade 3/4
Preferred term
n (%)
n (%)
-Total
13 (100)
11 (84.6)
NEUTROPENIA
9 (69.2)
8 (61.5)
FATIGUE
9 (69.2)
2 (15.4)
NAUSEA
6 (46.2)
0


Novartis
Confidential
Page 45
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
ANAEMIA
6 (46.2)
0
DECREASED APPETITE
5 (38.5)
0
WHITE BLOOD CELL COUNT
4 (30.8)
2 (15.4)
DIARRHOEA
4 (30.8)
0
VOMITING
3 (23.1)
0
THROMBOCYTOPENIA
3 (23.1)
0
ALANINE AMINOTRANSFERASE
2 (15.4)
1 (7.7)
ASPARTATE AMINOTRANSFERASE
2 (15.4)
1 (7.7)
PRURITUS
2 (15.4)
0
PLATELET COUNT DECREASED
3 (23.1)
0
DYSGEUSIA
2 (15.4)
0
ELECTROCARDIOGRAM QT
2 (15.4)
0
NEUTROPHIL COUNT DECREASED
2 (15.4)
2 (15.4)
BLOOD CREATININE INCREASED
2 (15.4)
0
LYMPHOCYTE COUNT DECREASED
2 (15.4)
0
ORAL PAIN
2 (15.4)
0
Preliminary results of ribociclib in combination with fulvestrant suggest that this combination 
is safe and tolerable. Preliminary PK analysis suggests that ribociclib (600 mg) and fulvestrant 
(500 mg) exposures were not affected in combination treatment. The best response for all 7 
(100%) patients has been stable disease thus far. 
Refer to the LEE011 (ribociclib) [Investigators Brochure] for more details.
2
Rationale
2.1
Study rationale and purpose
The rationale for combining ribociclib with fulvestrant is based on findings that a significant 
number of HR+, HER2-negative breast cancer patients are expected to have, or develop, 
resistance to endocrine therapies that have been given in the adjuvant or first line metastatic 
setting, and CDK4/6 pathway alterations appear to play a key role in the development of this 
resistance. Two related emerging mechanisms of endocrine resistance include the decoupling 
of cell cycle control from ER-signaling and the utilization of alternate growth signaling 
pathways such as the PI3K pathway (Miller et al 2011; Lange and Yee 2011). By targeting two 
distinct pathways (ER antagonism by fulvestrant, CDK4/6 pathway inhibition by ribociclib), it 
is hypothesized that this combination will result in prolonged progression free survival. 
Preclinically, improved responses have been shown with the addition of ribociclib to fulvestrant 
in various cell lines. Clinical experience has helped characterizing ribociclib safety profile and 
supported the initiation of phase III trials. A large number of patients have now been treated 
with ribociclib in phase I - III trials with an extensive number of patients having been exposed 
to doublet combination of ribociclib with endocrine therapy ([CLEE011X2107], 
[CLEE011X2108], [CLEE011X2106] [CLEE011A2301]).
Preclinical data (Novartis internal data, Figure 2-1), along with preliminary clinical safety and 
tolerability data from study [CLEE011X2108] (Section 1.2.3) for the combination of ribociclib 
and fulvestrant, support the conduct of this study.


Novartis
Confidential
Page 46
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Figure 2-1
Ribociclib plus fulvestrant in ER+ breast cancer xenograft models
The purpose of this study is to determine whether treatment with ribociclib plus fulvestrant will 
result in an improved clinical benefit compared to fulvestrant and placebo in men and 
postmenopausal women with HR+, HER2-negative advanced breast cancer who have received 
no or only one prior endocrine treatment for advanced disease.
2.2
Rationale for the study design
This is a randomized, placebo-controlled two-arm study with the objective to evaluate the 
efficacy and safety of adding ribociclib to fulvestrant in men and postmenopausal women with 
advanced breast cancer. The randomized, double-blind, placebo controlled, multicenter, parallel 
group design is the gold standard for phase III trials as it minimizes allocation bias, balancing 
both known and unknown prognostic factors in the assignment of treatments.
A randomization ratio (ribociclib+fulvestrant vs placebo+fulvestrant) of 2:1 is selected, since 
the efficacy and safety of fulvestrant is well characterized, a 2:1 randomization will allow a 
better evaluation of efficacy and safety of the ribociclib+fulvestrant combination. 
Randomization will be stratified by the following factors (see Section 4.1 for further details):
1. Lung or liver metastases (yes versus no)
2. Previous endocrine therapy
The stratification factors are selected because of their well-recognized prognostic value.
2.3
Rationale for dose and regimen selection
The ribociclib dose and regimen selected for this study is 600 mg daily 21 days on/7 days off. 
In the FIH study of single agent ribociclib in adult patients with solid tumors [CLEE011X2101], 
the MTD of ribociclib 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, low risk for QTcF prolongation, adequate 
exposure, and preliminary evidence of disease stabilization as single agent. In the phase III 
study of ribociclib/placebo (600 mg) combined with letrozole (2.5 mg once daily) in 
postmenopausal women with advanced breast cancer HR+ HER-2 negative [CLEE011A2301],


Novartis
Confidential
Page 47
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
the  DMC which took place on October 7, 2015 and reviewed safety of 664 patients  , 
recommended to continue the study without changes.
Fulvestrant will be administered at the dose according to its approved label, 500 mg IM as two 
250 mg 5 ml injections (one in each buttock) on days 1, 15, 29 and then monthly thereafter 
(FASLODEX® prescribing information).
Based on available data from preliminary results of patients treated with the combination of
ribociclib at 600 mg and fulvestrant at 500 mg in study [CLEE011X2108], the combination is 
tolerable and a DDI between ribociclib and fulvestrant is unlikely. Therefore, these doses will 
also be used in this study.
2.4
Rationale for choice of combination drugs
Recent clinical data indicate that inhibitors of CDK4/6 are active in advanced ER+ breast cancer. 
Fulvestrant is acknowledged as an acceptable therapy in the first-line metastatic setting (Cruz 
Jurado 2011) and is approved after failure to prior antiestrogen therapy. In this study, we 
propose to use ribociclib, which directly targets pRb to interfere with the proliferation cycle, in 
combination with fulvestrant to prolong PFS in HR+, HER2-negative postmenopausal women 
with advanced breast cancer who have received no prior therapy or only one line of prior 
endocrine treatment for advanced disease.
The rationale to combine ribociclib with fulvestrant is based on the following:

Preclinical data demonstrating additional benefit of the combination of CDK4/6 inhibition 
by ribociclib and estrogen pathway inhibition by fulvestrant compared to single agent 
activity (Section 2.1)

The efficacy of fulvestrant in this patient population (Section 1.2.2)

Preliminary safety findings of the combination of ribociclib and fulvestrant in study 
[CLEE011X2108]

The low likelihood of a drug-drug interaction between ribociclib and fulvestrant and 
preliminary PK data from [CLEE011X2108] suggesting no changes in exposures.
2.5
Rationale for choice of comparator drugs
Patients enrolled in the study will either be in first line or in second line for the treatment of 
their metastatic disease.
In first line setting, currently approved treatment options include tamoxifen, AI or letrozole in 
combination with palbociclib (Section 1.1.2).
The recently presented data from the FIRST study, conducted in HR+ HER2-negative advanced 
breast cancer patients with no prior endocrine therapy or with long DFS after adjuvant endocrine 
therapy, showed superiority of fulvestrant 500 mg compared to anastrozole (Robertson 2014, 
Ellis 2015). Despite methodological limitations linked to indirect comparisons, the benefit 
brought by fulvestrant over anastrozole appears to be of the same extent than the one brought 
by the addition of palbociclib to letrozole -the results of both studies are being confirmed by 
phase 3 trials (Falcon and Paloma 2). Taken together, these data support fulvestrant 500 mg as 
an acceptable therapy in the first-line metastatic setting.


Novartis
Confidential
Page 48
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
In second line setting, several acceptable options are available (NCCN 2.2015) and include 
Fulvestrant. In addition, Fulvestrant is currently approved for the treatment of HR+ MBC in 
postmenopausal women with disease progression following anti-estrogen therapy. Hence, 
fulvestrant is considered a standard therapy for patients who have progressed on or after 
treatment with other endocrine agents and who require a well-tolerated alternative therapy 
(Ciruelos 2014).
In conclusion, fulvestrant at the selected dose of 500 mg given intramuscularly at one month 
intervals, with an additional 500 mg dose given 2 weeks after the initial dose, is considered an 
appropriate comparator arm for this study.
2.6
Risks and benefits
2.6.1
Potential benefits to clinical trial participants
All patients enrolled in this trial will receive an active and valid endocrine therapy for first and 
second line treatment of men and post-menopausal women (see Section 2.5). They will be 
randomized to receive in addition ribociclib or placebo. Based on preclinical and preliminary 
clinical data (see Section 1.2.3), treatment with ribociclib in combination with fulvestrant is 
expected to be well tolerated and it is hypothesized that it will result in delayed disease 
progression by inhibiting proliferation of endocrine-resistant breast cancer cells.
2.6.2
Potential risks to clinical trial participants
Patients in this study will be carefully monitored for key toxicities that have been observed with 
ribociclib (see Section 1.2.1.2.1), fulvestrant (see Section 1.2.2) or the combination of both (see 
Section 1.2.3) with the following assessments (see Section 7): periodic laboratory, renal and 
liver function, urinalysis and ECG.
Risk will be further minimized by adherence to inclusion/exclusion selection criteria (see 
Section 5), avoidance of prohibited medication (see Section 6.6.3), close safety monitoring (see 
Section 8) and dose adjustment guidelines (see Section 6.5 and current fulvestrant prescribing 
information (FASLODEX® prescribing information). PK sampling will be conducted in 
patients to assess plasma concentration of the study drug to evaluate any potential drug 
interaction. 
An 
independent 
data 
monitoring 
committee 
(IDMC)
(see Section 8.6) will be constituted and will monitor safety, efficacy and available PK data as 
outlined in the protocol. A Steering Committee (SC) (see Section 8.7) will be established 
comprising of investigators and Novartis personnel participating in the trial to ensure 
transparent management of the trial according to the protocol. A Novartis Safety Management 
Team (SMT) periodically reviews and evaluates all emerging data across the ribociclib program 
for potential safety signal assessment in a timely manner.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


Novartis
Confidential
Page 49
Amended Protocol Version 03 (Clean)
Protocol No. CLEE011F2301
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To compare PFS between ribociclib in combination 
with fulvestrant to placebo in combination with 
fulvestrant among men and postmenopausal women 
with HR+, HER2-negative advanced breast cancer 
who received no or only one prior endocrine 
treatment for advanced disease
The primary end point is PFS based on local radiology assessments and 
using RECIST 1.1 criteria
Secondary
Refer to Section 10.5
To compare the two treatment arms with respect to 
overall survival.
Overall survival
To evaluate the two treatment arms with respect to 
overall response rate, clinical benefit rate, time to 
response and duration of response. 
ORR and as defined by RECIST 1.1. CBR, defined as percentage of 
patients with CR, PR or SD lasting 24 weeks or longer, TOR, DOR per 
RECIST 1.1
To evaluate the two treatment arms with respect to 
time to deterioration of ECOG performance status.
Time to definitive deterioration of ECOG performance status from 
baseline
To evaluate the safety and tolerability of ribociclib in 
combination with fulvestrant.
Frequency/severity of AEs, laboratory abnormalities
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
To characterize the pharmacokinetics (PK) of 
ribociclib (and relevant metabolites such as LEQ803) 
when given in combination with fulvestrant.
Concentration by time point for ribociclib (and relevant metabolites such 
as LEQ803)


Novartis
Confidential
Page 50
Amended Protocol Version 03 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 51
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
4
Study design
4.1
Description of study design
This is a randomized, phase III, double blind, placebo controlled, international study to 
determine the efficacy and safety of treatment with fulvestrant with ribociclib versus fulvestrant 
with placebo in men and postmenopausal women with HR+, HER2-negative advanced breast 
cancer. This study will consist of 4 phases: screening (up to 28 days), randomized treatment, 
post-treatment disease progression follow-up, and post-treatment survival follow-up.
Approximately 660 patients will be randomly assigned to one of the below treatment arms in a 
2:1 ratio.

Experimental arm (Arm A): fulvestrant (500 mg intramuscular [as two 5 mL injections] on 
Cycle 1 Days 1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + ribociclib (600 mg 
by mouth once daily for three weeks followed by one week break, in a 28-day cycle).
OR

Control arm (Arm B): fulvestrant (500 mg intramuscular [as two 5 mL injections] on Cycle 
1 Days 1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + placebo (by mouth once 
daily for three weeks followed by one week break, in a 28-day cycle).
Randomization will be stratified by the following factors:
1. Lung or liver metastases: (yes versus no)
2. Previous endocrine therapy according to the below definition:
A) Patients treatment naïve for metastatic/advanced disease include:
i.
Patients whose disease relapsed >12 months after completion of (neo)adjuvant 
endocrine therapy with no subsequent treatment for advanced/metastatic disease,
OR
ii.
Patients with de novo advanced/metastatic disease (no prior exposure to 
endocrine therapy).
B) Patients who received up to 1 line of treatment for metastatic/advanced disease 
include:
i.
Patients whose disease relapsed on or within 12 months from completion of (neo) 
adjuvant endocrine therapy, with no subsequent treatment for advanced/metastatic 
disease,
OR
ii.
Patients whose disease relapsed > 12 months from completion of (neo) adjuvant 
endocrine therapy, and progressed on or after subsequent endocrine treatment for 
advanced/metastatic disease,
OR
iii.
Patients with advanced/metastatic disease at the time of diagnosis that progressed 
on or after endocrine therapy for advanced/metastatic disease with no prior (neo) 
adjuvant treatment for early disease


Novartis
Confidential
Page 52
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Prior exposure to endocrine therapy subcategories included in groups A and B, were collated 
based on mPFS or TTP. Subcategory A grouped patients with PFS or TTP above 10 months 
(Paridaens et al. 2008; Mouridsen 2001; Robertson 2014; Finn 2015); whereas subcategory B 
grouped patients with shorter PFS or TTP around 4-6.5 months (Di Leo 2012; Dombernowsky 
1998; Buzdar 1998; Johnston 2012).
Patients will be treated until disease progression, unacceptable toxicity, or discontinuation from 
the study treatment for any other reason (see Figure 4-1).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.
Figure 4-1
Study Design
*Following Protocol Amendment 4, study participants are unblinded, with an opportunity for 
those patients still on study treatment in the placebo combination to cross-over to the LEE011 
combination. Cross-over is optional and will be conducted only upon documented consent of 
the study patient.
An Independent Data Monitoring Committee (IDMC) will be constituted and will monitor 
safety and efficacy as outlined in Section 8.6 and Section 10.7. A Steering Committee (SC) will 
be established comprised of investigators and Novartis personel participating in the trial to 


Novartis
Confidential
Page 53
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
ensure transparent management of the study according to the protocol as outlined in
Section 8.7.
If the study proceeds after a positive effect on PFS is declared (at final analysis of PFS), 
crossover to the experimental arm from the control arm is not permitted and investigators and 
patients will remain blinded to study treatment; all patients will continue to be followed for OS 
until the final OS analysis.
4.1.1
Screening phase
Men and postmenopausal 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 fulvestrant + ribociclib or fulvestrant + 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 tumor tissue will be retrieved. 
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. An eligibility 
review and confirmation will be embedded to the Interactive Response Technology (IRT) 
system. Please refer to and comply with detailed guidelines in the IRT manual. The IRT system 
will confirm the inclusion of eligible patients and randomize them in a 2:1 ratio to one of the 
two treatment groups described in 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). An end of treatment visit will be performed when 
patients permanently discontinue study treatment.
All patients will have PK sampling; a subset (of approximately 150 patients) will have sparse 
PK collections on 3 occasions while the remainder will have a single trough PK sample on 3 
occasions as detailed in Section 7.2.3.


Novartis
Confidential
Page 54
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Following protocol amendment 4, study participants will be unblinded, with an opportunity for 
those patients still in the study in the arm of placebo + fulvestrant to transition to the treatmentof 
ribociclib + fulvestrant. 
Crossover is optional and will be conducted only upon documented consent of the study patient
and protocol amendment 4 approval. A list of procedures to be performed is summarized in 
Table 7-1b.
4.1.3
Safety follow-up
After discontinuation of study treatment, all patients will be followed for safety, AEs and patient 
reported outcomes which will be collected until 30 days after last study therapy administration, 
except in case of death, loss to follow up or withdrawal of consent. For details please refer to 
Section 7.1.5.
4.1.4
Efficacy follow-up
Patients who discontinue treatment for reasons other than disease progression or withdrawal of 
consent for efficacy follow-up, will continue to be followed every 8 weeks for efficacy (i.e., 
tumor assessments and patient reported outcomes) 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. All scans will be acquired 
and analyzed for primary endpoint locally and will be sent to the CRO designated by Novartis 
for central imaging interpretation. If a patient starts a new anti-neoplastic treatment without 
withdrawing consent, the patient will continue to be followed for efficacy according to above 
specified protocol schedule until disease progression, death, withdrawal of consent, loss to 
follow-up, or subject/guardian decision. For further details please refer to Table 7-1a and Table 
7-1b and Section 7.1.6.
4.1.5
Survival follow-up
All patients will be followed for survival once they discontinue study treatment and tumor 
evaluations until the final number of OS events have been reached or the study is stopped for 
other reasons. Survival follow-up will be done every 12 weeks ± 1 week or earlier if a survival 
update is required to meet safety or regulatory needs. Survival information can be obtained by 
clinical visits or telephone calls (Section 7.1.7) until death, the patient is lost to follow-up, or 
the patient withdraws consent for survival follow-up.
4.2
Timing of interim analyses and design adaptations
There is no planned efficacy interim analysis for the primary PFS endpoint. Interim analysis of
the secondary endpoint of OS will be performed if PFS is statistically significant. as detailed in 
Section 10.5.1 and Section 10.7.2.


Novartis
Confidential
Page 55
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
4.3
Definition of end of the study
The end of the study for a given patient is defined as when the patient permanently discontinues 
study treatment with ribociclib + fulvestrant or placebo + fulvestrant and all the end of trial 
procedures are completed.
If the primary endpoint, PFS, is statistically significant at the final 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 the interim analysis 
for OS) and after all patients have discontinued study therapy and completed the safety follow-
up period (until 30 days after treatment discontinuation).
If the primary endpoint, PFS, is not statistically significant at the final PFS analysis then End 
of Study will be declared after all patients have discontinued study therapy and completed the 
safety follow-up period (until 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 with protocol amendment 4 and the statistically significant OS benefit demonstrated 
at the 2nd OS analysis, study participants will be unblinded with an opportunity for those patients 
still on study in the arm of placebo + fulvestrant to transition to arm of ribociclib + fulvestrant. 
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.
4.4
Early study termination
The study can be terminated at any time by Novartis. Should this be necessary, the patient 
should be seen as soon as possible and the assessments described in Section 7 for a discontinued 
or withdrawn patient should be performed. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development


Novartis
Confidential
Page 56
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
5
Population
5.1
Patient population
The study will include men and postmenopausal women with HR+, HER2-negative advanced 
(loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer who 
received no or only one line of prior endocrine treatment for advanced breast cancer.
Patients with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s best judgment will not be included in this 
study.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
The patients are not permitted to participate in any additional parallel investigational drug or 
device studies.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any screening procedures.
1. [Retired from protocol version 0.0]
1a. Patient is an adult male/female ≥ 18 years old at the time of informed consent and has 
signed informed consent before any trial related activities and according to local 
guidelines.
Note: sexually active males should use a condom during intercourse while taking drug and 
for 21 days after stopping medication and should not father a child in this period. A condom 
is required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via seminal fluid.
2. Female patients must be postmenopausal. Postmenopausal status is defined either by:

Prior surgical bilateral oophorectomy (with or without hysterectomy)

Age ≥60

Age <60 and amenorrheic 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 postmenopausal status (NCCN 2.2015). Ovarian radiation or 
treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) (goserelin 
acetate or leuprolide acetate) is not permitted for induction of ovarian suppression for the 
purpose of this trial.
3. 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 recent analyzed biopsy).


Novartis
Confidential
Page 57
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
4. Patient has HER2-negative breast cancer (based on most recent 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.
5. Patient must have either:

Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at 
a previously irradiated site may only be counted as a target lesion if there is a clear sign 
of progression since the irradiation).
OR

If no measurable disease is present, then at least one predominantly lytic bone lesion 
must be present (patients with no measurable disease and only one predominantly lytic 
bone lesion that has been previously irradiated are eligible if there is documented 
evidence of disease progression of the bone lesion after irradiation).
6. Patient has advanced (loco regionally recurrent not amenable to curative therapy (e.g. 
surgery and/or radiotherapy) or metastatic) breast cancer.
Patients may be :

newly diagnosed advanced/ metastatic breast cancer, treatment naïve

relapsed with documented evidence of relapse more than 12 months from completion 
of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease

relapsed with documented evidence of relapse on or within 12 months from completion 
of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease

relapsed with documented evidence of relapse more than 12 months from completion 
of (neo)adjuvant endocrine therapy and then subsequently progressed with documented 
evidence of progression after one line of endocrine therapy (with either an antiestrogen 
or an aromatase inhibitor) for advanced/metastatic disease

advanced/metastatic breast cancer at diagnosis that progressed with documented 
evidence of progression after one line of endocrine therapy (with either an antiestrogen 
or an aromatase inhibitor)
Note: Patient who relapsed with documented evidence of relapse on/or within 12 months from 
completion of (neo)adjuvant endocrine therapy and then subsequently progressed with 
documented evidence of progression after one line of endocrine therapy (with either an 
antiestrogen or an aromatase inhibitor) for metastatic/advanced disease will NOT be included 
in the study.
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
8. [Retired from protocol version 0.0]
8a. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory for eligibility):

Absolute neutrophil count ≥ 1.5 × 109/L

Platelets ≥ 100 × 109/L

Hemoglobin ≥ 9.0 g/dL

INR ≤1.5

Serum creatinine < 1.5 mg/dL


Novartis
Confidential
Page 58
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Total bilirubin < ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.

Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver metastasis, 
who are only included if the AST is < 5 × ULN

Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver metastasis, 
who are only included if the ALT is < 5 × ULN

Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements before the first dose of study medication:

Sodium

Potassium

Magnesium 

Total Calcium (corrected for serum albumin)
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s best judgment.
2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant 
chemotherapy), fulvestrant or any CDK4/6 inhibitor.
3. Patients has received prior neoadjuvant/adjuvant treatment with anthracyclines at 
cumulative doses of 450mg/m² or more for doxorubicin or 900 mg/m² or more for 
epirubicin.
4. Patient with a known hypersensitivity to any of the excipients of ribociclib or fulvestrant.
5. Patient with inflammatory breast cancer at screening.
6. Patient is concurrently using other anti-cancer therapy.
7. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects.
8. Patients with Child pugh score B or C.
9. 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.
10. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI 
CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of 
alopecia are allowed to enter the study.
11. Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 
weeks prior to randomization, and who has not recovered to grade 1 or better from related 
side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% (Ellis 
1961) of the bone marrow was irradiated.
12. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with 
the exception of adequately treated, basal or squamous cell skin carcinoma or curatively 
resected cervical cancer.


Novartis
Confidential
Page 59
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
13. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria:

At least 4 weeks from prior therapy completion (including radiation and/or surgery) to 
starting the study treatment.

Clinically stable CNS tumor at the time of screening and not receiving steroids and/or 
enzyme inducing anti-epileptic medications for brain metastases.
14. 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).
15. Patient has a known history of HIV infection (testing not mandatory)
16. Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol: (e.g. chronic 
pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or 
viral infections, etc.)
17. [Retired from protocol version 0.0]
17a.
Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality including any of the following:

History of angina pectoris, symptomatic pericarditis, or coronary artery bypass graft 
(CABG), myocardial infarction 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)

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

Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by 
safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting 
study drug) 

Inability to determine the QTcF interval 

Clinically significant cardiac arrhythmias including but not limited to (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)

Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg

Bradycardia (heart rate < 50 bpm at rest), by ECG (mean of triplicate) and pulse.

Tachycardia (heart rate > 90 bpm at rest), by ECG (mean of triplicate) and pulse.

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 screening ECG (mean of triplicate ECGs).


Novartis
Confidential
Page 60
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
18. Patient is currently receiving any of the following substances and cannot be discontinued 7 
days prior to Cycle 1 Day 1:

Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges.

Medications that have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5.

Herbal preparations/medications, dietary supplements (except vitamins).
19. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical applications
(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular).
20. Participation in a prior investigational study within 30 days prior to enrollment or within 5-
half lives of the investigational product, whichever is longer.
21. Not able to understand and to comply with study instructions and requirements.
6
Treatment
6.1
Study treatment
For this study, the term “investigational drug” refers to Novartis study drug ribociclib. 
Fulvestrant is also being used in this study. Study treatment in this study refers to the 
combination of drugs in each of the study arms and includes ribociclib/placebo and fulvestrant.
Ribociclib will be supplied by Novartis or its designee as 200 mg hard gelatin capsules as 
individual patient supply packaged in bottles.
Fulvestrant will be procured locally according to local practice and regulation, or supplied by 
Novartis (or its designee). Storage conditions are described in the medication label. Medication 
labels will comply with the legal requirements of each country and be printed in the local 
language.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
The study met its primary efficacy endpoint (PFS) at the time of the primary analysis. It also 
met the 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 and are currently allocated to 
the placebo + Fulvestrant arm, will be given the opportunity to transition to the ribociclib + 
Fulvestrant combination. 
Unblinded study treatment period will end once a patient discontinues from the study treatment 
for any reason or the end of study (EOS) is declared, whichever occurs first.  


Novartis
Confidential
Page 61
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Following protocol amendment 4 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 reference to placebo has been kept in places in the protocol to avoid
confusion.
6.1.1
Dosing regimen
All eligible patients will be randomized starting from Cycle 1 Day 1 to receive either:

Fulvestrant + ribociclib

Fulvestrant + placebo
Ribociclib or 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 ribociclib or placebo.
Fulvestrant will be administered intramuscularly into the buttocks slowly (1-2 minutes per 
injection) as two 5 mL injections, one in each buttock, on Cycle 1 Day 1 (C1D1), Cycle 1 Day 
15 (C1D15), Cycle 2 Day 1 (C2D1) and every 28 days thereafter (i.e., the first day of each 28 
day cycle) as per the (FASLODEX® prescribing information). There will be no “rest” in the 
fulvestrant schedule.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
fulvestrant
ribociclib/placebo
Two 5ml injections for i.m. 
administration
Capsule for oral use
500 mg
600 mg
Dosed every 28 days (Cycle n Day 1) with 1 
additional dose on Day 15 of Cycle 1
Once daily; days 1 to 21 in a 28-day Cycle
The study drugs will be administered as a flat-fixed dose and not by body weight or body surface 
area. There shall be no breaks between dosing cycles. A complete cycle of treatment is defined 
as 28 days. All study treatment drugs should be administered as described below in Section 
6.1.1.1 and Section 6.1.1.2.
The investigator or responsible site personnel will 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:

On scheduled visit days, patients must take study treatments in the clinic under the 
supervision of the Investigator or designee. On all other days patients will take 
ribociclib/placebo at home.

Patients should be instructed to take the study treatment of ribociclib/placebo capsules 
together with a large glass of water (~250 mL or ~8 oz) once a day at the same time each 
day. For the first cycle, patients must take ribociclib/placebo in the morning due to PK 
assessments. Once the PK assessments have been completed, patients can determine if 


Novartis
Confidential
Page 62
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
they prefer am or early afternoon dosing but should maintain a consistent time regardless 
of am or early afternoon 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 fasting lab assessments and for sparse 
PK collection.

Patients will be instructed to swallow the capsules whole and not to chew, crush or open 
them.

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 
6.6.1.4 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/pummelos,
starfruit, Seville oranges or products containing their juice 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 ribociclib.
Orange juice is allowed.

Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or 
those with a known risk of QT prolongation are not permitted. 

Multivitamins are permitted.
6.1.1.2
Additional guidelines for fasting lab assessments and sparse PK
Fasting considerations for lab assessments (e.g. glucose and lipid profile)

The patient should be fasting overnight (i.e., at least 8-12 hours prior to the blood 
collection) for all visits with fasting glucose, lipid profile sampling
 

Water is allowed during all fasting periods; however coffee, tea and juice are not 
permitted during the fasting period.
Meal considerations for sparse PK collection

Only for the sparse PK group, the meal condition (fasting, low fat, high fat) must be 
recorded on the eCRF within ± 30 minutes of the dose on C1D15 and C2D15. The meal 
condition is an estimate; however guidance is provided below.

On C1D15 and C2D15, when PK is paired with ECG assessments, patients may consume 
breakfast only after fasted pre-dose blood samples (fasting glucose, fasting lipid profile) 
have been collected.

Pre-dose PK should be collected approximately 24 hrs after the last dose (± 2 hrs) and 
immediately before the next dose.

A high-fat meal typically contains 800-1000 calories with approximately 50% of the 
calories coming from fat (500-600 calories) (FDA Guidance for Industry for Food-effect 
Bioavailability and Fed Bioequivalence Studies, December 2002). An example of a high-


Novartis
Confidential
Page 63
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
fat meal could be two eggs, 2 slices of bread, 1 tablespon butter, 1 tablespoon jelly, 3 strips 
of bacon, 4 ounces of hash brown potato, and 8 ounces of whole milk. A low-fat meal could 
be approximately 300-500 calories with approximately 25% of the calories coming from fat 
(75-125 calories) and could include 2 slices of bread, 1 tablespoon light fat margarine, 1 
tablespoon jelly, and 8 ounces of skim milk (USDA National Nutrient Database for Standard 
Reference, 2010).
6.1.1.3
Fulvestrant dosing
Fulvestrant 500 mg will be given after randomization at Cycle 1 Day 1, at Cycle 1 Day 15 (with 
a ± 3 day window) and then at Day 1 of each subsequent cycle during the randomized treatment 
phase (with ± 3 day window). Fulvestrant is administered intramuscularly into the buttocks 
slowly as two 5mL injections, one in each buttock. No dose modification of fulvestrant is 
planned in this study.
For information on fulvestrant and management of related adverse events, refer to the
FASLODEX® SmPC or local Prescribing Information.
6.1.2
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.5 Dosing modification.
Patients who permanently discontinue fulvestrant for any reason must discontinue 
ribociclib/placebo, and move to End of Treatment phase, but will remain on study for follow-
up evaluations (i.e. tumor follow-up and patient reported outcomes). Patients who permanently 
discontinue ribociclib/placebo may continue on the study on fulvestrant per investigator’s 
discretion and will continue to be followed for safety and/or efficacy.
6.1.3
Ancillary treatments
Not applicable.
6.1.4
Rescue medication
Not applicable.
6.1.5
Treatment duration
Patients will be treated until disease progression (radiologically documented according to 
RECIST 1.1) or until discontinuation of study treatment due to any other reason 
(see Section 7.1.5).
6.2
Dose escalation guidelines
Not applicable


Novartis
Confidential
Page 64
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
6.3
Patient numbering, treatment assignment or randomization
6.3.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.) that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface 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.
6.3.2
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 2:1.
Randomization will be stratified by the following factors:
1. Lung or liver metastases: (yes versus no)
2. Previous endocrine therapy
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 Global Clinical Supply (GCS) 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 4, 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 transition to the LEE011 combination. 


Novartis
Confidential
Page 65
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Those patients on the placebo arm who do not wish to cross-over from placebo to LEE011 can 
remain on their current treatment allocation (i.e. fulvestrant alone).
All of the study treatment cross-over registration and dispending will be managed by the study 
IRT system. After transition to the investigational treatment, placebo dispensing in IRT will 
stop. Comparator treatment (i.e. fulvestrant) will continue to be managed locally. 
6.3.3
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 (ribociclib or ribociclib 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 in the case of patient emergencies (Section 
8.3), for regulatory reporting purposes and at the conclusion of the study.
In rare cases when unblinding occurs because of emergency patient management, the actual 
treatment arm will not be communicated to any of the Novartis employees involved in running 
the trial in order to remain blinded.
An independent statistical group (external to Novartis), not involved in the trial conduct, will 
prepare data reports for the DMC. An independent clinical pharmacologist will analyze the data 
from patients with PK sampling if the data were to be presented at the DMC meetings. Details 
will be presented in the DMC charter.
Prior to the release of protocol amendment 4, the study met both its primary and secondary 
endpoints. Given the demonstrated survival benefit from LEE011 treatment, patients will be 
unblinded to their treatment allocation. 
6.4
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 ribociclib/placebo on an outpatient basis. The investigator shall provide the patient 
with instructions for ribociclib/placebo administration according to the protocol.
Fulvestrant should be dispensed according to local prescribing information and practice.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study treatment as per protocol. Study treatment will be dispensed to the patient by authorized 


Novartis
Confidential
Page 66
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.
6.4.1
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 6-2
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
ribociclib or placebo
Capsules in bottles
Labeled as ‘LEE011/placebo’
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.
fulvestrant
Refer to local product information
Refer to local product information
6.4.2
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 [ribociclib Investigators Brochure].
Study treatments will be procured locally according to local practice and regulation, or supplied 
by Novartis (or its designee).
6.4.3
Study drug compliance and accountability
6.4.3.1
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 ribociclib in plasma.


Novartis
Confidential
Page 67
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
6.4.3.2 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.
6.4.3.3 Handling of other study treatment
Not applicable.
6.4.4
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.
6.5
Dose modifications
6.5.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. These changes must be 
recorded on the Dosage Administration Record CRF.
6.5.1.1
Fulvestrant
The established clinical dose of fulvestrant (500 mg) will be used in each arm and no dose 
modification of fulvestrant is planned in this study (Table 6-3). For information on fulvestrant 
and management of related adverse events, refer to the FASLODEX® SmPC or local 
Prescribing Information.
6.5.1.2
Ribociclib/placebo
Recommendations for dose reduction, interruption or discontinuation of ribociclib in the 
management of study drug related adverse reactions are summarized in Table 6-4, Table 6-5, 
Table 6-6, Table 6-7 and Table 6-8. No dose modification for fulvestrant is permitted.


Novartis
Confidential
Page 68
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table 6-3
Dose modification guidelines
Ribociclib/placebo ( 3 weeks on/1 
week off schedule) 
Fulvestrant 
Dose
Number of capsules
& strength
Dose
Number of injections & 
strength
Starting dose
600 mg
3 x 200 mg capsules
500 mg
2 x 250mg (5 mL) injections
First dose reduction
400 mg
2 x 200 mg capsules
No dose modification allowed
Second dose reduction
200 mg
1 x 200 mg capsules
No dose modification allowed
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 6-4, Table 6-5, Table 6-6, Table 6-7 and Table 6-8 or listed in Section 7.1.3, treatment 
must be discontinued.
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 of the following criteria 
are met:

A treatment decision was made based on the local results, or

Local lab results document an adverse event not reported by the central lab, or

Local lab results document an adverse event severity is worse than the one reported by the 
central lab, or

There are no concomitant central results available.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used.
Table 6-4
Ribociclib/Placebo dose adjustment and management 
recommendations for hematological adverse reactions (CTC AE v4.03)
The results of the local laboratory will be recorded in the eCRF if any of the 
following criteria are met:
Toxicity/Grade
Dose Adjustment and Management 
Recommendations
Thrombocytopenia
Grade 1(≥75 x 109/L)
No dose adjustment required.
Grade 2 (≥50 x 109/L – <75 x 109/L)
Dose interruption until recovery to grade 1.
Re-initiate ribociclib/placebo at the same dose.
Grade 3 (≥25 x 109/L - <50 x 109/L)
Dose interruption until recovery to grade 1.
Re-initiate ribociclib/placebo at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption 
until recovery to grade 1 and reduce ribociclib/placebo to 
the next lower dose level.


Novartis
Confidential
Page 69
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Toxicity/Grade
Dose Adjustment and Management 
Recommendations
Grade 4(<25 x 109/L)
Dose interruption until recovery to grade 1.
Re-initiate ribociclib/placebo at the next lower dose level.
If toxicity recurs at grade 4: discontinue ribociclib/placebo.
Absolute neutrophil count (ANC)
Grade 1 (≥1.5 x 109/L)
No dose adjustment required.
Grade 2 (≥1.0 - <1.5 x 109/L)
No dose adjustment required.
Grade 3 (≥0.5 - <1.0 x 109/L)
Dose interruption until recovery to ≥1.0 x 109/L.
Re-initiate ribociclib/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 ribociclib/placebo dose 
to the next lower dose level.
Grade 4 (<0.5 x 109/L)
Dose interruption until recovery to ≥ 1.0 x 109/L.
Re-initiate ribociclib/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 
ribociclib/placebo at the next lower dose level.
Febrile neutropenia
Grade 3
ANC <1.0 x 109/L with a single temperature 
of >38.3 ºC (101 ºF) or a sustained temperature 
of ≥38 ºC (100.4 ºF) 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 
ribociclib/placebo.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue ribociclib/placebo.
Anemia
(Hemoglobin)
Grade 1 (≥10.0 – LLN g/dL)
No dose adjustment required.
Grade 2 (≥8.0 – <10.0 g/dL)
No dose adjustment required.
Grade 3 (<8.0 g/dL)
Dose interruption until recovery to grade 2.
Re-initiate ribociclib/placebo at the same dose.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue ribociclib/placebo.
Table 6-5
Ribociclib/placebo dose adjustment and management 
recommendation for hepatic toxicities (CTC AE v4.03)
Please refer to Section 6.5.1.2.1 for additional information.
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)
Maintain dose level with LFTs monitored bi-weekly.
Grade 2 (> 1.5 – 3.0 x ULN) 
Dose interruption of ribociclib/placebo
If resolved to ≤ grade 1 in ≤ 21 days, then maintain 
dose level
If resolved to ≤ grade 1 in > 21-28 days or toxicity 
recurs, then reduce 1 dose level
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 


Novartis
Confidential
Page 70
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
If toxicity recurs after two dose reductions, or recovery 
to ≤ grade 1 is > 28 days, discontinue ribociclib/placebo
Grade 3 (> 3.0 – 10.0 x ULN) 
Dose interruption of ribociclib/placebo, until  resolved to 
≤ grade 1, then lower 1 dose level of ribociclib/placebo
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
If resolved to ≤ grade 1 in > 28 days or toxicity recurs, 
discontinue ribociclib /placebo
Grade 4 (> 10.0 x ULN)
Discontinue ribociclib/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 liver metastases, 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, other 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.
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)
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or bi-weekly 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 ribociclib/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 
ribociclib/placebo 
Increase from baseline grade 0 or 1 to grade 3 (> 
5.0 – 20.0 x ULN)
Dose interruption of ribociclib/placebo until resolved to 
≤ baseline grade, then lower 1 dose level of 
ribociclib/placebo
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
If recovery to ≤ baseline grade is > 28 days, discontinue 
ribociclib/placebo
If toxicity recurs, discontinue ribociclib/placebo
Increase from baseline grade 2 to grade 3 (> 5.0 –
20.0 x ULN)
Dose interruption of ribociclib until resolved to ≤ 
baseline grade, then lower 1 dose level of 
ribociclib/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 
ribociclib./placebo
Grade 4 (> 20.0 x ULN)
Discontinue ribociclib/placebo
AST or ALT and concurrent Bilirubin


Novartis
Confidential
Page 71
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
For patients with normal ALT and AST and total 
bilirubin at baseline: AST or ALT > 3 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 >3.0x ULN] OR [AST or ALT 8.0 x 
ULN]- whichever is lower- combined with [total 
bilirubin >2 x baseline AND >2.0 x ULN]
Discontinue ribociclib/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.
6.5.1.2.1 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. 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. 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 the following LFTs: albumin, ALT, AST, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 
2 or higher), creatine 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. After dose 
resumption repeat liver enzyme and bilirubin tests twice weekly during the first 2 weeks, 


Novartis
Confidential
Page 72
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
afterwards the 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.

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.

Obtaining a 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. Results of tests as well as other clinically important information will be recorded 
in the eCRF.
6.5.1.2.2 Additional follow-up for QTcF prolongation
Table 6-6
Ribociclib/placebo dose adjustment and management 
recommendation 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 of the normal range, interrupt ribociclib/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 
ribociclib/placebo.
1*
QTcF 450-480 ms
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment 
required.


Novartis
Confidential
Page 73
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
2*
QTcF 481-500 ms
Interrupt ribociclib/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 <481 ms. 
Restart ribociclib/placebo with dose reduced by 1 dose level. Refer to Table 
6-31 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.
3
QTcF ≥ 501 ms on at least two 
separate ECGs
Interrupt ribociclib/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 indicated until the QTcF returns to < 481 
ms.

If QTcF returns to < 481 ms, ribociclib/placebo will be reduced by 1 
dose level. Refer to Table 6-3 for dosing schedule.

If QTcF remains ≥481 ms after performing steps 1-4 as directed in 
“For All Grades” discontinue ribociclib/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 ribociclib/placebo
4*
[QT/QTcF ≥ 501 or > 60 ms 
change from baseline]
and
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia]
Discontinue ribociclib/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 
Table 6-7
Ribociclib/placebo dose adjustment and management 
recommendation for ILD/pneumonitis (CTCAE v4.03)
Grade
Dose Adjustment and Management Recommendations
1
(asymptomatic)
No dose adjustment required. Initiate appropriate medical therapy and monitor as clinically 
indicated.
2
(symptomatic)
Interrupt ribociclib dose until recovery to Grade ≤1, then resume ribociclib at the next lower 
dose level*. 
3 and 4
(severe)
Discontinue ribociclib
*An individualized benefit-risk assessment should be performed before resuming ribociclib
6.5.1.2.3 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 ribociclib/placebo administration, correct electrolytes with supplements or appropriate 


Novartis
Confidential
Page 74
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
therapy as soon as possible, and repeat electrolyte testing until documented normalization of 
the electrolytes.
Patients who experience non-acute renal impairment of grade 2 or higher during the treatment 
period should discontinue ribociclib/ placebo treatment and should be followed for safety 
assessments.For all other adverse events, including Toxic Epidermal Necrolysis (TEN), which 
is a grade 4 event by CTCAE, please follow recommendations in Table 6-8.
Table 6-8
Ribociclib/placebo dose adjustment and management 
recommendation for all other adverse reactions 
Grade
Dose Adjustment and Management Recommendations
1
No dose adjustment recommended. Initiate appropriate medical therapy and monitor.
2
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor.
Re-initiate ribociclib/placebo at the same dose.
If the same toxicity recurs at grade 2, interrupt ribociclib/placebo until recovery to grade 1. Re-
initiate ribociclib/placebo at the next lower dose level.
3
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor.
Re-initiate ribociclib/placebo at the next lower dose level.
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade 1 and reduce 
ribociclib/placebo dose the next lower dose level.
If toxicity recurs at grade 3, discontinue ribociclib/placebo.
4
Discontinue ribociclib/placebo and treat with appropriate medical therapy.
6.5.1.2.4 Adjustment of starting dose in special populations
Renal Impairment
Based on rat ADME data, ribociclib was predominantly excreted in the in the bile as metabolites, 
with limited excretion of unchanged drug in urine. Based on a population pharmacokinetic 
analysis [CLEE011A2116], mild and moderate renal impairment had no effect on the exposure 
of ribociclib, therefore requiring no dose adjustment. For patients with severe renal impairment, 
a lower dose adjustment is recommended.
For fulvestrant, no dose adjustments are recommended for patients with mild to moderate renal 
impairment (creatinine clearance ≥30 ml/min). Safety and efficacy for fulvestrant have not been 
evaluated in patients with severe renal impairment (creatinine clearance <30 ml/min), and, 
therefore, caution is recommended in these patients (FASLODEX® prescribing information).
Hepatic Impairment
Based on a pharmacokinetic study [CLEE011A2109] in healthy subjects and non-cancer 
subjects with impaired hepatic function, no dose adjustment is necessary in subjects with mild 
hepatic impairment (Child-Pugh class A). Subjects with moderate (Child-Pugh class B) and 
severe hepatic impairment (Child-Pugh class C) can have increased exposure to ribociclib and
therefore a starting dose of 400 mg once daily is recommended.For fulvestrant, increased 
exposure to fulvestrant was observed in patients with moderate hepatic impairment (Child-Pugh 
class B). Fulvestrant has not been administered to patients with severe hepatic impairment 
(Child-Pugh class C) (FASLODEX® prescribing information). Therefore, patients with Child-
Pugh class B and C will not be enrolled. No dose reductions for fulvestrant will be allowed in 


Novartis
Confidential
Page 75
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
study CLEE011F2301 therefore patients with baseline hepatic impairment are excluded from 
the study.
Elderly
Physicians should exercise caution in monitoring the effects of ribociclib in the elderly. 
Insufficient data are available to provide a dosage recommendation.
6.5.2
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 
4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event. All 
patients will be followed for safety at least 30 days following the last dose of study treatment 
(fulvestrant and/or ribociclib/placebo).
6.5.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping 
recommendations are included in this protocol. Refer to Section 6.5 for details.
6.6
Concomitant medications
6.6.1
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 he/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.
6.6.1.1
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.


Novartis
Confidential
Page 76
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Patients taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. The days of PK blood 
sampling should be representative of the other study days with regard to the use of the 
chronically administered concomitant medications. However, if a concomitant medication is 
used intermittently during the study, this medication should be avoided on the days of PK 
sampling, if medically feasible.
6.6.1.2
Hematopoietic growth factors
Prophylactic use of WBC growth factors with ribociclib/placebo is not recommended.
6.6.1.3
Palliative radiotherapy
Palliative radiation is permitted. It should not be delivered to a target lesion. Cumulative courses
of 
RT
should 
not 
encompass 
more 
than 
25% 
of 
irradiated 
bone 
marrow 
(see Appendix 3).
If palliative radiotherapy is initiated after the 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 needed during palliative radiotherapy.
.
6.6.1.4
Use of antiemetic medications
Ribociclib 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 ribociclib/placebo and antiemetic medications should always 
be taken into consideration. For example the combination of the prohibited antiemetic 
medication ondansetron with ribociclib may precipitate TdP. Refer to Table 14-1 and Table 14-
2 for the list of medications that are prohibited or allowed to be used with ribociclib/placebo.  
6.6.2
Concomitant therapy requiring caution
Medications to be used with caution during combined ribociclib/placebo and fulvestrant 
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 from patient use if possible. If they must 
be given based on the investigator’s judgment, then use with caution and consider a 
ribociclib/placebo interruption if the concomitant medication is only needed for a short time.

Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib exposure, 
respectively)

Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib 
may increase exposure to these medications)


Novartis
Confidential
Page 77
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Strong inhibitors of BSEP (based on in vitro data, the co-administration with ribociclib 
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 and OCT2 (ribociclib 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 transporter BCRP (ribociclib has the potential to increase 
exposure to substrates of these transporters, although no animal or clinical data are 
available to support these statements)
6.6.2.1
Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially reducing ribociclib drug exposure to 
subtherapeutic 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)
6.6.3
Prohibited concomitant therapy
The following medications are prohibited during combined ribociclib/placebo and fulvestrant 
treatment in this study (see 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 
ribociclib exposure, respectively)

Substrates of CYP3A4/5 with a narrow therapeutic index (ribociclib may increase 
exposure to these medications resulting in toxicity to these medications)

Medications with a known risk for QT prolongation and/or Torsades de Pointes (TdP) 
(may precipitate QT prolongation and TdP in combination with ribociclib)

Other investigational and antineoplastic therapies

Herbal preparations/medications or 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.


Novartis
Confidential
Page 78
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
6.6.4
Drugs with QT prolongation
As far as possible, avoid co-administrering medications with a “Known”, “Possible” or 
“Conditional” risk of TdP (www.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 ribociclib 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, 
ribociclib/placebo must be interrupted (see Table 6-6). 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 (www.qtdrugs.org). Medication 
with a known risk for QT prolongation are prohibited during study treatment.
Refer to the ribociclib Investigators Brochure and other drug package insert and Appendix 1 for 
information on possible interactions with other drugs.
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).
The following CRF(s) will be used as source document(s): local lab results.
Allowed visit windows are specified as follows:

Screening assessments, apart from those listed below, must occur within 28 days of the 
randomization as per Table 7-1a.

Vital signs, physical exam, ECOG performance status, required labs, physical exam 
should be performed within 7 days of randomization.
Note: If the physical examination was performed ≤ 7 days prior to the first dose of 
ribociclib/placebo, then they do not need to be repeated on Cycle 1 Day 1.

In order for an accurate evaluation of baseline QTc, a total of three 12-lead ECGs will be 
performed at screening between -7 and -1 day.

Randomization and Cycle 1 Day 1 should preferably occur on the same day. A maximum 
of a 3 days window between randomization and Cycle 1 Day 1 visit is permitted.

For all visits (including PK visits C1D15, C2D1 and C2D15), a general ±3 days visit 
window is permitted on assessments to take into account scheduling over public holidays, 
if not explicitly specified otherwise.

For PK sampling, the samples may be obtained within the time window specified in 
Table 7-6 and Table 7-7.


Novartis
Confidential
Page 79
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Radiological and patient reported outcome assessments must be performed as outlined in 
Table 7-1a. 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).

Any screening assessments required within -7 to -1 days must be repeated if Cycle 1 Day 
1 visit is delayed more than 7 days after randomization visit.Every effort should be made 
to follow the schedule outlined in Table 7-1a.
Patients on placebo+fulvestrant that elect to transition to LEE011+fulvestrant arm or patient 
who continue with their current treatment (i.e. fulvestrant alone), should have safety 
assessments as per Table 7-1a and Table 7-1b. Tumor assessments will continue as clinically 
indicated as described in Section 7 (see Table 7-1b). 
The assessment schedule for patients who will cross-over is presented in Table 7-1b. Consult 
Table 6-4, Table 6-5 and Table 6-6 for monitoring frequency in cases of hematologic toxicity, 
liver function abnormalities or QT prolongation respectively.  
Instructions for patients electing to cross-over from placebo to LEE011 at the next scheduled 
visit: 

All patients commencing LEE011 after cross-over from placebo will need to have 
hematology, electrolytes and biochemistry tests performed on cross over Cycle 1 Day 1, 
Cycle 1 Day 15, Cycle 2 Day 1, at the beginning of cycles 3 to 6, then as clinically indicated, 
but not less frequently than every 12 weeks. 

Patients must 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.
ECGs should be repeated on cross-over Cycle 1 Day 15, Cycle 2 Day 1, Day 15 and then as 
clinically indicated. 


Novartis
Confidential
Page 80
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table 7-1a
Visit evaluation schedule - Patients that, after protocol amendment 4, continue with their originally randomized 
study treatment
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Screening
Study Informed 
Consent
D
7.1.1
x
IRT Screening (after 
ICF signature)
S
7.1.1
x
Disposition Assessment
End of Phase 
Disposition
D
x
x
x
Patient history
Demography
D
7.1.1.3
x
Inclusion/exclusion 
criteria
D
7.1.1.3
x
Medical history and 
current medical 
conditions
D
7.1.1.3
x
ER and PgR status
D
7.1.1.3
x


Novartis
Confidential
Page 81
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
HER2 status
D
7.1.1.3
x
Diagnosis and extent of 
cancer
D
7.1.1.3
x
Prior antineoplastic 
therapy
D
7.1.1.3
x
Prior / concomitant 
medications
D
7.1.1.3
Continuous – up to 30 days after last dose
Randomization
Eligibility checklist 
(within IRT)
S
7.1.1
x
IRT - Randomization
D
7.1.1
x
IRT - study drug 
administration
S
7.1.1
x
x
x
x
x
Physical examination
Physical examination
S
7.2.2.1
x
x
x
Every third 
cycle
x
Performance status
D
7.2.2.4
x
x
x
x
Every third 
cycle
x
Height 
D
7.2.2.3
x
Weight
D
7.2.2.3
x
x
x
x
x
x


Novartis
Confidential
Page 82
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Vital signs
D
7.2.2.2
x
x
x
x
x
Every third 
cycle
x
Laboratory assessments
Hematology
D
7.2.2.5.1
x
x
x
x
Every third 
cycle
x
Chemistry with fasting 
glucose
D
7.2.2.5.2
x
x
x
x
Every third 
cycle
x
Fasting Lipid Panel
D
7.2.2.5.3
x
x
x
Coagulation
D
7.2.2.5.4
x
As clinically indicated
x
Urinalysis
D
7.2.2.5.5
x
x
x
x


Novartis
Confidential
Page 83
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Tumor assessment
Tumor evaluation 
(RECIST 1.1)
D
7.2.1
x
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)
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
Cardiac assessment
Triplicate ECG 
(standard 12-lead)
D
7.2.2.6.1
x
x
x
x
x
x
x
For all 
cycles up to 
Cycle 6,
then as 
clinically 
indicated
As clinically indicated


Novartis
Confidential
Page 84
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
ECHO or MUGA with 
EF
D
7.2.2.6.2
x
As clinically indicated


Novartis
Confidential
Page 85
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Safety
Adverse events
D
8.1
Continuous – up to 30 days after last dose
Pharmacokinetics
Sparse PK
D
7.2.3
x
x
x
Meal record (high 
fat/low fat/fasting for 
sparse PK)
D
6.1.1.2
x
x
Trough PK
D
7.2.3
x
x
x


Novartis
Confidential
Page 86
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference to 
protocol 
section
Screening 
phase
Treatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 
3
Subsequent 
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-28 to
-1
-7 to -1 1
15
1
15
1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Patient Quality of life questionnaires
EORTC QLQ-C30
D
7.2.6.1
x
NA after protocol amendment 4.
EQ-5D-5L
D
7.2.6.2
x
NA after protocol amendment 4.
BPI-SF
D
7.2.6.3
x
NA after protocol amendment 4.
Study Drug administration
fulvestrant
D
x
x
x
x
x
ribociclib (LEE011) / 
placebo
D
Day 1 to Day 21 daily,
Day 22 to Day 28 off
Discontinuation
IRT – Discontinuation
S
7.1.3
x
Antineoplastic 
therapies since 
discontinuation of study 
treatment 
D
7.1.6
x
x
x
x
Survival follow-up
D
7.1.7
x


Novartis
Confidential
Page 87
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table 7-1b
Visit evaluation schedule – Cross over treatment phase for patients who cross over from placebo to LEE011 after 
protocol amendment 4. 
Category
Reference 
to 
Protocol 
Section
Treatment Phase -
only applies to cross-over patients for cross over 
treatment cycles 
Post treatment follow-up phase
Survival 
phase
Visit name
Cross 
over    
Cycle 1
Cross 
over
Cycle 
2
Cross 
over 
Cycles 3 
to 6
All 
subsequent 
Cross over
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-
up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
1
15
1
15
1
1
Within 15 
days from 
last dose
Last 
dose + 
30 
days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Dispensing
IRT – cross over 
registration
x
IRT – study drug 
administration
x
x
x
x
x
Physical Examination
Physical examination
S
7.2.2.1 
x
x
x
Every 3rd
cycle
x
Performance status 
(ECOG)
D
7.2.2.4 
x
x
x
Every 3rd
cycle
x
Weight
D
7.2.2.3 
X
x
x
As clinically 
indicated
x
Vital signs
D
7.2.2.2 
x
x
x
Every 3rd
cycle
x
Laboratory assessments


Novartis
Confidential
Page 88
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference 
to 
Protocol 
Section
Treatment Phase -
only applies to cross-over patients for cross over 
treatment cycles 
Post treatment follow-up phase
Survival 
phase
Visit name
Cross 
over    
Cycle 1
Cross 
over
Cycle 
2
Cross 
over 
Cycles 3 
to 6
All 
subsequent 
Cross over
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-
up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
1
15
1
15
1
1
Within 15 
days from 
last dose
Last 
dose + 
30 
days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Hematology
D
7.2.2.5.1 
x
x
x
x
Every 3rd
cycle
x
Biochemistry (including 
fasting glucose)
D
7.2.2.5.2 
x
x
x
x
Every 3rd
cycle
x
Fasting Lipid Panel
D
7.2.2.5.3
x
x
Coagulation
D
7.2.2.5.4 
As clinically indicated
x
Urinalysis
D
7.2.2.5.5 
As clinically indicated
x
Tumor Assessments
Tumor Evaluation 
(RECIST 1.1)
D
7.2.1
As clinically indicated
Fluid/Tissue collection 
results (if available)
D
7.2.1 
As clinically indicated until disease progression
Whole body bone scan
D
7.2.1 
As clinically indicated
Safety
Triplicate ECG (standard 
12-lead)
D
7.2.2.6.1 
x
x
x
x
As clinically indicated  
x
ECHO or MUGA with EF
D
7.2.2.6.2 
As clinically indicated


Novartis
Confidential
Page 89
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference 
to 
Protocol 
Section
Treatment Phase -
only applies to cross-over patients for cross over 
treatment cycles 
Post treatment follow-up phase
Survival 
phase
Visit name
Cross 
over    
Cycle 1
Cross 
over
Cycle 
2
Cross 
over 
Cycles 3 
to 6
All 
subsequent 
Cross over
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-
up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
1
15
1
15
1
1
Within 15 
days from 
last dose
Last 
dose + 
30 
days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Concomitant 
medications/procedures
D
6.6 
Continuous - up to 30 days after last dose
Adverse events
D
8.1 
Continuous  – up to 30 days after last dose
Study Drug administration
Fulvestrant
D
6.1.1
x
x
x
Day 1 of 
each cycle
Ribociclib (LEE011)
D
6.1.1
Day 1 to Day 21 daily,
Day 22 to Day 28 off
Disposition Assessment
End of Phase Disposition
x
x
Discontinuation
IRT – Discontinuation
S
7.1.3
x


Novartis
Confidential
Page 90
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Reference 
to 
Protocol 
Section
Treatment Phase -
only applies to cross-over patients for cross over 
treatment cycles 
Post treatment follow-up phase
Survival 
phase
Visit name
Cross 
over    
Cycle 1
Cross 
over
Cycle 
2
Cross 
over 
Cycles 3 
to 6
All 
subsequent 
Cross over
cycles
End of 
study 
treatment 
(EOT)
Safety 
follow-
up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
1
15
1
15
1
1
Within 15 
days from 
last dose
Last 
dose + 
30 
days
Every 8 
weeks (if 
applicable) 
Every 12 
weeks
Survival follow-up
D
7.1.7
x


Novartis
Confidential
Page 91
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
7.1.1
Screening
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to randomization or within 1 to 7 days prior to randomization for selected assessments (see 
Table 7-1a for the list of assessments to be performed).
Note: Any screening assessment that is done outside the screening window (Day -28 to Day -1 
or Day -7 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.
Any screening assessments required within -7 to -1 days must be repeated if Cycle 1 Day 1 visit 
is delayed more than 7 days after randomization visit.For laboratory evaluations used to 
determine eligibility, a repeated evaluation within the screening window is permitted for 
screening results out of the defined range. If the repeated laboratory result meets the criteria, 
that result may be used to determine eligibility. If the repeated laboratory result does not meet 
the criteria, the patient will be considered a screening failure. In case rescreening occurs, all 
evaluations re-assessed should meet the eligibility criteria. 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.
7.1.1.1
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.
7.1.1.2
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 
experienced a Serious Adverse Event during the Screening Phase (see Section 8.2 for SAE 
reporting details).


Novartis
Confidential
Page 92
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
7.1.1.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Date of birth and initials (where permitted), sex, race, ethnicity, source of 
patient referral)

Diagnosis and extent of cancer (including staging at study entry and histology/cytology)

Medical history (e.g., important medical, surgical, and allergic conditions from the patient’s 
medical history which could have an impact on the patient’s evaluation) / current medical 
conditions (e.g., all relevant current medical conditions which are present at the time of 
signing informed consent). Ongoing medical conditions, symptoms and disease which are 
recorded on the Medical History 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, EQ-5D-5L, and BPI-SF (See 
Section 7.2.6).
Furthermore the following assessments will be performed:

Vital signs

Height, weight

Physical examination

Performance status (ECOG)

Laboratory evaluations (hematology, PT, INR, chemistry, lipid panel, urinalysis)

ECG

ECHO/MUGA

Radiological assessments (e.g. CT Scan)
7.1.2
Treatment period
Patients will be treated with fulvestrant + ribociclib or fulvestrant + placebo until disease 
progression, unacceptable toxicity, withdrawal of consent by the patient, patient is lost to follow 
up, death, discontinuation from the study treatment due to any other reason or the sponsor 
terminates the study. For details of assessments, refer to Table 7-1a and Table 7-1b.
7.1.3
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 a reasonable
effort (e.g. telephone, e-mail, letter) to understand the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate CRF pages. They may be 


Novartis
Confidential
Page 93
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 voluntarily 
withdraw from the study or be dropped from it at the discretion of the investigator at any time.
Patient may be withdrawn from the study treatment under the following circumstances:
Emergence of adverse events where the recommendation as per Section 6.5.1.2 is 
discontinuation of ribociclib therapy (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; complete heart block 
(Grade III AV block) or Second degree AV block Mobitz type II as well as any relevant 
hepatotoxicity events).

Lost to follow up

Physician decision

Progression of disease

Study terminated by the sponsor

Protocol deviation

Technical problems.
Patient 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 due to toxicity that result in discontinuation. Please refer 
to Section 6.5

Use of prohibited medication. Please refer to Section 6.6.3

Any other protocol deviation that results in a significant risk to the patient’s safety.
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any patient whose treatment code has been broken inadvertently for any 
reason.
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1.5 and Section 7.1.6. If they fail 
to return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) 
should be made to contact them as specified in Section 7.1.7. The patient remains on study until 
such time as he/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.
Patients who 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 


Novartis
Confidential
Page 94
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
time all of the assessments listed for the EOT visit will be performed. For details of assessments, 
refer to Table 7-1. 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.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
7.1.3.1
Replacement policy
Not applicable.
7.1.4
Withdrawal of Consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

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 subject’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 subject are 
not allowed unless safety findings require further communication or follow-up.
-
All efforts should be made to complete the assessments prior to study withdrawal. A 
final evaluation at the time of the subject’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 subject’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.


Novartis
Confidential
Page 95
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
7.1.5
Follow up for Safety Evaluations
All patients will be followed up for safety up to 30 days after last dose of study treatment 
(fulvestrant + ribociclib/placebo). Patients whose treatment is interrupted or 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.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF.
7.1.6
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 7.2.1.1) and patient 
reported outcomes (see Section 7.2.6) must continue to be performed every 8 weeks during the 
first 18 months, then every 12 weeks until 36 months and thereafter clinically indicated until 
disease progression, death, lost to follow-up, or any other reasons listed in Section 7.1.9. 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 and Table 7-1b) until 
disease progression is documented. 
7.1.7
Survival follow-up
All patients will be followed for survival status every 12 weeks (see Section 4.1.5) regardless 
of start of new antineoplastic therapy or any other treatment discontinuation reason, 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.
 
 
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
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.


Novartis
Confidential
Page 96
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
7.1.9
End of post-treatment follow-up
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 one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Progressive disease

Protocol deviation

Study terminated by the sponsor

Technical problems

Subject/guardian decision

Death
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Imaging tumor assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.1 (Appendix 2) 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. 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.
Imaging assessments will be performed at screening within 28 days prior to randomization and 
subsequently every 8 weeks during the first 18 months, every 12 weeks until 36 months, then 
change to as clinically indicated See Table 7-2 for details of assessments. The interval (8 week, 
12 week, or as clinically indicated) should be respected regardless of whether study treatment 
is temporarily withheld or unscheduled assessments performed.
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 and Table 7-1b and Table 
7-2.


Novartis
Confidential
Page 97
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 and 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 patients 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 screening 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 7-1.
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 2).
If possible, a single radiologist 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.


Novartis
Confidential
Page 98
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.
Note: 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,
then every 12 weeks 
(± 7 days) until 36 
months and thereafter 
as clinically indicated
until disease 
progression, death, 
withdrawal of consent, 
loss to follow-up, or 
subject/guardian 
decision (±7 days).
Mandated
Every 8 weeks during the first 
18 months, every 12 weeks 
(±7 days) until 36 months, 
and thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, loss to 
follow-up, or subject/guardian 
decision (±7 days). In the 
absence of disease 
progression, continue the 
assessment even if a new 
anti-neoplastic therapy is 
started until disease 
progression, only in this case 
a ±14 days window is 
allowed.
Brain CT or 
MRI
Mandated at 
screening if history 
of, existing or 
suspected brain 
metastases
If brain lesion at 
screening: every 8 
weeks during the first 
18 months then every 
12 weeks (± 7 days)
until 36 months and 
thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, 
loss to follow-up, or 
subject/guardian 
decision (±7 days).
Mandated 
only if 
brain 
lesion at 
screening
If brain lesion at screening: 
Every 8 weeks during the first 
18 months then every 12 
weeks (±7 days) until 36 
months and thereafter as 
clinically indicated until 
disease progression, death, 
withdrawal of consent, loss to 
follow-up, or subject/guardian 
decision (±7 days). In the 
absence of disease 
progression, continue the 
assessment even if a new 
anti-neoplastic therapy is 
started until disease 
progression, only in this case 
a ±14 days window is 
allowed.


Novartis
Confidential
Page 99
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Procedure
Screening: Day 
−28 to Day -1
Treatment phase*
End of 
treatment*
Post-Treatment Phase
Whole body 
bone scan**
Mandated, within 
42 days ( 6 weeks) 
prior to 
randomization. 
As clinically indicated
Bone X-ray, CT 
or MRI
Only if skeletal 
abnormalities 
identified by whole 
body bone scan ** 
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 then every 
12 weeks (± 7 days)
until 36 months and 
thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, 
loss to follow-up, or 
subject/guardian 
decision (±7 days).
Mandated 
only if 
bone 
lesion at 
screening
If bone lesion at screening, 
every 8 weeks during the first 
18 months then every 12 
weeks (±7 days) until 36 
months and thereafter as 
clinically indicated until 
disease progression, death, 
withdrawal of consent, loss to 
follow-up, or subject/guardian 
decision (±7 days). In the 
absence of disease 
progression, continue the 
assessment even if a new 
anti-neoplastic therapy is 
started until disease 
progression, only in this case 
a ±14 days window is 
allowed.
Skin color 
Photography
Only if skin lesions 
at screening
If skin lesions at 
screening, every 8 
weeks during the first 
18 months then every 
12 weeks (± 7 days)
until 36 months and 
thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, 
loss to follow-up, or 
subject/guardian 
decision (±7 days).
Mandated 
if skin 
lesions at 
screening
If skin lesions at screening, 
every 8 weeks during the first 
18 months then every 12 
weeks (±7 days) until 36 
months and thereafter as 
clinically indicated until 
disease progression, death, 
withdrawal of consent, loss to 
follow-up, or subject/guardian 
decision (±7 days). In the 
absence of disease 
progression, continue the 
assessment even if a new 
anti-neoplastic therapy is 
started until disease 
progression, only in this case 
a ±14 days window is 
allowed.


Novartis
Confidential
Page 100
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Procedure
Screening: Day 
−28 to Day -1
Treatment phase*
End of 
treatment*
Post-Treatment Phase
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 then every 
12 weeks (± 7 days)
until 36 months and 
thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, 
loss to follow-up, or 
subject/guardian 
decision (±7 days).
Mandated 
if lesion at 
screening
If lesion identified at 
screening, every 8 weeks 
during the first 18 months 
then every 12 weeks (±7 
days) until 36 months and 
thereafter as clinically 
indicated until disease 
progression, death, 
withdrawal of consent, loss to 
follow-up, or subject/guardian 
decision (±7 days). In the 
absence of disease 
progression, continue the 
assessment even if a new 
anti-neoplastic therapy is 
started until disease 
progression, only in this case 
a ±14 days window is 
allowed.
*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.
7.2.1.3
Blinded independent review committee (BIRC) assessment
The primary end point of the study is the local investigator assessed PFS. The BIRC assessed 
PFS will serve as a supportive evidence of the primary end point. 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, whose BIRC randomization identity will be unknown to the investigators. 
The central review of the scans will be carried out in a blinded fashion. The decision regarding 
patient management will remain with the investigators. If consistency of treatment effect is not 
established, the BIRC may perform an assessment of PFS data for all patients.  Further details 
regarding BIRC assessment will be provided in the BIRC charter.
At present, radiology review from the blinded independent review committee has been 
completed.


Novartis
Confidential
Page 101
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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, hepatic safety markers and INR) as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.1.
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
Clinical laboratory analyses (Hematology, Chemistry, Coagulation, Urinalysis, Lipid Panel) are 
performed by the central laboratory as per schedule in the Table 7-1a and Table 7-1b. Details 


Novartis
Confidential
Page 102
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
on the collection, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. Visit windows of ± 3 days are allowed for 
all visits.
Novartis must be provided with a copy of the central laboratory’s certification (if applicable), 
and a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study must 
be reported via an updated tabulation indicating the 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.
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 of the following criteria 
are met:

A treatment decision was made based on the local results, or

Local lab results document an adverse event not reported by the central lab, or

Local lab results document an adverse event severity is worse than the one reported by the 
central lab, or

There are no concomitant central results available
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used.
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the Common Terminology Criteria for 
Adverse events (CTCAE) version 4.0.3. Additional analyses are left to the discretion of the 
investigator.
Table 7-4
Central clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
White blood cell count (WBC) with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils), hemoglobin (Hgb) and platelet count.
Biochemistry with 
fasting glucose
Sodium, potassium, urea or BUN, creatinine, fasting glucose, calcium, corrected 
calcium, magnesium,phosphorous total protein and albumin.
AST (SGOT), ALT (SGPT), total bilirubin, direct bilirubin, GGT and alkaline 
phosphatase, amylase, lipase and LDH.
Fasting Lipid Panel
Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides
Coagulation
PT, International normalized ratio [INR]


Novartis
Confidential
Page 103
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Test Category
Test Name
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)
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.
7.2.2.5.2 Biochemistry
Biochemistry tests are to be performed according to the Visit Schedules outlined in
Table 7-1a and Table 7-1b. For details of the biochemistry panel refer to Table 7-4.
7.2.2.5.3 Lipid panel
Lipid panel tests are to be performed according to the Visit Schedules outlined in Table 7-1a
and Table 7-1b. For details of the lipid panel refer to Table 7-4.
7.2.2.5.4 Coagulation
Coagulation tests are to be performed according to the Visit Schedules outlined in Table 7-1a
and Table 7-1b. For details of the coagulation panel refer to Table 7-4. 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.
7.2.2.5.5 Urinalysis
Urinalysis is to be performed according to the Visit Schedules outlined in Table 7-1a and Table 
7-1b. For details of the urinalysis panel refer to Table 7-4.
7.2.2.5.6 Hepatic Safety Markers
Following protocol amendment 4, hepatic safety marker collection will stop.
 
 
 
 
 
 
Blood samples will be collected from all patients at Day 1 of Cycles 1 through 6. Patients should 
be fasted overnight for at least 8 hours.
An additional blood sample is requested from patients in response to rise in ALT/AST or in 
total bilirubin (as described below) if this rise occurs outside of the scheduled collection dates:


Novartis
Confidential
Page 104
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

In patients with normal AST and ALT and total bilirubin at baseline that present a rise of 
AST or ALT ≥ grade 2 with total bilirubin > 2 x ULN without evidence of cholestasis 
(defined as: ALP elevation > 2.0 x ULN with R value [ALT/ALP in x ULN] < 2 in 
patients without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis). 
OR

For patients with elevated baseline AST or ALT or total bilirubin that present [AST or 
ALT >2 x baseline AND >3.0x ULN] OR [AST or ALT 8.0x ULN]- whichever is lower-
combined with [total bilirubin 2xbaseline AND >2.0 x ULN] 
OR

ALT or AST > 8 x ULN without bilirubin increase
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
Following protocol amendment 4, central ECG collection ceases and all ECGs should be 
read locally. No timematched PK samples should be collected with ECG assessments.
Standard triplicate 12 lead ECG assessments will be performed after the patient has been resting 
for 5-10 min prior to each time point indicated in Table 7-5a and Table 7-5b 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 to PK sampling (if applicable).
Table 7-5a
Local ECG collection plan
Cycle
Patients
Day
Time
ECG Type
Screening
All
-7 to -1
Anytime
Triplicate 12 Lead
1
All
Day 152
Pre-dose1
Triplicate 12 Lead


Novartis
Confidential
Page 105
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Cycle
Patients
Day
Time
ECG Type
All
2h post-dose (± 15 min)
Triplicate 12 Lead
All
4 h post-dose (± 15 min)
Triplicate 12 Lead
2
All
Day 12
Pre-dose1
Triplicate 12 Lead
All
Day 152
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
3
All
Day 1
Pre-dose1
Triplicate 12 Lead
2h 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
All
As clinically 
indicated
Anytime
Triplicate 12 Lead
EOT
Anytime
Triplicate 12 Lead
Unscheduled ECG
Anytime
Triplicate 12 Lead
1The exact date and time of dosing must be recorded on the appropriate eCRF
Table 7-5b
Local ECG collection plan – for crossover patients
Patients 
Cross Over Cycle 
Day / time 
ECG type 
All 
1
Day 1 / Pre-dose1
Triplicate 12 Lead
All 
1 
Day 15 / anytime 
Triplicate 12 Lead
All 
2 
Day 1 / anytime 
Triplicate 12 Lead
All
2
Day 15 / anytime
Triplicate 12 Lead
All 
All other cycles 
As clinically indicated
Triplicate 12 Lead
All
EOT
Anytime
Triplicate 12 Lead
All
Unscheduled ECG
Anytime
Triplicate 12 Lead
1The exact date and time of dosing must be recorded on the appropriate eCRF
Patients in the placebo arm who elect to transition from placebo to LEE011 must 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. ECGs should be repeated on cross-
over Cycle 1 Day 15, Cycle 2 Day 1, Day 15 and then as clinically indicated as per Table 7-5b.
In order for an accurate evaluation of baseline QTcF, a total of three 12-lead ECGs will be 
performed within 7 days prior to randomization (at screening between Day -7 and 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 a QTcF value of ≥ 481 ms is observed in a single ECG or as the average (when collected as 
a triplicate) at any time after randomization, study treatment must be interrupted, repeat ECG(s)
and follow management guidelines detailed in Table 6-6.
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 


Novartis
Confidential
Page 106
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
should be collected in triplicate. Additionally, a local cardiologist may be consulted at any time 
during the study at the discretion of the investigator. If an unscheduled ECG is performed at an 
external medical facility, a copy of the ECG should be obtained and forwarded to the ECG 
central laboratory, and a copy kept in the source documents at the study site. Centrally reviewed 
ECG findings should be documented on the ECG CRF page.
In the event that a QTcF value of ≥501ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure. If PK sampling is possible, 
refer to the section PK sampling and detail appropriate procedures to be followed (Section 7.2.3).
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.
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
Cardiac imaging will be performed by MUGA scan or ECHO in order to assess the left 
ventricular ejection fraction. 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.
7.2.3
Pharmacokinetics
Following protocol amendment 4, there will be no more PK blood collection, including 
patients that cross-over to the LEE011 combination arm. 
Pharmacokinetic blood samples will be obtained from all patients for the analysis of ribociclib 
(and any relevant metabolites such as LEQ803). Patients will be assigned to the sparse PK 
collection group or the trough PK collection group.

Sparse PK collection group: In the sparse PK group, approximately the first 150 patients 
enrolled will have PK collections as described in Table 7-6.


Novartis
Confidential
Page 107
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Trough PK collection group: In all remaining patients, PK collections will be collected as 
described in Table 7-7.
Meal conditions (fasting, low fat, high fat) will be recorded within ± 30 minutes of a dose on 
the meal record eCRF page for patients assigned to the sparse PK collection group on Cycle 1 
Day 15 and Cycle 2 Day 15; the impact of meal conditions on PK in patients may be explored.
Refer to Section 6.1.1.2 and Section 10.6.3 for details.
An unscheduled PK blood sample may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion. If a patient discontinues 
from the study treatment due to toxicities related to study treatment, an unscheduled PK blood 
sample may be obtained as soon as possible after the last dose and the date and time of last dose 
recorded. In addition, an unscheduled blood sample may be collected if additional ECG 
measurements are conducted.
The date and exact time of dosing on PK collection days, as well as the date and actual time of 
blood sampling must be recorded on the appropriate eCRF pages. In addition, the exact time of 
dosing on the previous day must be precisely recorded.
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed, and 
medication should resume on the next day. The occurrence and frequency of any vomiting must 
be noted in the adverse events section of the eCRF. In addition, the date and exact time of 
vomiting should only be recorded if it occurs within 4 hours of dosing on the days of PK 
sampling. If a vomiting episode occurs within the first 4 hours post-dosing during the day of 
the last dose prior to trough PK samples the exact time (whenever possible) must be noted on 
the eCRF. A detailed description of the planned analyses for PK is given in Section 10.5.4.
7.2.3.1
Pharmacokinetic blood sample collection and handling
Blood samples will be obtained from all patients either by direct venipuncture or through an 
indwelling cannula (e.g., inserted in a forearm vein, or central venous line) for the analysis of 
plasma concentrations of ribociclib (and any relevant metabolites such as LEQ803), when 
feasible. At the specified time points described in Table 7-6 and Table 7-7, one single 3mL 
blood draw will be collected into a tube containing EDTA and gently inverted several times to 
thoroughly mix the anticoagulant. The blood tube will be centrifuged to separate the plasma.
Plasma will immediately be split and transferred into separate pre-labeled tubes for ribociclib. 
Plasma samples will be stored frozen in an upright position until shipment.
Any sampling problems (e.g., patient took study drug before blood sample, scheduled sampling 
time is missed, sample is not drawn according to the schedule) should be noted as a comment 
on the eCRF.
Refer to the [Central Laboratory documents] for detailed instructions for the collection, 
handling, and shipment of PK samples.


Novartis
Confidential
Page 108
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Table 7-6
Sparse pharmacokinetic blood collection log
Note: Sparse PK sampling will be performed on approximately the first 150 patients in this study. Blood for 
Sparse PK profiling will be collected on C1D15 and C2D15 at Pre-dose (0), 2, 4, 6hr, and C2D1 Pre-dose (0hr) 
for ribociclib/placebo. Only for the sparse PK group, the meal condition (fasting, low fat, high fat) will be 
collected within ± 30 minutes of the dose on the eCRF on days C1D15 and C2D15.
Cycle
Day
Scheduled Time Point 
Relative to Dosing
DRID No. for 
ribociclib/ 
placebo
PK Sample No. 
for ribociclib/ 
placebo
Blood Volume 
(mL)
1
15
Pre-dosea 
101/1001d
101
3
2h post-dose (± 15 min)
101
102
3
4h post-dose (± 15 min)
101
103
3
6h post-dose (± 15 min)
101
104
3
2
1
Pre-dosea
102
105
3
15
Pre-dosea
103/1003d
106
3
2h post-dose (± 15 min)
103
107
3
4h post-dose (± 15 min)
103
108
3
6h post-dose (± 15 min)
103
109
3
Unscheduled
Anytimeb
NA
1001+
3
PK samples related to a QTcF 
≥ 501 msc
NA
1051+
3
a.
Collect Pre-dose PK sample immediately before drug administration (approximately 24-hrs after the last 
dose and immediately before the next dose)
b.
Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, sequentially 
numbered 1001, 1002, etc., for ribociclib/placebo
c.
Unscheduled PK samples related to a QTcF ≥ 501 ms will be uniquely, sequentially numbered 1051, 1052, 
etc., ribociclib/placebo
d.
The first dose reference ID (DRID) No. is for the current dose, while the second DRID No. is for the last 
dose the subject received prior to the collection of the PK sample
Table 7-7
Trough pharmacokinetic blood collection log
Note: Trough PK sampling will be performed in all remaining patients Pre-dose on C1D15, C2D1 and C2D15.
Cycle
Day
Scheduled Time Point Relative 
to Dosing
DRID No. for 
ribociclib/ 
placebo
PK Sample 
No. for 
ribociclib/ 
placebo
Blood Volume (mL)
1
15
Pre-dosea
201/2001d
201
3
2
1
Pre-dosea
202
202
3
15
Pre-dosea
203/2003d
203
3
Unscheduled
Anytimeb
NA
2001+
3
PK samples related to a QTcF ≥ 
501msc
NA
2051+
3
a.
Collect Pre-dose PK sample immediately before drug administration (approximately 24-hrs after the last 
dose and immediately before the next dose)
b.
Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, sequentially 
numbered 2001, 2002, etc., for ribociclib/placebo
c.
Unscheduled PK samples related to a QTcF ≥ 501 ms will be uniquely, sequentially numbered 2051, 2052, 
etc., ribociclib/placebo
d.
d. The first DRID No is for the current dose, while the second DRID No is for the last dose the subject 
received prior to the collection of the PK sample


Novartis
Confidential
Page 109
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Additional guidelines for pharmacokinetic sampling/ECG
On days with PK sampling and/or ECG testing (collection days are outlined in Table 7-1a), the 
following additional guidelines must be followed:

Pre-dose ECGs must be done first, prior to pre-dose PK sampling and prior to dosing.

The time of PK collection and the time the study medication was taken must be precisely 
recorded in the eCRF.

Furthermore, the date and time the study medication was taken on the day before the PK 
collection must be precisely recorded in the eCRF.

Post-dose ECGs and/or PK samples should be collected after dosing of the study treatment. 
ECGs must be done prior to PK sampling.

ECG and PK sample collection will be performed according to Section 7.2.3 and 
Table 7-5a and Table 7-5b, Table 7-6 and Table 7-7.

In the case where ribociclib/placebo is being temporarily interrupted or has been 
permanently interrupted, no PK samples will be collected for the corresponding visit.
7.2.3.2
Analytical method
Plasma concentrations of ribociclib (and any relevant metabolite such as LEQ803) will be 
measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
methods with a lower limit of quantification (LLOQ) of approximately 1.0 ng/ml for ribociclib. 
Sample analysis will be performed by Novartis or a Novartis designated laboratory using 
validated methods. Any results below the LLOQ and any missing samples will be recorded 
accordingly.
Leftover plasma from analysis may be used for 
 other 
bioanalytical purposes (e.g., cross check between different sites, stability assessment).


Novartis
Confidential
Page 110
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 111
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 112
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 113
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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), the EuroQoL 5-level instrument (EQ-5D-5L, 
tablet version), and the Brief Pain Inventory-Short form questionnaire (BPI-SF, copyright 1991) 
will be used to evaluate patient-reported outcome measures of health-related quality-of-life, 
functioning, disease symptoms, treatment-related side effects, global health status, and cancer-
related pain. The EORTC QLQ-C30, EQ-5D-5L, and BPI-SF are recognized reliable and valid 
measures (Aaronson 1993, Rabin 2001, Cleeland 1994) frequently used in clinical trials of 
patients with advanced or metastatic breast cancer.
All patient-reported outcome (PRO) measures (eg, EORTC QLQ-C30, EQ-5D-5L, and BPI-SF) 
will be administered before any study drug administrations at the visits indicated in Table 7-1a
and Table 7-9. Collection of PRO measures have a ± 7 day window unless otherwise indicated.
All PRO data will be collected using an electronic tablet device and should be administered in 
the patient’s local language at the beginning of the study visit prior to any interaction with the 
study investigator including any tests, treatments or receipt of results from any tests to avoid 
biasing the patient’s perspective. Patients should be given sufficient space and time to complete 
all study questionnaires and all administered questionnaires should be reviewed for 
completeness. If missing responses are noted, patients should be encouraged to complete any 
missing responses. Attempts should be made to collect responses to all questionnaires for all 
patients, including from those who discontinue prior to the study evaluation completion visit, 
however, if patients refuse to complete questionnaires, this should be documented in study 
source records. Patient’s refusal to complete study questionnaires are not protocol deviations.
The use of electronic data collection of clinical outcome assessments (eCOA), including PROs, 
has been endorsed as standard. The use of both eCOA and paper PRO collection of the same 


Novartis
Confidential
Page 114
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
COA measure in a single study is not endorsed. However, paper PRO may be utilized as a 
backup shoud there be a failure with the electronic version/system.
Paper should be used as a last resort option. In case of any issues with the device use, which 
cannot be resolved within the visit time window, PRO questionnaires could be completed on 
paper form and transcribed into the tablet at the next possible opportunity.
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.
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 4, no additional PRO measures should be collected from 
any patients.
Table 7-9
Patient reported outcomes collection plan
Patient 
Questionnaire
Cycle
Visit
Time
EORTC QLQ-C30
EQ-5D-5L
BPI-SF
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. Thereafter, PRO collection should align 
with periodic efficacy assessments until disease 
progression, death, withdrawal of consent, loss 
to follow-up, or subject/guardian decision
End of 
treatment
Day of EOT 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 only in case 
end of treatment occurs for reasons other than 
death, lost to follow-up, withdrawal of consent, 
or disease progression
7.2.6.1
EORTC QLQ-C30
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson et al 1993).
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a high / 


Novartis
Confidential
Page 115
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 (tablet version) 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 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 (Oemar and Janssen 2013).
7.2.6.3
Brief Pain Inventory-Short Form
The BPI-SF is a short, self-administered 11-item questionnaire designed to evaluate the 
intensity of and impairment caused by cancer pain. All questions in the BPI-SF are scored using 
an 11-point rating scales. Four questions measure pain intensity (pain now, average pain, worst 
pain, and least pain) using 0 ("no pain") to 10 ("pain as bad as you can imagine") numeric rating 
scales; and seven additional questions measure the level of interference caused by pain (general 
activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment 
of life) using 0 (no interference) to 10 (complete interference) rating scales.
Questions from the BPI-SF are aggregated into a pain severity index defined based on the sum 
of four items focused on pain intensity, and pain interference indices defined as subscale scores 
of pain interference with activity (interference with walking, general activity and work) and 
affect (interference with relations with others, enjoyment of life and mood) and an overall 
interference score (all seven items) (Cleeland 1994). Missing values will be handled as 
recommended by the developers of the BPI-SF (Cleeland 2009). All four severity items must 
been completed for aggregating a pain severity index. The pain interference indices are scored 
as the mean of the item scores multiplied given that more than 50%,of the items have been 
completed.


Novartis
Confidential
Page 116
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
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 
(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)


Novartis
Confidential
Page 117
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met
If the event worsened the event should be reported a second time in the CRF noting the start 
date when the even 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 
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.


Novartis
Confidential
Page 118
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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:
a. Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.
b. 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.
c. 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 
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.
Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way 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 


Novartis
Confidential
Page 119
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant 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 4, the emergency unblinding procedures are no longer 
applicable as all patients will be unblinded and made aware of their study treatment.
Emergency unblinding should only be undertaken for safety reasons when it is essential for 
effective treatment of the patient. Most often, study treatment discontinuation and knowledge 
of the possible treatment assignments are sufficient to treat a study patient who presents with 
an emergency condition. Emergency code breaks are performed using the IRT. When the 
investigator contacts the IRT to unblind a patient, he/she must provide the requested patient 
identifying information and confirm the necessity to unblind the patient. The investigator will 
then receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact his/her 
backup in cases of emergency when he/she is unavailable. The protocol number, study treatment 
name if available, patient number and instructions for contacting the local Novartis CPO (or 
any entity to which it has delegated responsibility for emergency code breaks) will be provided 
to the patient in case emergency unblinding is required at a time when the investigator and 
backup are unavailable. However, if a mechanism is already in place to ensure that the 
investigator and/or back-up can always be reached in case of emergency then the procedure 
above is not required.
Study treatment must be discontinued once emergency unblinding.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 


Novartis
Confidential
Page 120
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
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 
results of ribociclib in an unblinded manner. The IDMC will be responsible for reviewing the 
safety results and overseeing the safety data accruing in the trial at regular intervals of 
approximately every six months, provided that sufficient patients have been randomized. Also, 
if requested by the 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.
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


Novartis
Confidential
Page 121
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

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 


Novartis
Confidential
Page 122
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.
Blood and tumor samples for laboratory data, PK 
 assessments will be collected 
by sites and sent to the Novartis designated central laboratory for processing. The laboratory 
results and IRT data will be sent electronically to Novartis. Imaging and ECG data will be 
collected at the sites and the data will be transmitted to a designated CRO for centralized 
analysis, as well as further processing. PRO data will be recorded by patients onto the electronic 
tablet device maintained at the study site. The device will be programmed to ensure that all
relevant observations are recorded.
As detailed in Section 7.2 following Protocol Amendment 4, no additional PK, ePRO data,
central ECGs 
will be collected for all patients, including 
patients who elect to transition from placebo to LEE011 combination treatment.
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 (e.g. PK, 
ECG, imaging, safety samples) will be processed 
centrally and the results will be sent electronically to Novartis. PRO data collected using an 
electronic tablet device will be documented into a separate study-specific database supplied and 
managed by a designated vendor. The PRO database will be accessible to study sites and 
Novartis personnel (or a designated CRO) for data management. All PRO data will be sent 
electronically to Novartis personnel (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an 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). 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 


Novartis
Confidential
Page 123
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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.
Following protocol amendment 4, the emergency unblinding procedures are no longer 
applicable as all patients will be unblinded and made aware of their study treatment.
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.
10.1
Analysis sets
10.1.1
Full analysis set
The 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.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study medication defined 
as fulvestrant, or ribociclib/placebo and had at least one post-baseline safety assessment. 
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. Please note: the statement that a patient had no 
adverse events (on the Adverse Event eCRF) constitutes a valid safety assessment.
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.
10.1.4
Pharmacokinetic analysis set
The PK Analysis Set (PAS) will consist of all patients who receive at least one dose of study 
treatment (ribociclib/placebo or fulvestrant) and have at least one evaluable post-dose 
concentration measurement.


Novartis
Confidential
Page 124
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.1.5
Cross-over analysis set
The cross-over analysis set includes all patients in the placebo arm of the Safety set, ongoing at 
the time of protocol amendment 4, who elected to cross-over to receive LEE011 combination 
therapy and received at least one dose of LEE011. This population will be used for the analysis 
of cross-over phase data. The cross-over phase refers to the time from first dose of LEE011
treatment following cross-over 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.
The actual dose and duration of fulvestrant, and ribociclib/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 fulvestrant 
and ribociclib/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 cross-over phase in patients who crossed over to LEE011 combination 
therapy after unblinding (i.e. using the Cross-over analysis set).
10.4
Primary objective
The primary objective in the study is to determine whether treatment with fulvestrant +
ribociclib prolongs PFS compared to treatment with fulvestrant + ribociclib placebo in men and 
postmenopausal women with HR+, HER2- advanced breast cancer who received no or only 1 
line of prior hormonal therapy for advanced breast cancer.


Novartis
Confidential
Page 125
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 2 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.
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 (fulvestrant+ribociclib arm vs. fulvestrant + placebo arm) of 
PFS.
The primary efficacy endpoint PFS will be analyzed at the interim look/analysis and final look 
of a group sequential design based on the FAS population according to the treatment group 
patients were randomized to and the strata they were assigned to 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.
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 cutoff 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 2).
10.4.4
Supportive analyses
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 PPS if the primary analysis 
is statistically significant. 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.
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 


Novartis
Confidential
Page 126
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
may be performed; details about the subgroups to be included will be provided in the study 
analysis plan.
Patterns of censored data will be examined by the treatment groups using descriptive statistics 
(the numbers of censored patients and reasons for censoring).
PFS assessed by BIRC will serve as supportive evidence of the primary end point. Two methods 
will be used to summarize the data from the BIRC assessment. 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 for central review. This estimate and its one-
sided 95% CI will be provided.  Details of the audit sample size calculation for the BIRC 
assessment are provided in Section 10.8. The NCI method will be used for audit sample size 
determination and summary of treatment effect (HR, 95% confidence intervals) based on the 
supportive BIRC assessment.
The data from the BIRC assessment generated following the sampling scheme as above will 
also be summarized using the method proposed by Amit et al. 2011, referred to as the PhRMA 
(Pharmaceutical Research and Manufacturers of America) method. With this approach, the DD 
(differential discordance) of early discrepancy rate (EDR) and late discrepancy rate (LDR) 
between the two arms will be estimated as the rate on the fulvestrant+ribociclib arm minus the 
rate on the fulvestrant+placebo arm. The EDR and LDR results will also be summarized by 
treatment arm.
 
 
Since the primary endpoint of PFS was met at the time of the primary analysis, no further formal 
analyses of PFS are planned. 
Note: A descriptive analysis of PFS was performed at the time of second OS interim analysis 
with the aim to update the PFS median for the first line patients since the median for that patient 
population was not met in the primary PFS analysis. 
If any descriptive analyses of PFS are performed after allowing patients ongoing on study 
treatment in the placebo arm to cross-over 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 cross-over for patients in the cross-over analysis set.
10.5
Secondary objectives
The secondary objectives in this study are to compare the two treatment groups with respect to 
overall survival (OS), and evaluate  overall response rate (ORR), clinical benefit rate (CBR), 
time to response (TOR), duration of response (DOR) and time to definitive deterioration in the 
quality of life and ECOG PS, safety. OS between the 2 treatment arms will be statistically 
compared. 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.


Novartis
Confidential
Page 127
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.5.1
Overall Survival
One of the secondary objectives of the study is to determine whether treatment with fulvestrant 
+ ribociclib prolongs overall survival (OS) compared to treatment with fulvestrant + 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 (fulvestrant+ribociclib arm vs. fulvestrant+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 final PFS analysis, but after 
additional follow-up. Therefore, a four-look design is considered for OS.
1. OS will be hierarchically tested (provided the primary PFS analysis is statistically 
significant)in the following way.The first potential time point for OS analysis will be at 
the time of the primary PFS  analysis at which time approximately 161 deaths are 
expected. If PFS is statistically significant at this stage, OS will also be tested. If OS is not 
statistically significant at this stage, the 2nd OS analysis is planned after approximately
263 deaths are expected. If OS is not statistically significant at this stage, the final OS 
analysis will be planned after approximately 351 deaths. 
The type I error probability for OS tests will be controlled by using a separate Lan-DeMets 
(O’Brien-Fleming) alpha spending function independent of the one used for the primary 
efficacy analysis of PFS 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 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 cross-over 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. 


Novartis
Confidential
Page 128
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.5.2
Other secondary efficacy objectives
10.5.2.1
Overall response rate
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
(BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1.
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 factor) 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, 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.
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 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. Time to response data will be 
listed and summarized by treatment group. The distribution of time to response may be 
summarized through Kaplan-Meier method if sufficient number of events are observed.
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.


Novartis
Confidential
Page 129
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.5.2.5
ECOG performance status
ECOG PS scale as described in Section 7.2.2.4 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. Deterioration is considered definitive if no improvements in 
ECOG PS status is observed at a subsequent time of measurement during the treatment period 
following the time point where the deterioration is observed.
Patients receiving any further therapy prior to definitive worsening will be censored at their 
date of last assessment prior to start of therapy. Patients that have not worsened at the data cut-
off point will be censored at the date of last assessment prior to start of therapy. 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
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 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 secondary endpoint of 
OS, 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:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2
Adverse events (AEs)
Summary tables for adverse events (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 


Novartis
Confidential
Page 130
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 biostatistical and reporting team will grade laboratory data accordingly. 
For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values 
not graded as 1 or higher. Grade 5 will not be used.
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)

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,
 
 might 
be specified in the analysis plan.
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.


Novartis
Confidential
Page 131
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.5.3.5
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
Pharmacokinetics
PK concentrations of ribociclib (and any relevant metabolites such as LEQ803) will be 
summarized by time point using descriptive statistics by treatment only for fulvestrant + 
ribociclib arm. All PK concentration data will be listed as appropriate.
10.5.4.1
Data handling principles
Plasma samples will be assayed for ribociclib concentrations by Novartis or Novartis designated 
laboratory using validated LC-MS/MS methods with a LLOQ of approximately 1.00 ng/mL for 
ribociclib.
All concentrations below the LLOQ will be displayed in listings as zero with a flag and handled 
as zero in any calculations of summary statistics, but handled as missing for the calculation of 
the geometric means and their CV. Any missing PK parameter data will not to be imputed.
10.5.5
Patient-reported outcomes
The EORTC QLQ-C30 questionnaire and the EuroQol EQ-5D-5L will be used to collect 
patient’s QoL data. The BPI-SF will be used to assess patient’s subjective assessment of cancer-
related pain. The global health status/QoL scale score of the QLQ-C30 is identified as the 
primary patient-reported outcome variable of interest. Physical functioning, emotional 
functioning and social functioning scale scores of the QLQ-C30, the health status index score 
and overall health status of the EQ-5D-5L, and worst pain item (based on question 3), pain 
severity index, and pain interference indices of the BPI-SF are identified as secondary patient-
reported QoL variables of interest.
Scoring of PRO data and methods for handling of missing items or missing assessments will be 
handled according to the scoring manual and user guide for each respective patient 
questionnaire (Fayers 2001; Oemar and Janssen 2013; Cleeland 2009). No imputation 
procedures will be applied for missing items or missing assessments. Five health states from 
the EQ-5D-5L will be converted to index values during the data analysis stage and will be 
further defined in the analysis plan. In addition, the visual analog scale (ranging from 0 to 100) 
will be evaluated for patient’s rating of their overall health status.
The number of patients completing the each questionnaire and the number of missing or 
incomplete assessments will be summarized by treatment group for each scheduled assessment 
time points for each cohort. No formal statistical tests will be performed of 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 of the QLQ-C30; health states, 
overall health status, and index values of the EQ-5D-5L, and the worst pain item (question 3), 
pain severity index, and pain interference indices of the BPI-SF at each scheduled assessment 
time point for each cohort. Additionally, change from baseline in the domain scores, health 
states, overall health status, and index values at the time of each assessment will be summarized. 


Novartis
Confidential
Page 132
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Shift tables will be produced to describe worsening of pain from baseline based on the worst 
pain item from the BPI-SF. Patients with an evaluable baseline score and at least one evaluable 
post baseline score during the treatment period will be included in the change from baseline 
analyses.
In addition, a repeated measurement analysis model may be used to compare the two treatment 
groups with respect to changes in the domain scores (global health status/QoL scale score, 
physical functioning, emotional functioning and social functioning scale scores of the QLQ-
C30 index score and overall health status of the EQ-5D-5L, longitudinally over time. 
 
 
Time to definitive 10% deterioration in the global health status/QoL, physical functioning, 
emotional functioning, social functioning will be assessed. The time to definitive 10% 
deterioration is defined as the time from the date of randomization to the date of event, which 
is defined as at least 10% relative to baseline worsening of the corresponding scale score or 
death due to any cause. If a patient has not had an event, time to deterioration will be censored 
at the date of the last adequate QoL evaluation. The distribution will be presented descriptively 
using Kaplan-Meier curves. Summary statistics from Kaplan-Meier distributions will be 
determined, including the median time to definitive 10% deterioration along with two-sided 95% 
confidence interval. Additionally, time to definitive deterioration with different cutoff 
definitions (e.g. 5%, 15%) may be specified in the RAP as deemed appropriate. A stratified Cox 
regression will be used to estimate the hazard ratio (HR), along with two-sided 95% confidence 
interval.


Novartis
Confidential
Page 133
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 134
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 135
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
10.7
Interim analysis
10.7.1
Progression free survival
No PFS interim analysis is planned in this study. 
10.7.2
Overall survival (OS)
OS will be compared between the two treatment groups, provided the primary endpoint PFS is 
statistically significant favoring the test treatment arm (ribociclib + fulvestrant). A gatekeeping 
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 3 analyses is 
planned for OS; at the time of  the final analysis for PFS (provided PFS is significant), at which 
point approximately 161 deaths are expected, after approximately 263 events have been 


Novartis
Confidential
Page 136
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
documented), and a final analysis for OS when approximately 351 deaths are expected 
(expected 56 months from date of first patient to be randomized).
An α-spending function according to Lan-DeMets (O’Brien-Fleming) independent of the one 
used for the primary efficacy analysis, (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 (ribociclib +fulvestrant). 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
Power (%) 
against a hazard 
ratio of 0.67
OS 
events
Cumulative Conditional 
Power (%)
against hazard ratio of 0.71
26
364 (100%)
90
161(46%)
14
39
--
--
263(75%)
60
56
--
--
351(100%)
85
Statistical significance of OS will only be declared if significance for primary PFS analysis has 
been declared.
At the time of final 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 the secondary endpoint (OS), any 
analysis and update after protocol amendment 4 will be descriptive. 
10.8
Sample size calculation
The median time to progression (TTP) for fulvestrant in first line post-menopausal advanced 
breast cancer patients is estimated to be between 8 month (Howell 2004) and 23 months in 
FIRST trial (Robertson et al 2012). For sample size calculation, the median PFS for 1st line 
patients is assumed to be 18 month. The median PFS for fulvestrant in relapsed advanced breast 
cancer is estimated to be between 4.8 months (SoFEA trial, Johnston et al 2013) and 6.5 months 
(CONFIRM trial, Di Leo et al 2010). Since the study population is closer to the population in 
CONFIRM trial, for sample size calculation, the mPFS for fulvestrant in second line is assumed 
to be 6.5 months. It is assumed that 40% and 60% of the patients will be from first line and 
second line respectively. The median PFS in the control arm (fulvestrant + placebo) is estimated 
via simulation to be around 9 months. It is hypothesized that the addition of ribociclib will result 
in a clinically meaningful 33% reduction in the hazard rate of PFS, corresponding to an increase 


Novartis
Confidential
Page 137
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
in median PFS to 13.4 months. A maximum of 364 PFS events will be required to detect a 
hazard ratio of 0.67 with 95% power using the log-rank test at one-sided cumulative 2.5% level 
of significance (EAST 6.3). The increase in power from 90% to 95% while targeting the same 
hazard ratio and the number of events as in the original protocol is primary due to the 
elimination of the futility interim analysis. 
Assuming that enrollment will continue for 
approximately 19 months at a uniform rate and 10% dropout rate by the time of PFS final 
analysis, a total of 660 patients should be randomized to the two treatment groups in 2:1 ratio 
to observe 364 events at approximately 7 months following the randomization of the last patient, 
i.e., 26 months from the randomization date of the first patient in this study. The sample size 
calculation was conducted with software package East 6.3. The sample size calculations are 
based on the estimates from data available from prior studies. A mid-study sample size re-
assessment based on blinded pooled data may be performed prior to any efficacy analysis if 
data from the study indicate substantial deviation from the study assumptions.A Monte-Carlo 
simulation based on 10,000 samples was carried out to characterize the probability of the study 
outcomes under various assumptions of the true hazard ratios (Table 10-2). If the alternative 
hypothesis is true, that is, the true hazard ratio is 0.67, then there is 96% probability the primary 
analysis will be statistically significant.
Table 10-2
Probability of Study Outcomes under various true Hazard Ratios
True Hazard Ratio
% statistical significance*
0.5
100
0.6
99.7
0.67
96
0.7
91
0.8
53
0.9
16
A total of 660 patients will be enrolled with exponential dropout hazard rate 0.0105 (about 10% drop out rate)
*: Based on 10,000 simulations using EAST 6.3
The primary objective of the study is to compare investigator assessed PFS between arms in 
the overall population (both 1st line and 2nd line patients). If  the primary analysis is 
statistically significant, treatment effect will be evaluated in 1st and 2nd line patients 
separately. Based on the estimated median PFS and proportion of patients in 1st line and 2nd 
line respectively, it is expected that the accumulation of events in 1st line will be slower than 
2nd line patients. To ensure enough information coming from 1st line patients, the final 
analysis will be done after approximately 125 events in the first line patients or approximately 
364 events in both arms whichever comes later. 
Audit size for BIRC assessed 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 0 (i.e. HR < 1) if 
the correlation between investigator assessment and BIRC assessment is 0.7 (the estimated 


Novartis
Confidential
Page 138
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
correlation based on data from the BELLE-2 [CBKM120F2302] study in metastatic breast 
cancer). 
Power for analysis of overall survival
OS will be compared between the two treatment arms, provided that the primary endpoint, PFS, 
is statistically significant. The power statements for overall survival below are therefore 
conditioned on significant primary PFS result. Estimate of first line median OS with fulvestrant 
alone is not published. However the median OS with fulvestrant alone in first line setting is 
expected to be between 34 months (letrozole alone, Mouridsen 2003) and 38 months 
(anastrozole alone, FACT trial, Bergh et al 2012) based on results from endocrine based 
monotherapy studies. For sample size calculation, we assume the median OS for fulvestrant 
alone in first line to be 38 month. Median OS for fulvestrant in relapsed post-menopausal 
advanced breast cancer patients is estimated to be between 19 months (SoFEA trial, Johnston 
et al 2013) and 26 months (CONFIRM trial, Di Leo et al 2014). For sample size calculation, 
the mOS for fulvestrant in second line is assumed to be 26 months. Based on the expected split 
of first line and second line patients mentioned above, the median overall survival of control 
arm is estimated via simulation to be approximately 30 months. It is hypothesized that adding 
ribociclib to fulvestrant will result in a 29% reduction in the hazard rate for OS (corresponding 
to an increase in median survival to 42 months). To detect a hazard ratio of 0.71 with 85% 
cumulative power, a maximum of 353 deaths need to be observed, (using a log-rank test and a 
3-look [superiority only] group sequential design at one-sided cumulative 2.5% level of 
significance). The sample size calculation was conducted with software package East 6.3.
Based on the number of patients planned to be randomized and 10% dropout rate by the time 
of OS final analysis, it is estimated that these 353 deaths will be observed at approximately 56
months after the randomization of the first patient. Therefore the estimated time for the final 
OS evaluation will be 30 months after the primary analysis of the PFS endpoint.
Sample size justification for PK collection
Sparse PK sampling will be performed on approximately 150 patients (Table 7-6). Assuming a 
2:1 ratio between the ribociclib and placebo arm, sparse plasma concentrations for ribociclib 
will be available in approximately 100 patients. Trough PK sampling will be performed in all 
remaining patients (Table 7-7). PK data collected from this study may also be combined with 
data from other studies to support a population PK analysis of ribociclib using non-linear mixed 
effect modeling. The choice of sampling time points was selected to ensure capture of Cmax. 
The aim of this analysis is to analyze the pharmacokinetics of ribociclib in a sample size as 
large as possible. This sample is anticipated to represent the covariate distributions in the 
targeted population. No specific hypothesis will be tested and therefore no specific sample size 
calculation has been performed. The decisions on number of sparse PK samples and number of 
patients needed are driven by feasibility.


Novartis
Confidential
Page 139
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given her understanding. If the patient is capable of doing 
so, he/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.


Novartis
Confidential
Page 140
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


Novartis
Confidential
Page 141
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
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.


Novartis
Confidential
Page 142
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
13
References (available upon request)
Aaronson NK, Ahmedzai S, Bergman B, et al (1993) The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst. Mar 3;85(5):365-76.
Addo S, Yates RA, Laight A.(2002) A phase I trial to assess the pharmacology of the new 
oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal 
volunteers. Br J Cancer. Dec 2;87(12):1354-9.
Agrawal A, Ayantunde A, Rampaul R et al, 2007. Male breast cancer: a review of clinical
management Breast Cancer Res Treat 103:11–21
American Cancer Society: Cancer facts and figures 2015. Atlanta, GA: American Cancer 
Society, 2015. Also available online (PDF-1444 KB).
Amit O, Mannino F, Stone AM, et al (2011) Blinded independent central review of 
progression in cancer clinical trials: results from a meta-analysis. European Journal of Cancer 
2011; 47: 1772-1778.
Antoine DJ, Jenkins RE, Dear JW et al (2012) Molecular forms of HMGB1 and keratin-18 as 
mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen 
hepatotoxicity. J Hepatol. 2012 May;56(5):1070-9.
ASCO Guidelines 2006 Update of ASCO Practice Guideline Recommendations for the Use of 
White Blood Cell Growth Factors: Guideline Summary (J Clin Oncol 24:3187-3205, 2006)
ars.usda.gov/Services/docs.htm?docid=22115
Baselga J, Campone M, Piccart M, Burris HA et al (2012) Everolimus in postmenopausal 
hormone-receptor-positive advanced breast cancer. N Engl J Med. Feb 9;366(6):520-9
Bergh J, Jönsson PE, Lidbrink EK,et al (2012). FACT: an open-label randomized phase III 
study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-
line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol.
2012 Jun 1;30(16):1919-25. doi: 10.1200/JCO.2011.38.1095. Epub 2012 Feb 27.
Beroukhim R, Mermel CH, Porter D, et al (2010) The landscape of somatic copy-number 
alteration across human cancers. Nature. 463(7283):899-905.
Beslija S, Bonneterre J, Burstein HJ, et al (2009). Third consensus on medical treatment of 
metastatic breast cancer. Ann Oncol; 20: 1771-85.
Bosco EE, Wang Y, Xu H, et al (2007) The retinoblastoma tumor suppressor modifies the 
therapeutic response of breast cancer. J Clin Invest, 117: 218-28
Buzdar AU, Jonat W, Howell A, et al (1998) Anastrozole versus megestrol acetate in the 
treatment of postmenopausal women with advanced breast carcinoma: Results of a survival 
update based on a combined analysis of data from two mature phase III trials. Arimidex Study 
Group. Cancer 83:1142-1152, 1998
Caldon CE, Daly RJ, Sutherland RL, et al (2006) Cell cycle control in breast cancer cells. J 
Cell Biochem. 2006 Feb 1;97(2):261-74
Ciruelos E, Pascual T, Arroyo Vozmediano ML et al (2014) Blanco M, Manso L, Parrilla L, 
Muñoz C, Vega E, Calderón MJ, Sancho B, Cortes-Funes H. The therapeutic role of 


Novartis
Confidential
Page 143
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
fulvestrant in the management of patients with hormone receptor-positive breast cancer.
Breast. 2014 Jun;23(3):201-8. doi: 10.1016/j.breast.2014.01.016. Epub 2014 Mar 1
Cleeland CS (2009) The Brief Pain Inventory. User Guide. Houston, Texas.
Cleeland CS, Ryan KM. (1994) Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med Singapore 23(2): 129-138.
Cristofanilli M, Bondarenko I, Ro J, Im S-A, Masuda N, Colleoni M, DeMichele AM, Loi S, 
Verma S, Iwata H, Huang Bartlett C, Zhang K, Puyana Theall K, Turner NC, Slamon DJ.
PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal 
women with hormone receptor-positive, HER2-negative metastatic breast cancer that 
progressed on prior endocrine therapy—confirmed efficacy and safety poster  P4-13-01 SABC 
Cruz Jurado J, Richart Aznar P, et al (2011) Management of patients with metastatic breast 
cancer. Adv Ther. 2011 Sep;28 Suppl 6:50-65. Epub 2011 Sep 16.
Di Leo, A ; Jerusalem, G ; Petruzelka, L et al (2014) Final Overall Survival: Fulvestrant 500 
mg vs 250 mg in the Randomized CONFIRM Trial. Jnci-Journal Of The National Cancer 
Institute, 2014 Jan, Vol.106(1)
Di Leo A, Malorni L. Polyendocrine treatment in estrogen receptor-positive breast cancer: a 
"FACT" yet to be proven. J Clin Oncol. 2012 Jun 1;30(16):1897-900.
Di Leo A, Jerusalem G, Petruzelka L, et al (2010) Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with 
estrogen receptor-positive advanced breast cancer. J.Clin.Oncol.; 28 (30):4594-4600.
Dodd E L, Korn L E, Freidlin B, Gray R, Bhattacharya S. An audit strategy for
progression-free survival. Biometrics, Vol 67, Issue 3; 1092-99, 2011.
Dombernowsky P, Smith I, Falkson G, et al (1998) Letrozole, a new oral aromatase inhibitor 
for advanced breast cancer: double-blind randomized trial showing a dose effect and 
improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998 
Feb;16(2):453-61.
Eisenhauer et al (2009) New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Journal of Cancer 45(2009)228-247
Ellis R. E. (1961) The Distribution of Active Bone Marrow in the Adult, Phy. Med. Biol. 
5,255-258
Ellis et al (2015) Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of 
Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study. 
JCO .2015.61.5831
Ertel A, Dean JL, Rui H, et al (2010) RB-pathway disruption in breast cancer: differential 
association with disease subtypes, disease-specific prognosis and therapeutic response. Cell 
Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
 
 
EuroQol Group (1990) EuroQol-a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199-208.


Novartis
Confidential
Page 144
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Faslodex US Prescribing Information (2014) available at: 
//azpicentral.com/faslodex/faslodex.pdf#page=1 (last accessed 03-Mar-2015).
Fayers PM, Aaronson NK, Bjordal K, et al (2001) on behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European 
Organisation for Research and Treatment of Cancer,Brussels 2001.
FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies.
fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsad
visorycommittee/ucm311141.pdf
Finn, Rs, Crown, JP, Lang, I; et al (2015). The cyclin-dependent kinase 4/6 inhibitor 
palbociclib in combination with letrozole versus letrozole alone as first-line treatment of 
oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): 
a randomised phase 2 study. Lancet Oncology, 2015 Jan, Vol.16(1), pp.25-35
Finn RS, Dering J, Conklin D, et al (2009) PD 0332991, a selective cyclin D kinase 4/6 
inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human 
breast cancer cell lines in vitro. Breast Can Res 11:R77.
Foerster R, Schroeder L, Foerster F, et al (2014). Metastatic male breast cancer: a
retrospective cohort analysis Breast Care.;9(4):267-71.
Giordano S, Buzdar A, Hortobagyi G, et all 2002 Breast Cancer in Men. Ann Intern
Med.;137:678-687
Glimm, E., Maurer, W., and Bretz, F. (2010) Hierarchical testing of multiple endpoints in 
group-sequential trials. Statistics in Medicine 29, 219-228
Grunberg SM, Espersen BT, et al (2010) Evaluation of new antiemetic agents and definition 
of antineoplastic agent emetogenicity--state of the art. Support Care Cancer.;19 Suppl 1:S43-
7.
Holm K, Staaf J, Jönsson G, et al (2012) Characterisation of amplification patterns and target 
genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. 
Breast Cancer Res Treat. 133(2):583-94.
Howell A, Robertson JF, Abram P,et al (2004) Comparison of fulvestrant versus tamoxifen 
for the treatment of advanced breast cancer in postmenopausal women previously untreated 
with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004
May 1;22(9):1605-13.
Huang H, Groth J, Sossey-Alaoui K, et al (2005) expression of novel and previously 
described cell membrane markers in human breast cancer cell lines and tumors. Clin Cancer 
Res. 2005 Jun 15;11(12):4357-64.
Jeffrey R. Infante A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with 
advanced solid tumors and lymphomas. ASCO 2014; abstract 2528
Johnston SR, Kilburn LS, Ellis P, et al (2013); SoFEA investigators. Fulvestrant plus 
anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase 
inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or 


Novartis
Confidential
Page 145
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet 
Oncol. 2013 Sep;14(10):989-98.
Johnston S., Kilburn L.S., Ellis P. et al (2012) Fulvestrant alone or with concomitant 
anastrozole vs Exemestane following progression on non-steroidal aromatase inhibitor: first 
results of the SoFEa trial. EJC Volume 47, Supplement 2.
Knudsen ES, Knudsen KE (2008) Tailoring to RB: tumour suppressor status and therapeutic 
response. Nat Rev Cancer. 2008 Sep;8(9):714-24.
Lan KK, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika; 70: 
659-63
Lange CA, Yee D (2011) Killing the second messenger: targeting loss of cell cycle control in 
endocrine-resistant breast cancer. Endocrine-Related Cancer; 18: C19–C24.
Leung BS, Potter AH (1987) Mode of estrogen action on cell proliferation in CAMA-1 cells: 
II. Sensitivity of G1 phase population. J Cell Biochem, 34: 213-25
McMahon C, Suthiphongchai T, DiRenzo J, et al (1999) P/CAF associates with cyclin D1 and 
potentiates its activation of the estrogen receptor. Proc Natl Acad Sci USA; 96: 5382-7
Miller TW, Balko JM, Fox EM, et al (2011) ERα- dependent E2F transcription can mediate 
resistance to estrogen deprivation in human breast cancer. Cancer Discov; 1: 338-51.
Mouridsen H, Gershanovich M, Sun Y, et al (2003) Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis 
of survival and update of efficacy from the International Letrozole Breast Cancer Group. J 
Clinl Oncol 2003; 21: 2101-9.
Mouridsen H, Gershanovich M, Sun Y, et al (2001) Superior efficacy of letrozole versus 
tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: 
results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol; 
19: 2596-606
Musgrove EA, Caldon CE, Barraclough J, et al (2011) Cyclin D as a therapeutic target in 
cancer. Nat Rev Cancer 11:558-72.
National Cancer Center Network Treatment Guidelines for Breast Cancer, Version 2.2015.
//nccn.org/professionals/physician_gls/pdf/breast.pdf.
Neuman E, Ladha MH, Lin N, et al (1997) Cyclin D1 stimulation of estrogen receptor 
transcriptional activity independent of cdk4. Mol Cell Biol; 17: 5338-47
Nicholson RI, Hutcheson IR, Hiscox SE, et al (2005) Growth factor signalling and resistance 
to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth 
factor therapies to treat or delay endocrine resistance in breast cancer. Endocr Relat Cancer. 
Suppl 1:S29-36. Review.
O'Brien NA, di Tomaso E, Ayala R, et al (2014) In vivo efficacy of combined targeting of 
CDK4/6, ER and PI3K signaling in ER+ breast cancer. In: Proceedings of the 105th Annual 
Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. 
Philadelphia (PA): AACR; 2014. Abstract nr 4756
Oemar M, Jannsen B. (2013) EQ-5D-5L User Guide: Basic information on how to use the 
EQ-5D-5L instrument. Version 2.0, October 2013. © EuroQol Group 2013.


Novartis
Confidential
Page 146
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 5(6):649-55
Paridaens RJ, Dirix LY, Beex LV,et al (2008) Phase III study comparing exemestane with 
tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal 
women: the European Organisation for Research and Treatment of Cancer Breast Cancer 
Cooperative Group. J Clin Oncol. 2008 Oct 20;26(30):4883-90. doi: 
10.1200/JCO.2007.14.4659. Epub 2008 Sep 15.
Patten D, Sharifi L, Fazel M. (2013) New Approaches in the Management of Male Breast
Cancer Clin Breast Cancer, Vol. 13, No. 5, 309-14.
Perou CM, Sorlie T, Eisen MB, et al (2000) Molecular portraits of human breast tumours. 
Nature; 406 (6797):747-752.
Rabin R, de Charro F (2001) EQ-5D: a measure of health status from the EuroQol Group. 
Ann Med. 33:337–343
Robertson, Jfr, Lindemann, J, Garnett, S et al (2014) A Good Drug Made Better: The 
Fulvestrant Dose-Response Story. Clinical Breast Cancer, 2014 Dec, Vol.14(6), pp.381-389
[Peer Reviewed Journal]
Robertson JFR, Llombart-Cussac A, Feltl D, et al (2014) Fulvestrant 500 mg versus 
anastrozole as first-line treatment for advanced breast cancer: Overall survival from the phase 
II “first” study. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 
2014; San Antonio, Texas. Abstract S6-04.
Robertson JFR, Lindemann JPO, et al (2012) Fulvestrant 500 mg versus anastrozole 1 mg for 
the first-line treatment of advanced breast cancer: follow-up analysis from the randomized 
‘FIRST’ study. Breast Cancer Res Treat (2012) 136:503–511.
Roila F, van der Wetering M, et al (2016) 2016 MASCC and ESMO guideline update for the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea 
and vomiting in advanced cancer patients. Ann Oncol. 27(suppl 5):v119-v133.
Roussel MF, Theodoras AM, Pagano M, et al (1995) Rescue of defective mitogenic signaling 
by D-type cyclins. Proc Natl Acad Sci USA; 92: 6837-41Russmann S, Jetter A, Kullak-Ublick 
GA. (2010) Pharmacogenetics of drug-induced liver injury. Hepatology. 2010 Aug;52(2):748-
61. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. 
Genes Dev; 9: 1149-63
Russmann S, Jetter A, Kullak-Ublick GA (2010) Pharmacogenetics of drug-induced liver 
injury. Hepatology; 52(2):748-61.
Sherr CJ, Roberts IM (1999) CDK inhibitors: positive and negative regulators of G1-phase 
progression. Genes Dev; 13: 1501-12
Sotiriou C, Pusztai L (2009) Molecular Origins of Cancer Gene-Expression Signatures in 
Breast Cancer. New England Journal of Medicine; 360 (8):790-800.
Thangavel C, Dean JL, Ertel A, et al (2011) Therapeutically activating RB: reestablishing cell 
cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. Apr 
28;18(3):333-45. doi: 10.1530/ERC-10-0262. Print 2011 Jun


Novartis
Confidential
Page 147
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
The Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human 
breast tumours. Nature. 490: 61-70.
Turner N.C. et al (2015) Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. 
N Engl J Med 373:209-219
Wakeling AE. (2000) Similarities and distinctions in the mode of action of different classes of 
antioestrogens. Endocr Relat Cancer. Mar;7(1):17-28.
Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell; 81: 323-30
Zhang JJ, Chen H, He K, Tang S, Justice R, Keegan P, Pazdur R and Sridhara R. Evaluation 
of blinded independent central review of tumor progression in oncology clinical trials: a meta-
analysis. Therapeutic innovation & regulatory science: 2012, 47(2): 167-174.
Zwijsen RM, Buckle RS, Hijmans EM, et al (1997) CDK-independent activation of estrogen 
receptor by cyclin D1. Cell; 88: 405-15
Zwijsen RM, Buckle RS, Hijmans EM, et al (1998) Ligand-independent recruitment of steroid 
receptor coactivators to estrogen receptor by cyclin D1. Genes Dev; 12: 3488-98


Novartis
Confidential
Page 148
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 ribocilcib.
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Novartis PK Sciences Memorandum , Drug-Drug Interaction (DDI) and Co-
Medication Considerations for Novartis Clinical Trials (release date: January 2018), which was 
compiled from the Indiana University School of Medicine’s P450 Drug Interaction Table 
(http//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) 
(http//wwwfda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m292362.pdf), 
and 
the 
University 
of 
Washington’s 
Drug 
Interaction 
Database
(http//wwwdruginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(wwwqtdrugs.org/). 
Please contact the medical monitor with any questions.
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, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)2, 3
CYP3A 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


Novartis
Confidential
Page 149
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Category
Drug Name
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 the study drug.
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 wwwcrediblemeds.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.


Novartis
Confidential
Page 150
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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, cobimetinib, cannabinoids6, 
cannabidiol6, darifenacin,  dasatininb, ebastine, eletriptan, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole, 
ivabradine, ivacaftor, lumefantrine, lurasidone, maraviroc, midazolam, 
midostaurin, naloxegol, neratinib, 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
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, granisertron, 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, olanzapine,
osimertinib, 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, vorinostat, ziprasidone
MATE1/2 substrates3
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline
OCT1/2 substrates4
Amantadine, carboplatin, cisplatin cephalexin, cephradine, ipratropium, 
lamivudine, linagliptin, metformin, oxaliplatin, 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


Novartis
Confidential
Page 151
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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 https wwwcrediblemeds.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 is prohibited when combined with ritonavir (see Table 14-1)
6 Based 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.


Novartis
Confidential
Page 152
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2
Appendix 2 - Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.2: 11-Feb-2016
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
11-Feb-2016
Authors (Version 3.2):
Authors (Version 3.1):
Authors (Version 3):
Authors (Version 2):
Authors (Version 1):


Novartis
Confidential
Page 153
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


Novartis
Confidential
Page 154
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2.1 Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.2.2 and the definition of best response in
Section 14.2.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.29 of 
this guideline describes data handling and programming rules. This section is to be referred to
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.2.2 Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.2.3 Definitions
14.2.4 Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.2.27.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.


Novartis
Confidential
Page 155
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.2.5 Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
14.2.27.
14.2.6 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.


Novartis
Confidential
Page 156
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up assessments 
by CT will be needed to determine if there is truly progression occurring at that site. In all cases 
PD will be the date of confirmation of new disease by CT (or some other conventional technique 
such as MRI) rather than the date of the positive PET scan. If there is a positive PET scan 
without any confirmed progression at that site by CT, then a PD cannot be assigned.

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers. 

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 


Novartis
Confidential
Page 157
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.2.7 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.2.4.

Nodal target: See Section 14.2.4.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 


Novartis
Confidential
Page 158
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.2.8 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-3) and non-target lesions (Table 14-4) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-5) as well as the presence or absence of new lesions.
14.2.9 Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
14.2.10
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
14.2.11
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 


Novartis
Confidential
Page 159
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.2.12
Determination of target lesion response
Table 14-3
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 14.2.6.)
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following  
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-3 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 


Novartis
Confidential
Page 160
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.


Novartis
Confidential
Page 161
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

A change in method for the evaluation of one or more lesions will usually lead to an 
UNK target lesion response unless there is progression indicated by the remaining lesions 
which have been evaluated by the same method. In exceptional circumstances an 
investigator or central reviewer might over-rule this assignment to put a non-UNK 
response using expert judgment based on the available information. E.g. a change to a 
more sensitive method might indicate some tumor shrinkage of target lesions and 
definitely rule out progression in which case the investigator might assign an SD target 
lesion response; however, this should be done with caution and conservatively as the 
response categories have well defined criteria.
14.2.13
Determination of non-target lesion response
Table 14-4
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 judgment to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK)

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 


Novartis
Confidential
Page 162
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.2.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.2.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.2.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.2.6.
14.2.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in
Table 14-5.
Table 14-5
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


Novartis
Confidential
Page 163
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.2.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.2.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.27 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.2.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
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.


Novartis
Confidential
Page 164
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
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.


Novartis
Confidential
Page 165
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of  SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
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).


Novartis
Confidential
Page 166
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.2.19
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
14.2.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.2.21
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.2.22
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 


Novartis
Confidential
Page 167
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.2.24
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).


Novartis
Confidential
Page 168
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.2.25
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.2.24. 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.


Novartis
Confidential
Page 169
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2.26
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.2.27).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

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 


Novartis
Confidential
Page 170
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.2.27
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-6.
Table 14-6
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.2.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
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.


Novartis
Confidential
Page 171
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2.28
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.2.26, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:
Table 14-7
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 14.2.26
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.2.26.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.


Novartis
Confidential
Page 172
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (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 


Novartis
Confidential
Page 173
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-7 the
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.2.29
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.2.30
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.2.31
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 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


Novartis
Confidential
Page 174
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment
Treatment duration completed as per protocol (optional, to be used if only a fixed number of 
cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial. 
14.2.32
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
14.2.33
Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 


Novartis
Confidential
Page 175
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.2.34
Programming rules
The following should be used for programming of efficacy results:
14.2.35
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.36
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.2.26). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.2.37
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.2.38
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.2.39
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.


Novartis
Confidential
Page 176
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.2.40
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-7)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.2.26. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.2.41
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man


Novartis
Confidential
Page 177
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
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


Novartis
Confidential
Page 178
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.3
Appendix 3 - 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


Novartis
Confidential
Page 179
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
14.4
Appendix 4 - Patient reported outcomes
Figure 14-1
EORTC QLQ-C30


Novartis
Confidential
Page 180
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 181
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Figure 14-2
EQ-5D-5L


Novartis
Confidential
Page 182
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 183
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301


Novartis
Confidential
Page 184
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301
Figure 14-3
Brief Pain Inventory-Short Form


Novartis
Confidential
Page 185
Amended Protocol Version 04 (Clean)
Protocol No. CLEE011F2301

SAP_003.pdf: 
Clinical Development
LEE011 (ribociclib)
CLEE011F2301 (MONALEESA-3) / NCT02422615
MONALEESA-3: A randomized double-blind, placebo-controlled 
study of ribociclib in combination with fulvestrant for the treatment 
of men and postmenopausal women with hormone receptor 
positive, HER2-negative, advanced breast cancer who have 
received no or only one line of prior endocrine treatment
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


Novartis
Confidential
Page 2
SAP 
CLEE011F2301
Document History – Changes compared to previous version of SAP.
Version
Date
Changes
1.0
09-Jan-2023
First version


Novartis
Confidential
Page 3
SAP 
CLEE011F2301
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 ...............................................................................11
2.1
Definitions .............................................................................................................11
2.1.1
Study drug and study treatment.............................................................11
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 ......................................12
2.1.6
Study day...............................................................................................12
2.1.7
Baseline.................................................................................................12
2.1.8
On-treatment assessment/event.............................................................13
2.1.9
Last contact date....................................................................................13
2.2
Data included in the analysis .................................................................................14
2.3
Analysis sets ..........................................................................................................15
2.3.1
Full analysis set (FAS)..........................................................................15
2.3.2
Safety Set ..............................................................................................15
2.3.3
Cross-over analysis set..........................................................................15
2.3.4
Patient classification..............................................................................15
3
Statistical methods used in reporting.................................................................................16
3.1
Background and demographic characteristics .......................................................16
3.1.1
Basic demographic and background data..............................................16
3.2
Protocol deviation summaries................................................................................16
3.3
Groupings for analysis...........................................................................................16
3.4
Patient disposition..................................................................................................16
3.5
Study treatment......................................................................................................17
3.5.1
Duration of study treatment exposure...................................................17
3.5.2
Cumulative dose and average daily dose ..............................................18
3.5.3
Dose intensity and relative dose intensity.............................................18
3.5.4
Dose reductions, or interruptions..........................................................19


Novartis
Confidential
Page 4
SAP 
CLEE011F2301
3.5.5
Discontinuation of study treatment components...................................20
3.6
Concomitant and post-treatment therapy...............................................................20
3.7
Safety evaluation ...................................................................................................20
3.7.1
Adverse events (AEs)............................................................................21
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


Novartis
Confidential
Page 5
SAP 
CLEE011F2301
List of tables
Document History – Changes compared to previous version of SAP........................................2
Table 1-1
Study objectives ....................................................................................10
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...........................................................................19
Table 3-2
Clinically notable ECG values..............................................................25
List of figures
Figure 1-1
Study Design ...........................................................................................9


Novartis
Confidential
Page 6
SAP 
CLEE011F2301
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


Novartis
Confidential
Page 7
SAP 
CLEE011F2301
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


Novartis
Confidential
Page 8
SAP 
CLEE011F2301
1
Introduction
This document describes the detailed statistical methodology to be used for the final Clinical 
Study Report (CSR) of study CLEE011F2301, a phase III, randomized, double-blind, placebo-
controlled study of ribociclib or placebo in combination with fulvestrant for the treatment of 
men and postmenopausal women with hormone receptor positive, HER2-negative, advanced 
breast cancer who have received no or only one line of prior endocrine treatment. 
The content of this SAP is based on CLEE011F2301 protocol amendment 4 (Jan 29, 2020). 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 Tables Figures and Listings (TFL) shells and Programming Datasets 
Specifications (PDS) documents, respectively.
1.1
Study design
This is a randomized, phase III, double blind, placebo controlled, international study to 
determine the efficacy and safety of treatment with fulvestrant with ribociclib versus fulvestrant 
with placebo in men and postmenopausal women with HR+, HER2-negative advanced breast 
cancer. This study will consist of 4 phases: screening (up to 28 days), randomized treatment, 
post-treatment efficacy follow-up, and post-treatment survival follow-up.
Approximately 660 patients will be randomly assigned to one of the following treatment arms 
in a 2:1 ratio.

Experimental arm: fulvestrant (500 mg intramuscular [as two 5 mL injections] on Cycle 1 
Days 1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + ribociclib (600 mg by mouth 
once daily for three weeks followed by one week break, in a 28-day cycle)
OR

Control arm: fulvestrant (500 mg intramuscular [as two 5 mL injections] on Cycle 1 Days 
1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + ribociclib placebo (by mouth once 
daily for three weeks followed by one week break, in a 28-day cycle)
Randomization will be stratified by the following factors:
1. Lung or liver metastases: (yes vs no)
2. Previous endocrine therapy (A vs B) according to the following definition:
A) Patients treatment naïve in the metastatic/advanced disease setting:
i- whose disease relapsed >12 months after completion of (neo)adjuvant endocrine 
therapy with no subsequent treatment for advanced/metastatic disease,
OR
ii- with de-novo advanced/metastatic disease (no prior exposure to endocrine therapy).
B) Patients who received up to 1 line of treatment for metastatic/advanced disease:
i- whose disease relapsed on or within 12 months from completion of (neo) adjuvant 
endocrine therapy, with no subsequent treatment for advanced/metastatic disease,


Novartis
Confidential
Page 9
SAP 
CLEE011F2301
OR
ii- whose disease relapsed > 12 months from completion of (neo) adjuvant endocrine 
therapy, and progressed
on or after subsequent endocrine treatment for 
advanced/metastatic disease,
OR
iii- with advanced/metastatic disease at the time of diagnosis that progressed on or after 
endocrine therapy for advanced/metastatic disease with no prior (neo) adjuvant 
treatment for early disease.
Following the statistically significant PFS and OS benefit, with protocol amendment 4, 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.
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 secondary endpoint. Both PFS and OS have been 
tested statistically significant and results have been summarized by previous study reports. 


Novartis
Confidential
Page 10
SAP 
CLEE011F2301
Table 1-1
Study objectives
Objective
Endpoint
Primary
To compare PFS between ribociclib in combination 
with fulvestrant to placebo in combination with 
fulvestrant among men and postmenopausal 
women with HR+, HER2-negative advanced breast 
cancer who received no or only one prior endocrine 
treatment for advanced disease
PFS based on local radiology assessments and using 
RECIST 1.1 criteria
Secondary
To compare the two treatment arms with respect 
to overall survival.
Overall survival
To evaluate the two treatment arms with respect to 
overall response rate, clinical benefit rate, time to 
response and duration of response. 
ORR as defined by RECIST 1.1. CBR, defined as 
percentage of patients with CR, PR or SD lasting 24 weeks 
or longer, TTR, DOR per RECIST 1.1
To evaluate the two treatment arms with respect to 
time to deterioration of ECOG performance status.
Time to definitive deterioration of ECOG performance 
status from baseline
To evaluate the safety and tolerability of ribociclib
in combination with fulvestrant.
Frequency/severity of AEs, laboratory abnormalities
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
To characterize the pharmacokinetics (PK) of 
ribociclib
(and relevant metabolites such as
LEQ803) 
when 
given 
in 
combination 
with 
fulvestrant.
Concentration by time point for ribociclib (and relevant 
metabolites such as LEQ803)


Novartis
Confidential
Page 11
SAP 
CLEE011F2301
Objective
Endpoint
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 + fulvestrant, or matching placebo + fulvestrant.
Cross-over open-label ribociclib treatment will refer to ribociclib drug administered to 
patients randomized to placebo plus fulvestrant arm who subsequently cross-over to ribociclib 
plus fulvestrant (cross-over period).
Cross-over open-label ribociclib plus fulvestrant treatment will refer to the combination of 
drugs ribociclib plus fulvestrant 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 


Novartis
Confidential
Page 12
SAP 
CLEE011F2301
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 fulvestrant 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 fulvestrant treatment is defined as the last date when a non-zero dose of 
any component of the cross-over open-label ribociclib plus fulvestrant 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 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.
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. 


Novartis
Confidential
Page 13
SAP 
CLEE011F2301
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 fulvestrant 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:
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 fulvestrant
treatment, date of last administration of the cross-over open-label ribociclib plus fulvestrant 
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.


Novartis
Confidential
Page 14
SAP 
CLEE011F2301
Source data
Conditions
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
PK collection dates
At least 1 non-missing PK concentration
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)
Hospitalization admission/discharge date
Non-missing type of facility admitted to
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.


Novartis
Confidential
Page 15
SAP 
CLEE011F2301
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.
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. 


Novartis
Confidential
Page 16
SAP 
CLEE011F2301
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 
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)


Novartis
Confidential
Page 17
SAP 
CLEE011F2301
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 fulvestrant treatment will be 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
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 ribociclib/placebo (days) = (last date of exposure to 
ribociclib/placebo) – (date of first administration to ribociclib/placebo) + 1.
Duration of exposure to fulvestrant (days) = (last date of exposure to fulvestrant) – (date of 
first administration to fulvestrant) + 1.
The last date of exposure is defined as follows for the study treatment components:

For ribociclib /placebo: the last date of exposure is defined as the date of last 
administration of the corresponding medication;

For fulvestrant, the last date of exposure is defined as following:
1. If patient discontinues fulvestrant before C2D1 dose, then:
a.
Last date of exposure = last date of administration + 13 days. 
b. If patient died or lost to follow-up within last date of administration + 13 days, 
then last date of exposure is date of death or last contact date, respectively.
2. If patient discontinues fulvestrant after C2D1 dose, then:
a.
Last date of exposure = last date of administration + 27 days.
b. If patient died or lost to follow-up within last date of administration + 27 days, 
then last date of exposure is date of death or last contact date, respectively.
The duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). The duration of study treatment exposure will be 
summarized 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 fulvestrant treatment will be calculated as above considering the 


Novartis
Confidential
Page 18
SAP 
CLEE011F2301
combination of drugs ribociclib plus fulvestrant 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 ribociclib/placebo for patients with non-zero duration of exposure to 
ribociclib/placebo is defined as follows: 
DI (mg / day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib/placebo
(day),
where adjusted duration of exposure (days) to ribociclib/placebo is the number of ribociclib
/placebo dosing days a patient would be expected to have received per protocol, given their 
duration of exposure. 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 for ribociclib /placebo. The adjusted duration of 
exposure to ribociclib/placebo (in days) is therefore 21 * (# completed 28 day period) + 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) days, then the adjusted duration of exposure to ribociclib/placebo is 21*2+10=52
days. 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 above 
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 ribociclib/placebo is displayed in Table 3-1. Note that 
DI will also be calculated and DI for ribociclib/placebo will be reported in the units displayed 
in Table 3-1, whereas duration of exposure itself will be summarized in months.


Novartis
Confidential
Page 19
SAP 
CLEE011F2301
Table 3-1
Planned dose intensity
Medication
PDI (dose unit/unit of time)
ribociclib /placebo
600 mg/day (3 weeks on 1 week off)
Ribociclib/placebo relative dose intensity (RDI) is defined as:
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).  
Fulvestrant RDI is defined as:
RDI = actual cumulative dose / planned cumulative dose, where planned cumulative dose is 
defined as 500* (# completed D1 in a 28-days cycle) and added by 500 mg if patients completed 
C1D15.
DI for ribociclib/placebo and RDI for ribociclib/placebo and fulvestrant will be summarized 
separately for each of the study treatment.
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 by cross-over open-label 
ribociclib plus fulvestrant 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.


Novartis
Confidential
Page 20
SAP 
CLEE011F2301
3.5.5
Discontinuation of study treatment components
The reasons for discontinuation of ribociclib/placebo will be summarized by treatment arm for 
the double-blind on-treatment period, based on the information on the ribociclib/placebo DAR 
CRF for patients who have the “dose permanently discontinued” box checked.
Partial discontinuation: A 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 fulvestrant 
when the permanent discontinuation checkbox is checked in the ribociclib/placebo DAR page.
Partial discontinuation of ribociclib/placebo will be summarized by treatment for the double-
blind on-treatment period.
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 fulvestrant 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 fulvestrant 
treatment. The AEs started before the first dose but worsening during the treatment period are 
also considered as ‘on-treatment’ events. 


Novartis
Confidential
Page 21
SAP 
CLEE011F2301
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.
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 fulvestrant 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 fulvestrant 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.


Novartis
Confidential
Page 22
SAP 
CLEE011F2301
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 

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

Grade 3 or 4 adverse events, irrespective of causality, by primary system organ class, 
preferred term and maximum grade

Grade 3 or 4 adverse events with suspected relationship to study treatment by primary 
system organ class, preferred term and maximum grade

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


Novartis
Confidential
Page 23
SAP 
CLEE011F2301
AEs of interest will also be summarized. See Section 3.7.1.5 for the grouping details.
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 
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 adverse 
events which are not serious adverse events with an incidence greater than 5% and serious 
adverse events and SAE suspected to be related to study treatment will be provided by system 
organ class and preferred term on the safety set and the cross-over analysis set population.
If for a 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
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 or the date of the day prior to the start of 
open-label ribociclib plus fulvestrant treatment.


Novartis
Confidential
Page 24
SAP 
CLEE011F2301
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):

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 fulvestrant 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


Novartis
Confidential
Page 25
SAP 
CLEE011F2301

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:

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 fulvestrant 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 

Notable ECG 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 


Novartis
Confidential
Page 26
SAP 
CLEE011F2301
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 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.
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 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.
3.7.7
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 fulvestrant treatment will be flagged in the listings.


Novartis
Confidential
Page 27
SAP 
CLEE011F2301
Notable values starting or worsening during the cross-over on-treatment period will be listed 
separately.
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.  


Novartis
Confidential
Page 28
SAP amendment 1 
9-Jan-2023 (5:59)
CLEE011F2301
Appendix 1
CTC grades for laboratory values in Novartis Oncology


Novartis
Confidential
Page 29
SAP amendment 1 
9-Jan-2023 (5:59)
CLEE011F2301


Clinical Development 
LEE011 (ribociclib) 
CLEE011F2301 (MONALEESA-3) / NCT02422615 
MONALEESA-3: A randomized double-blind, placebo-controlled 
study of ribociclib in combination with fulvestrant for the treatment 
of men and postmenopausal women with hormone receptor 
positive, HER2-negative, advanced breast cancer who have 
received no or only one line of prior endocrine treatment 
Statistical Analysis Plan 
Author: 
 Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final Amendment v2.0 
Release date: 
11-Oct-2017
Number of pages: 
77 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Document History – Changes compared to previous version of SAP. 
Version 
Date 
Changes 
1.0 
8/27/2015 
Final version  
2.0 
6/06/2017 
Amendment 1 
Title:  
• 
Change the title to “statistical analysis plan” to align with 
new naming of analysis plan. 
• 
Update the name of the trial per protocol amendment. 
Section 1:  
• 
Add the protocol amendment the SAP is based on. 
• 
Update the naming of RAP M7 and M8. 
Section 1.1:  
• 
Clarify BIRC assessed PFS is a supporting end point for 
primary analysis.  
• 
Clarify the stratification factor definition, patient population, 
screening window per protocol amendment.  
Section 1.2:  
• 
Remove BIRC assessed PFS as a secondary end point per 
protocol amendment.  
• 
Remove PK parameters as secondary end points per 
protocol amendment. 
• 
 
 
• 
 
  
Section 2.1.7: clarify assessments done post dose on first day of 
treatment is not considered in safety baseline.  
Section 2.1.9: update last contact date definition per new SAP 
template and alignment with ML2 (CLEE011A2301) submission. 
Section 2.2:  Remove PFS interim analysis and update OS interim 
analysis per protocol.  
Section 2.3.3, 2.3.5: Modify per protocol set definition to align with 
ML2 submission.  
Section 2.3.4: Clarify the definition of PAS.  
Section 2.4: Replace the prohibited medication table with a 
reference to the protocol and clarify that the most up to date list will 
be used for CSR purpose. Describe which analyses are affected by 
new anti-neoplastic therapies.  
Section 2.5.3: Add clarification about BOR analysis per protocol 
amendment and team discussion. 
Section 2.5.4: Update change in methodology per updated RECIST 
guidance.  
Section 2.5.5:  
• 
Remove the footnote of randomization as day 0 in Table 2-3 
to avoid confusion.  
• 
Remove new anti-neoplastic therapy as a censoring reason 
since the primary analysis doesn’t censoring patients at new 
cancer therapy. 


Novartis 
Confidential 
Page 3 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Version 
Date 
Changes 
Section 2.5.7, Remove the algorithm for constructing water graphs 
section per new SAP template.  
Section 3.2.1: Clarify when the stratification factors are per IRT.  
Section 3.2.2: Add disease free interval and number of de novo 
patients to align with ML2 submission.  
Section 3.2.4: Clarify how surgery, biopsy and radiotherapy will be 
reported. 
Section 3.3: add the PD list leading to exclusion from PPS.  
Section 3.5:  
• 
Add the summary for screening phase disposition. 
Section 3.6.1,  
• 
Add the definition of duration of exposure to 
LEE011/placebo, duration of exposure to fulvestrant to align 
with ML2 submission. 
• 
Update the definition of last date of exposure to fulvestrant 
to align with X2108 (CLEE011X2108).  
Section 3.6.3,  
• 
Remove dose intensity definition for fulvestrant since it is 
difficult to interpret.  
• 
Amend the definition of adjusted dose intensity for 
ribociclib/placebo to align with ML2 submission.  
• 
Remove the definition of RDI per patient since it is not used 
anywhere.  
• 
Update the definition of RDI for fulvestrant to align with 
X2108. 
Section 3.6.4,  
 Align definition for dose interruption, dose delay, dose reduction 
with ML2 submission with the exception that partial discontinuation 
will not be considered as dose reduction. 
Section 3.6.5 Align the definition of partial discontinuation with ML2 
submission.  
Section 3.7: add summary of anti-neoplastic medication after 
discontinuation by medication type.  
Section 3.8, Update the language to reflect the change of reading 
paradigm in BIRC assessment.  
Section 3.8.1.1, Update the PFS censoring option to match the 
updated RECIST guidance and add a table to summarize 
event/censoring cases for primary analysis.  
Section 3.8.1.4,  
• 
Add section audit-based BIRC assessment of PFS per PA 
(protocol amendment). Add a decision rule triggering full 
BIRC assessment. 
• 
Add derived local radiology assessment as one of the 
supportive analyses to align with ML2 submission.  
• 
Update “central radiology review” to “BIRC assessment” to 
align with BIRC read paradigm change.  
• 
Remove supportive analysis due to forced randomization 
since forced randomization is not allowed. 


Novartis 
Confidential 
Page 4 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Version 
Date 
Changes 
• 
Remove IPCW analysis as a supportive analysis per team 
discussion. 
• 
Clarify how multivariate Cox regression will be done.  
• 
Clarify how the analysis using CRF based stratification 
factors will be done. 
Section 3.8.2,  
• 
Remove central assessed PFS as a secondary end point 
per protocol amendment.  
• 
Remove misplaced PK objective. 
Section 3.8.2.1:  
• 
Update the interim analysis for OS per protocol amendment. 
• 
Simplify the subgroup analysis by making a reference to the 
subgroup analysis section.  
• 
Clarify that the OS analysis will be done only after the 
primary analysis is statistically significant.  
• 
Clarify how the multivariate Cox regression should be done. 
Section 3.8.2.2: remove BIRC PFS section which has been replaced 
by Audit-based BIRC assessment of PFS in section 3.8.1.5.  
Section 3.8.2.5: Clarify censoring rule for DOR.  
Section 3.8.2.6: ECOG PS 
• 
Update the rule when 2 ECOG assessments fall in the same 
window to align with ML2 submission. 
• 
Clarify the definition of definitive deterioration.  
• 
Add estimation of HR to align with ML2 submission. 
Section 3.8.2.7:  
• 
Update the mixed model to align with ML2 submission. 
• 
Add EOT and efficacy FU to table 3-5.  
• 
Add linear model for selected time points. 
• 
Clarify time is a continuous variable in mixed model. 
Section 3.9.1.4: Add number of occurrences output per safety 
guidance. 
Section 3.9.1.5: Update CNAE to AESI per new SAP template. 
Section 3.9.2:  
• 
Add definition of Total ANC. 
• 
Update analysis for LFT to align with ML2 submission and 
add clarification. 
• 
Add analysis for time to onset and duration of AE to align 
with ML2 submission. 
• 
Add box plot. 
• 
Clarify that CTCAE calculation is based on observed data 
only.  
Section 3.9.4:  
• 
Add language to clarify how unscheduled assessment is 
summarized.  
• 
Remove parameter RR to align with the notable ECG table. 
• 
Update notable heart rate criteria to align with new SAP 


Novartis 
Confidential 
Page 5 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Version 
Date 
Changes 
template. 
• 
Clarify the ECG baseline definition to align with ML2 
submission. 
• 
Add the time to G2 or worse QT prolongation analysis.  
Section 3.9.6: add urinalysis section to align with ML2 submission. 
Section 3.10.1: Clarify what are evaluable concentrations.  
Section 3.10.2: Remove PK parameter section per protocol 
amendment. Clarify that the Asian subgroup is based on race.  
Section 3.10.3:  
• 
Add summary of PK concentration by dose.  
• 
Remove PK geometric mean graphic presentation per 
protocol amendment. 
• 
Add meal record listing. 
Section 3.10.4:  
• 
Delete the Exposure vs. tumor size analysis due to presence 
of non-measurable disease.  
• 
Add exposure vs PFS and TTR since PFS and TTR are 
more relevant end points in registration trial.  
• 
Delete the exposure vs. neutropenia analysis since the 
relationship is already clear based on ML2 data.  
• 
Remove scatter plot from exposure vs liver function analysis 
given that the boxplots will characterize the relationship 
between exposure and liver function.  
• 
Replace model based exposure vs ECG analysis by 
summary of ECG by dose group. 
Section 3.10.5: remove PK parameter imputation rule to align with 
protocol amendment. 
 
Section 3.13 (old): update projected interim analysis timeline table 
per protocol amendment.  
Section 3.13.1: remove PFS interim analysis per protocol 
amendment. Move the projected timeline table to OS section.  
Section 3.13.2: update OS interim analysis per protocol amendment. 
Section 14: clarify that subgroups will be derived based on non-IRT 
data.   
Section 3.14: update subgroups per team discussion. 
 


Novartis 
Confidential 
Page 6 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Version 
Date 
Changes 
• 
Add audit size for BIRC assessed PFS section.  
Section 3.16: update numbers related to OS interim analysis per 
protocol amendment.  
Section 4.2: add other time to event end points mentioned in the 
document. 
Section 4.2.2: remove the SAS code per new SAP template 
Section 4.2.3:  
• 
Remove SAS code per new SAP template. 
• 
Align the log rank test with the test in section 3.  
Section 4.2.4: align the Kaplan-Meier estimates language with new 
SAP template.  
Section 4.3: remove PFS interim analysis per protocol amendment. 
Section 4.3.1: remove beta spending function section since futility 
interim analysis has been removed.  
Section 4.3.1.1: Remove predictive probability of success (PPOS) 
section since PFS interim analysis has been removed per protocol 
amendment. 
Section 4.3.2: remove technical detail about familywise type I error 
rate control about both PFS and OS tests due to the removal of PFS 
interim analysis. 
Section 4.4:  
• 
Remove typo about PFS calculation. 
• 
Add GAP analysis. 
Section 4.5: Remove IPCW per team discussion.  
Section 4.6: Remove the exposure vs ECG section.  
Section 4.7: Add audit-based BIRC PFS section 
Section 5: Add new references. 
Appendix 1: add lab CTC grades table. 
 
 
 
2.0 
10/11/2017 
Amendment 2 
Section 2.1.7 
• 
Add clarification that a windows of 7 days is allowed for RECIST 
baseline if investigators overall response is within 7 days of 
treatment start date 
Section 3.2 
• 
Clarify the definition of disease free interval 
• 
Add the subgroup definition by prior endocrine therapy status 
Section 3.6.3 
• 
Clarify the definition of planned cumulative dose for fulvestrant 
Section 3.8 
• 
For EQ-5D-5L PRO, change “index score” to “visual analog 
scale” to be consistent with the protocol 
Section 3.9 
• 
Remove the definition of total ANC since some of the 
percentages of immature WBC is not available 


Novartis 
Confidential 
Page 7 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Version 
Date 
Changes 
Section 4.2 
• 
Add time to first chemotherapy only 
• 
Correct the number of strata K in the stratified log-rank test 
• 
Add threshold of ±7 days for the agreement between local and 
central response   
 
 
 
 


Novartis 
Confidential 
Page 8 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Table of contents 
 
Table of contents ................................................................................................................. 8 
List of tables ...................................................................................................................... 11 
List of figures .................................................................................................................... 11 
1 
Introduction ....................................................................................................................... 14 
1.1 
Study design........................................................................................................... 14 
1.2 
Objectives .............................................................................................................. 16 
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 ............................................. 18 
2.1.3 
Date of last administration of study drug .............................................. 18 
2.1.4 
Date of first administration of study treatment ..................................... 18 
2.1.5 
Date of last administration of study treatment ...................................... 18 
2.1.6 
Study day ............................................................................................... 18 
2.1.7 
Baseline ................................................................................................. 19 
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 .......................................................................................................... 21 
2.3.1 
Full analysis set (FAS) .......................................................................... 21 
2.3.2 
Safety set ............................................................................................... 21 
2.3.3 
Per protocol set ...................................................................................... 21 
2.3.4 
Pharmacokinetic analysis  set ................................................................ 22 
2.3.5 
Patient classification .............................................................................. 22 
2.4 
Concomitant medications with specific impact on the analysis ............................ 22 
2.5 
Implementation of RECIST ................................................................................... 23 
2.5.1 
Overall lesion responses for patients with only non-measurable 
lesions at baseline .................................................................................. 23 
2.5.2 
Disease progression ............................................................................... 24 
2.5.3 
Best overall response (BOR) ................................................................. 24 
2.5.4 
Change in imaging modality ................................................................. 25 
2.5.5 
Determination of missing adequate assessments .................................. 25 
2.5.6 
No baseline tumor assessments ............................................................. 27 
2.5.7 
Construction of waterfall graphs ........................................................... 27 


Novartis 
Confidential 
Page 9 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 ............................................................. 29 
3.2.3 
Medical history ...................................................................................... 29 
3.2.4 
Prior anti-neoplastic therapy ................................................................. 30 
3.2.5 
Other ...................................................................................................... 30 
3.3 
Protocol deviation summaries................................................................................ 30 
3.4 
Groupings for analysis ........................................................................................... 30 
3.5 
Patient disposition .................................................................................................. 30 
3.6 
Study treatment ...................................................................................................... 31 
3.6.1 
Duration of study treatment exposure ................................................... 31 
3.6.2 
Cumulative dose and average daily dose .............................................. 32 
3.6.3 
Dose intensity and relative dose intensity ............................................. 32 
3.6.4 
Dose reductions, interruptions and delays ............................................ 33 
3.6.5 
Discontinuation of study treatment components ................................... 34 
3.7 
Concomitant and post-treatment therapy ............................................................... 34 
3.8 
Efficacy evaluation ................................................................................................ 35 
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 
Urinary Analysis ................................................................................... 54 
3.9.7 
Other safety data ................................................................................... 54 
3.10 
Pharmacokinetic (PK) analyses ............................................................................. 55 
3.10.1 
General principle ................................................................................... 55 
3.10.2 
PK concentrations ................................................................................. 55 
3.10.3 
Analysis of relationship between efficacy or safety endpoints and 
exposure ................................................................................................ 56 
3.10.4 
Handling missing and invalid values .................................................... 57 
 
 58 


Novartis 
Confidential 
Page 10 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
 
 58 
 
 58 
 
 59 
 
 59 
 
 60 
 
 60 
 
 60 
 
 61 
 
 61 
3.14 
Interim analyses ..................................................................................................... 62 
3.14.1 
Primary Endpoint: PFS ......................................................................... 62 
3.14.2 
Overall Survival .................................................................................... 62 
3.14.3 
Confidentiality of Interim OS results .................................................... 63 
 
 63 
 
. 63 
 
 64 
3.16 
Sample size calculation .......................................................................................... 65 
3.17 
Power for analysis of secondary variable .............................................................. 66 
3.18 
Sample size considerations for PK analysis .......................................................... 67 
4 
Details of the statistical analysis ........................................................................................ 67 
4.1 
Baseline comparability .......................................................................................... 67 
4.2 
Time-to-event analyses .......................................................................................... 67 
4.2.1 
Analysis of time-to-event data with ties ................................................ 68 
4.2.2 
Hazard ratio ........................................................................................... 68 
4.2.3 
Hypothesis and test statistic .................................................................. 68 
4.2.4 
Kaplan-Meier estimates ........................................................................ 69 
4.2.5 
Audit-based BIRC assessment of PFS .................................................. 69 
4.3 
Group sequential design used in Phase III studies ................................................. 70 
4.3.1 
Alpha-spending function ....................................................................... 70 
4.4 
Duration of follow-up ............................................................................................ 71 
4.5 
Confidence intervals for response rate and clinical benefit rate ............................ 71 
5 
References ......................................................................................................................... 72 
Appendix 1 
CTC grades for laboratory values in Novartis Oncology ...................... 76 
 


Novartis 
Confidential 
Page 11 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
 
List of tables 
Document History – Changes compared to previous version of SAP. ....................................... 2 
Table 1-1 
Study objectives .................................................................................... 16 
Table 2-1 
Last contact date data sources ............................................................... 19 
Table 2-1 
Patient classification based on protocol deviations and non-
protocol deviation criteria ..................................................................... 22 
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 ............................................................................... 28 
Table 3-1 
Planned dose intensity ........................................................................... 33 
Table 3-2 
Sources for overall lesion response ....................................................... 35 
Table 3-3 
Outcome and event/censor dates for primary PFS analysis .................. 36 
Table 3-3 
ECOG Performance Scale ..................................................................... 43 
Table 3-4 
Time windows for ECOG PS assessments............................................ 44 
Table 3-5 
Time windows for patient reported outcomes ....................................... 45 
Table 3-6 
Clinically notable ECG values .............................................................. 53 
 
 58 
 
 61 
Table 3-9 
Projected timelines for interim and final analyses ................................ 63 
Table 4-1 
Local versus central disease progression assessments .......................... 70 
 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 15 
 


Novartis 
Confidential 
Page 12 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BIRC 
Blinded independent review committee 
BOR 
Best overall response 
BPI-SF 
Brief Pain Inventory – Short form 
CI 
Confidence Interval 
CBR 
Clinical benefit rate 
CR 
Complete response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Case retrieval sheet 
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 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
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 
EQ-5D-5L 
EuroQol 5-level scale 
ER 
Estrogen receptor 
FAS 
Full analysis set 
GGT 
Gamma-glutamyl transferase 
HER2 
Human epidermal growth factor receptor 2 
HR  
Hazard Ratio 
HR  
Hormone receptor 
HRQoL  
Health-Related Quality of Life 
IRT 
Interactive Response Technology 
LATA 
Last adequate tumor assessment 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantification 
MBC 
Metastatic breast cancer 


Novartis 
Confidential 
Page 13 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NMQ 
Novartis MedDRA queries 
ORR  
Overall response rate  
OS 
Overall survival  
PAS 
Pharmacokinetic analysis set 
PD 
Progressive disease 
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 
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 
TEAE 
Treatment-emergent adverse event 
TFL 
Tables Figures and Listings 
TBIL 
Total Bilirubin 
TTP  
Time to progression  
UNK 
Unknown 


Novartis 
Confidential 
Page 14 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 CLEE011F2301, a phase III, randomized, 
double-blind, placebo-controlled study of ribociclib or placebo in combination with 
fulvestrant for the treatment of men and postmenopausal women with hormone receptor 
positive, HER2-negative, advanced breast cancer who have received no or only one line of 
prior endocrine treatment.  
The content of this SAP is based on CLEE011F2301 protocol amendment 2 (July 28, 2016). 
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 Tables Figures and Listings (TFL) shells and Programming Datasets 
Specifications (PDS) documents, respectively. 
1.1 
Study design 
This is a randomized, phase III, double blind, placebo controlled, international study to 
determine the efficacy and safety of treatment with fulvestrant with ribociclib versus 
fulvestrant with placebo in men and postmenopausal women with HR+, HER2-negative 
advanced breast cancer. This study will consist of 4 phases: screening (up to 28 days), 
randomized treatment, post-treatment efficacy follow-up, and post-treatment survival follow-
up. 
Approximately 660 patients will be randomly assigned to one of the following treatment arms 
in a 2:1 ratio. 
• Experimental arm: fulvestrant (500 mg intramuscular [as two 5 mL injections] on Cycle 1 
Days 1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + ribociclib (600 mg by 
mouth once daily for three weeks followed by one week break, in a 28-day cycle) 
OR 
• Control arm: fulvestrant (500 mg intramuscular [as two 5 mL injections] on Cycle 1 Days 
1 and 15 (C1D1 and C1D15), and on CnD1 thereafter) + ribociclib placebo (by mouth 
once daily for three weeks followed by one week break, in a 28-day cycle)  
Randomization will be stratified by the following factors: 
1. Lung or liver metastases: (yes vs no) 
2. Previous endocrine therapy (A vs B) according to the following definition: 
 
A) Patients treatment naïve in the metastatic/advanced disease setting: 
i- whose disease relapsed >12 months after completion of (neo)adjuvant endocrine 
therapy with no subsequent treatment for advanced/metastatic disease, 
OR 
ii- with de-novo advanced/metastatic disease (no prior exposure to endocrine therapy). 
 


Novartis 
Confidential 
Page 15 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
B) Patients who received up to 1 line of treatment for metastatic/advanced disease: 
i- whose disease relapsed on or within 12 months from completion of (neo) adjuvant 
endocrine therapy, with no subsequent treatment for advanced/metastatic disease, 
OR 
ii- whose disease relapsed > 12 months from completion of (neo) adjuvant endocrine 
therapy, and progressed on or after subsequent endocrine treatment for 
advanced/metastatic disease, 
OR 
iii- with advanced/metastatic disease at the time of diagnosis that progressed on or 
after endocrine therapy for advanced/metastatic disease with no prior (neo) adjuvant 
treatment for early disease. 
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 review 
committee (BIRC) will be a supporting end point for primary analysis.   
An Independent Data Monitoring Committee (IDMC) will be constituted and will monitor 
safety and efficacy data. A Steering Committee (SC) will be established comprised of 
investigators and Novartis personnel participating in the trial to ensure transparent 
management of the study according to the protocol. 
Overall survival is a secondary endpoint in this study and will be tested 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 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 
 


Novartis 
Confidential 
Page 16 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
 
 
1.2 
Objectives 
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1. 
Table 1-1 
Study objectives 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 3.8.1 
To compare PFS between ribociclib 
in combination with fulvestrant to 
placebo 
in 
combination 
with 
fulvestrant 
among 
men 
and 
postmenopausal women with HR+, 
HER2-negative advanced breast 
cancer who received no or only one 
prior 
endocrine 
treatment 
for 
advanced disease 
PFS based on local radiology assessments and 
using RECIST 1.1 criteria 
 
Secondary 
 
 
To compare the two treatment arms 
with respect to overall survival. 
Overall survival 
Refer to section 3.8 
To evaluate the two treatment arms 
with respect to overall response 
rate, clinical benefit rate, time to 
response and duration of response.  
ORR as defined by RECIST 1.1. CBR, defined 
as percentage of patients with CR, PR or SD 
lasting 24 weeks or longer, TTR, DOR per 
RECIST 1.1 
Refer to section 3.8 


Novartis 
Confidential 
Page 17 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Objective 
Endpoint 
Analysis 
To evaluate the two treatment arms 
with respect to time to deterioration 
of ECOG performance status. 
Time 
to 
definitive 
deterioration 
of 
ECOG 
performance status from baseline 
Refer to section 3.8 
To 
evaluate 
the 
safety 
and 
tolerability 
of 
ribociclib 
in 
combination with fulvestrant. 
Frequency/severity 
of 
AEs, 
laboratory 
abnormalities 
Refer to section 3.9 
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 
 
Refer to section 3.8 
To 
characterize 
the 
pharmacokinetics (PK) of ribociclib 
(and relevant metabolites such as 
LEQ803) 
when 
given 
in 
combination with fulvestrant. 
Concentration by time point for ribociclib (and 
relevant metabolites such as LEQ803) 
Refer to section 3.10 
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. 


Novartis 
Confidential 
Page 18 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Study treatment is defined as ribociclib + fulvestrant, or matching placebo + fulvestrant. 
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. 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 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 (e.g., 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. 


Novartis 
Confidential 
Page 19 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 including PFS and response rates, a window 
of 7 days from the start of study treatment will be allowed, i.e. the investigator/BIRC-reported 
responses will be maintained and baseline considered valid if the baseline assessment is 
within 7 days of treatment start date.  
For safety evaluations (e.g. laboratory assessments and ECG), the last available assessment 
before or at date of start of study treatment will be used as the ‘baseline’ assessment. 
Assessments specified to be collected post-dose on the first date of treatment are not 
considered as baseline values. 
If patients have no value as defined above, the baseline results will be considered missing. 
2.1.8 
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 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 
Non-missing medication/procedure term. 


Novartis 
Confidential 
Page 20 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Source data 
Conditions 
therapy 
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  
PK collection dates 
At least 1 non-missing PK concentration 
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) 
Hospitalization admission/discharge date 
Non-missing type of facility admitted to 
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.  
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 analysis will be carried out after approximately 364 events have been 
documented based on local investigator assessment. Up to 3 analyses for OS may be 
performed as described in section 3.8. For each of the analysis time points, statistical analyses 
will be performed using all data collected in the database up to the data cutoff date. Any data 


Novartis 
Confidential 
Page 21 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 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. 
2.3.3 
Per protocol set 
The Per-Protocol Set (PPS) includes the subset of the patients in the FAS without major 
protocol deviations, and 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 is not post-menopausal; 
• Patient without HR+ and HER2- advanced breast cancer at baseline; 
• Patient received prior fulvestrant treatment; 
• Patient received prior CDK4/6 inhibitor; 
• Patient with recurrence on or within 12 month of adjuvant therapy and subsequent 
advanced treatment.  
• Baseline ECOG performance status>1; 
• Neither measurable disease nor predominantly lytic bone lesion at baseline; 
• Patient received more than 1 line of prior hormonal anti-cancer therapy for advanced 
breast cancer; 
• Patient received prior chemotherapy for advanced breast cancer; 
• Patient received different treatment throughout the study than the one randomized to. 
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. 


Novartis 
Confidential 
Page 22 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
2.3.4 
Pharmacokinetic analysis set  
The Pharmacokinetic analysis set (PAS) consists of all patients who provide at least one 
evaluable PK concentration (see Section 3.10.1 for definition of evaluable PK concentration). 
2.3.5 
Patient classification 
Patients may be excluded from the analysis sets defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules as defined in 
Table 2-1. 
Table 2-1 
Patient classification based on protocol deviations and non-protocol 
deviation criteria 
Analysis set 
Protocol deviations leading 
to exclusion 
Non-protocol deviation 
criteria leading to exclusion 
FAS  
No written informed consent 
NA 
Safety set 
No written informed consent 
No post-baseline safety 
assessment or no dose of 
study treatment  
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 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.  
Death events may be used in the analysis if captured from public records (registers), local law 
and patient informed consent permitting. 
 
 
2.4 
Concomitant medications with specific impact on the analysis 
According to the study protocol, the following medications are prohibited during treatment in 
this study: 
• Strong inhibitors or inducers of CYP3A4/5  
• Substrates of CYP3A4/5 with a narrow therapeutic index 
• Medications with a known risk of QT prolongation 
• Other investigational and antineoplastic therapies with the exception of palliative 
radiotherapy 
• Herbal medications preparations and dietary supplements (except for vitamins)  


Novartis 
Confidential 
Page 23 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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. 
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 drugs (apart 
from study treatment) and other investigational drugs is not allowed during study treatment. 
Patients who take anti-neoplastic drugs after randomization but before end of treatment will 
be identified through data review. Clinical review of individual study data will be performed 
in order to identify those anti-neoplastic medications which are considered disallowed. 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 
(TOR) and duration of response (DOR) (Section 3.8.2.2-3.8.2.5). In addition, a sensitivity 
analysis will be performed for the primary 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. Patient reported outcome (PRO) and ECOG based time to event 
end point 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 2 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 lesion responses for patients with only non-measurable 
lesions at baseline 
Patients with at least one predominantly lytic bone lesion but not having measurable disease 
per RECIST 1.1 are allowed to enter the study. For patients with non-measurable lesions only 
at baseline, the overall lesion response will be based solely on non-target lesion response or an 
occurrence of a new lesion. Non-measurable lesions will be entered as non-target lesions. 
Therefore, the best overall response is determined from non-target lesion response and 
presence of new lesions (refer to RECIST Novartis guidelines as described in detail in 
Appendix 2 of the Clinical Study Protocol). 


Novartis 
Confidential 
Page 24 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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. CT scan photos for skin lesions, etc.). If a new lesion is detected 
using an objective assessment method other than radiologic scan then it should also be entered 
on the ‘New lesion’ RECIST CRF with appropriate method. Discontinuation due to disease 
progression or death due to study indication in death CRF page, 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 2 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 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. 
The standard definition of a best overall response evaluation of ‘stable disease’, ‘disease 
progression’ or ‘unknown’ given in the Appendix 2 of the Clinical Study Protocol will be 
used for this study.  Best overall response (as reported by the investigator for local BOR, and 
as reported by BIRC for central BOR) for each patient is determined from the sequence of 
overall (lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR). 
• SD = at least one SD assessment (or better) > 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: 


Novartis 
Confidential 
Page 25 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
• 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 as per Novartis 
calculated response. However, a response from 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’ is defined as assessments that are not done or 
assessments for which the overall lesion response equals ‘Unknown’. The ‘missing adequate 
assessment’ is also referred to as ‘missing assessment’. 
As detailed in Section 3.8.1 and in [Appendix 2 of the 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 assessment 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 windows 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* 


Novartis 
Confidential 
Page 26 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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. 
. 
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 in 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 primary PFS analysis) can be refined as follows: if the distance between the last 


Novartis 
Confidential 
Page 27 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 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 lost to follow-up 
Is smaller 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 the 
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 the [Appendix 2 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. 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 such assessments will be represented by a special symbol (e.g.  
) in the waterfall graph. 


Novartis 
Confidential 
Page 28 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 2-34. 
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 
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, all stratification information (including stratified analyses, 
analyses by “stratum”, strata as covariates) will be based on stratification data from IRT.  


Novartis 
Confidential 
Page 29 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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, time from initial diagnosis to first recurrence/progression, stage at 
time of study entry, presence/absence of target and non-target lesions, number and type of 
metastatic sites involved,  HER-2 / estrogen / progesterone receptor status, number of de novo 
patients. disease free interval (DFI) for non-de novo patients and prior endocrine therapy 
status (ET). Estrogen and progesterone receptor status summary will be combined into 3 
categories (ER+ PR+, ER+ PR-, ER- PR+).  
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. 
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 also be grouped as follows based on prior endocrine therapy: 
• No prior ET, including two groups of patients: 
• De novo patients who diagnosed with advanced disease and never treated.  
• Patient diagnosed with early stages of disease, treated with surgery and/ or RT and/ or 
chemotherapy (but no endocrine therapy) for that early setting and relapsed afterwards 
with advanced disease.  
• Prior ET therapy 
• 1st line ET  
• Progression while on or within 12 months of end of (neo-)adjuvant ET 
• Progression >12 months after end of (neo-)adjuvant ET 
• 2nd line ET including patients who had endocrine therapy under advanced/metastatic 
setting and then progressed. 
Time since initial diagnosis and time from initial diagnosis to first recurrence/progression will 
be summarized in months. A month is defined as 365.25/12=30.4375 days. 
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. 


Novartis 
Confidential 
Page 30 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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. 
• For radiotherapy, the setting (e.g. adjuvant) 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 
 
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 per protocol set will be tabulated separately 
by treatment arm.  
All protocol deviations as well as protocol deviations leading to exclusion from per protocol 
set will be listed. 
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 strata per IRT.  
3.5 
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 discontinued study treatment (based on the ‘End of 
Treatment’ page) 
4. Reasons for study treatment discontinuation (based on ‘End of Treatment’ page) 


Novartis 
Confidential 
Page 31 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 “Screening Phase Disposition” eCRF page 
 
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 ribociclib/placebo (days) = (last date of exposure to 
ribociclib/placebo) – (date of first administration to ribociclib/placebo) + 1. 
Duration of exposure to fulvestrant (days) = (last date of exposure to fulvestrant) – (date of 
first administration to fulvestrant) + 1. 
The last date of exposure is defined as follows for the study treatment components: 
• For  ribociclib /placebo: the last date of exposure is defined as the date of last 
administration of the corresponding medication; 
• For fulvestrant, the last date of exposure is defined as following:  
1. If patient discontinues fulvestrant before C2D1 dose, then: 
a. Last date of exposure = last date of administration + 13 days.  
b. If patient died or lost to follow-up within last date of administration + 13 days, 
then last date of exposure is date of death or last contact date, respectively. 
2. If patient discontinues fulvestrant after C2D1 dose, then: 
a. Last date of exposure = last date of administration + 27 days. 
b. If patient died or lost to follow-up within last date of administration + 27 days, 
then last date of exposure is date of death or last contact date, respectively. 
The duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). The duration of study treatment exposure will be 
summarized by treatment arm. In addition, the duration of exposure to study treatment will be 


Novartis 
Confidential 
Page 32 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 ribociclib/placebo for patients with non-zero duration of exposure to 
ribociclib/placebo  is defined as follows:  
DI (mg / day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib/placebo 
(day), 
where adjusted duration of exposure (days) to ribociclib/placebo is the number of ribociclib 
/placebo dosing days a patient would be expected to have received per protocol, given their 
duration of exposure. 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 for ribociclib /placebo. The adjusted duration of 
exposure to ribociclib/placebo (in days) is therefore 21 * (# completed 28 day period) + 
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) days, then the adjusted duration of exposure to ribociclib/placebo is 
21*2+10=52 days. 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 above  
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 ribociclib/placebo is displayed in Table 3-1. 
Note that DI will also be calculated and DI for ribociclib/placebo will be reported in the units 
displayed in Table 3-1, whereas duration of exposure itself will be summarized in months. 


Novartis 
Confidential 
Page 33 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Table 3-1 
Planned dose intensity 
Medication 
PDI (dose unit/unit of time) 
ribociclib /placebo 
600 mg/day (3 weeks on 1 week off) 
 
 
Ribociclib/placebo relative dose intensity (RDI) is defined as: 
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).   
Fulvestrant RDI is defined as: 
RDI = actual cumulative dose / planned cumulative dose, where planned cumulative dose is 
defined as 500* (# completed D1 in a 28-days cycle) and added by 500 mg if patients 
completed C1D15. 
DI for ribociclib/placebo and RDI for ribociclib/placebo and fulvestrant will be summarized 
separately for each of the study treatment component. 
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.  
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. Delay: A special case of ribociclib/placebo 
interruption occurs at the start of a new cycle, after a planned rest period. It will be 
determined based on ribociclib / placebo dose administration record where a planned dose 
break is followed by a dose interruption. Such instances will be identified as a subset of the 
interruptions and will be summarized separately as dose delays. 
Reduction: A reduction is defined as a decrease from the previous non-zero dose to another 
non-zero dose less than protocol planned dose, even if this decrease has been directly 
preceded by an interruption.  For example, in the sequence of 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. 


Novartis 
Confidential 
Page 34 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
3.6.5 
Discontinuation of study treatment components 
The reasons for discontinuation of ribociclib/placebo will be summarized by treatment arm, 
based on the information on the ribociclib/placebo DAR CRF for patients who have the “dose 
permanently discontinued” box checked. 
Partial discontinuation: A 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 
fulvestrant when the permanent discontinuation checkbox is checked in the ribociclib/placebo 
DAR page. 
 Partial Discontinuation of ribociclib/placebo will be summarized by treatment 
3.7 
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. These summaries will include:  
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 CYP3A 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-neoplastic therapy 


Novartis 
Confidential 
Page 35 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 line and 2nd line anti-neoplastic medications after 
discontinuation of study drug 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 [Appendix 2 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 
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 will be used for supportive efficacy analysis. The BIRC comprises of two 
independent radiologists and an adjudicator. The BIRC-reported  overall tumor response data 
will be used to derive the supportive BIRC-based endpoints. Data from the two independent 
central 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 2 of the study 
protocol]. 


Novartis 
Confidential 
Page 36 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 14-7 of study protocol Appendix 2], 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 consecutive missing tumor 
assessments (see Section 2.5.5). For 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 for 
the purposes of PFS derivation , i.e. option F(1) in [Table 14-7 of protocol Appendix 2] 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 primary PFS analysis 
 
Situation 
Date 
Outcome 
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 assessment  
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. 
 


Novartis 
Confidential 
Page 37 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 (fulvestrant+ ribociclib arm vs. fulvestrant + 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 (double log) option 
available within PROC LIFETEST will be used to compute the confidence intervals. 
Hazard Ratio 
The PFS hazard ratio with two-sided 95% confidence interval will be derived from 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 only covariate and the STRATA statement will include the stratum information as 
obtained via IRT. 
3.8.1.4 
Sensitivity and supportive analyses of the primary endpoint PFS 
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 


Novartis 
Confidential 
Page 38 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 4.6 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. 
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 4.6 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+fulvestrant arm minus the rate on the placebo+fulvestrant 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. 


Novartis 
Confidential 
Page 39 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Sensitivity analyses and further 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 consecutive missing tumor 
assessments. The following options from [Table 14-7 of Study Protocol Appendix 2 ] 
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’ 
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 14-7 in Section 3.2.9 of Study Protocol Appendix 2 ] 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 radio-therapy. 
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 the treatment arm and the following key prognostic factors as covariates: age (>=65 vs 
<65), prior chemo therapy in (neo)adjuvant setting (yes vs no), ECOG performance status (0 
vs. 1), and bone only lesion at baseline (yes or no), .In addition,  stratified multivariate cox 
models will be fitted including the treatment arm and each of these prognostic 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 will be 
presented along with the hazard ratio for treatment effect obtained using the Cox 
proportional hazards regression with corresponding confidence intervals. No p-values 
will be presented for this analysis. K-M plots of survival distributions will be 
presented by stratum. 


Novartis 
Confidential 
Page 40 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
• If there is a high rate of discrepancy between the strata classifications constructed 
using the eCRF data and those obtained from the IRT, a supportive 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 as per local investigator 
radiology and BIRC assessment.  
• Comparison of PFS event type/censor between local investigator radiology review and 
BIRC assessment 
• If the primary analysis for PFS is statistically significant, the treatment effect for 
patients treatment naïve in the metastatic setting and for patients who received up to 1 
line of treatment for advanced disease (groups A and B as defined in section 1.1) 
based on CRF data will be evaluated using unstratified Cox regression models. The 
hazard ratio with 95% CI will be displayed for each subgroup and Kaplan-Meier 
estimates will also be summarized.
 
 
  
 
3.8.1.5 
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 imputation rules in section 3.8.2.1 will be implemented. 
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, time to response and duration of response; 
• 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. 
The analysis of all secondary efficacy endpoints will be performed based on the FAS. 
3.8.2.1 
Overall survival 
Comparing the overall survival (OS) between ribociclib +fulvestrant and placebo+fulvestrant 
is a secondary objective in this study. 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 at the time of analysis 


Novartis 
Confidential 
Page 41 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
cut-off, then OS will be censored at the date of last contact.  Assuming proportional hazards 
for OS, the following statistical hypotheses will be tested: 
H02: θ2  ≥0   vs.   HA2: θ2 < 0 
Where θ2 is the log OS hazard ratio (fulvestrant+ ribociclib arm vs. fulvestrant + placebo 
arm). The analysis to test this hypothesis is a stratified log-rank test at an overall one-sided 
2.5% level of significance. The stratification will be based on the randomization stratification 
factors. 
A maximum of 3 analyses are planned for OS: at the time of the analysis for PFS (provided 
PFS is significant), at which point a total  161 deaths (46% of OS events) are expected, after 
263 events (75% of OS events) have been documented, and a final analysis for OS when 351 
deaths (100% of OS events) are expected (expected 56 months from date of first patient to be 
randomized).  
OS tests will be carried out  using a Lan-Demets (O’Brien-Fleming) alpha spending function. 
OS will only be tested if the primary efficacy analysis has been shown to be statistically 
significant. Analyses will be based on the FAS population according to the randomized 
treatment group and strata assigned at randomization. All deaths recorded up to the cut-off 
date will be included in the analysis. The survival distribution of OS  will be estimated using 
the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals 
of the medians intervals along with the proportion of patients alive at 6 month interval starting 
from 12 month  will be presented for each treatment group. The hazard ratio for OS will be 
calculated, along with its 95% confidence interval, using a stratified Cox model using the 
same stratification factors as the log-rank test. 
If OS is statistically significant, a stratified multivariate Cox proportional hazard model 
adjusting for covariates will be fitted, including the treatment arm and the following key 
potential prognostic factors  as covariates: age (>=65 vs <65), prior chemo therapy in 
(neo)adjuvant setting (yes vs no),  ECOG performance status (0 vs. 1), and bone only lesion at 
baseline (yes or no). In addition, 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.  
 
 
 
 The pattern of censored data will be examined between 
the treatment arms: reasons for censoring (‘Alive’ or ‘Lost to follow-up’) and death cause will 
be summarized by treatment arm. In addition, survival status, reason for censoring and death 
cause will be listed. Patients not known to have died will be censored as ‘Lost to follow-up’ if 
the time between their last contact date and the analysis cut-off date is longer than the 
protocol specified interval between the survival follow-up assessments plus 2 weeks, i.e., 14 
weeks (98 days) for this study. 


Novartis 
Confidential 
Page 42 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 following imputation rules will be implemented: 
- If only day is missing, then date of death is imputed as max [(1 mmm-yyyy), min(last 
contact date +1, cutoff date)].  
- If both day and month are missing, then date of death is imputed as max [(1 Jan-yyyy), 
min (last contact date +1, cutoff date)].  
 
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 2 
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 a supportive analysis, ORR will also be summarized based on the BIRC review of tumor 
data. As a sensitivity analysis, ORR will be calculated and summarized for patients with only 
measurable disease at baseline.  
3.8.2.3 
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 
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. CBR based on (1) BIRC review, and (2) only including patients with 
measurable disease at baseline, will be summarized for the two treatment arms using 
descriptive statistics. 
3.8.2.4 
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 


Novartis 
Confidential 
Page 43 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
patients in the FAS will be included in the time to response calculation. Patients without 
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 are observed. A descriptive summary of time to response for the responders will 
also be presented. 
3.8.2.5 
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 will be censored at the date of last adequate tumor assessment using the same 
censoring rule 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 are observed. 
3.8.2.6 
ECOG performance status 
The ECOG PS scale (Table 3-3) will be used to assess physical health of patients, ranging 
from 0 (most active) to 5 (least active): 
Table 3-3 
ECOG Performance Scale 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
The following intervals will be used to group the ECOG PS data over time. Day in columns 2 
and 3 is defined as date of ECOG PS assessment date – randomization date + 1. The 
corresponding Day in column 1 assumes that a patient is treated on the day of randomization; 
however the definition of Day in columns 2 and 3 still applies if this is not the case, i.e. 
randomization date is taken as the reference for the windows. 


Novartis 
Confidential 
Page 44 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Table 3-4 
Time windows for ECOG PS assessments 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
 
Day 1 (if not available use 
screening) 
Cycle 2 Day 1 
29 
Day 2 to day 42  
Cycle k Day 1 (k≥3) 
d=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the end 
of treatment visit 
If 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. Definitive 
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 consecutive missing assessments, 
time to deterioration will be censored at the date of the last ECOG PS assessment prior to the 
deterioration. The number of missing assessments is calculated based on the time window in 
Table 3-4 and a rule similar for tumor assessments (see detail in section 2.5.5).  
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 worsened 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 worsening of performance status between treatment arms. A 
(stratified) Cox proportional hazards model will be used to estimate the hazard ratio (with 
95% confidence interval). 
 
3.8.2.7 
Patient reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) and the EuroQoL 5-level instrument (EQ-5D-
5L, Version 4.0) will be used to evaluate patient-reported outcome measures of health-related 
quality-of-life, functioning, disease symptoms and treatment-related side effects. The BPI-SF 
will be used to assess patient’s subjective assessment of pain. 


Novartis 
Confidential 
Page 45 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 3-5 
Time windows for patient reported outcomes 
 
Time Interval 
Baseline 
 
Screening assessment 
 
Cycle 3, 5, 7, 9 until 
cycle 19 Day 1 
+/- 4 weeks centered around the planned assessment date (except for 
the first window and the last window): 
i.e. days (1, 85] for Day 1 of cycle 3 (2th assessment) 
      days (85, 141] for Day 1 of cycle 5 (3th assessment) 
      days (k*56-27; k*56+29] for  (k+1th assessment) 
     days (477, 547] for 10th assessment on Day 1 cycle 19 
Cycle 22, 25, 28, … 
Day 1 
+/- 6 weeks centered around the planned assessment date: 
i.e. days (547, 631] for 11th assessment 
    days (631, 715] for 12th assessment 
   days (715, 799] for 13th assessment 
End of treatment 
Assessment taken 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. If the 
closest assessment to the target date has two questionnaires filled out on the same date, then 
the worst score of these assessments will be used for each subscale score. 
The FAS will be used for all PRO summaries and listings. 
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 visual analog scale (VAS) of the 
EQ-5D-5L, and worst pain item (based on question 3), pain severity index, and pain 
interference indices of the BPI-SF are identified as secondary PRO variables of interest. High 
scores in the EORTC QLQ-C30 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. A higher score in BPI-SF corresponds to more pain.    
The number of patients completing PRO questionnaires and the number of patients 
missing/expected to have PRO assessments will be summarized by treatment arm for 
scheduled assessment time points (the number of ongoing patients will be used as 


Novartis 
Confidential 
Page 46 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
denominator). Furthermore, the amount and the pattern of missing data may be explored by 
treatment arm and over time using summary statistics. The following categories will be used 
to describe whether the questionnaire was completed at a specific time point: 
- yes, fully completed 
- yes, partly completed 
- no. 
Scoring of raw data and methods for handling missing items or missing assessments will be 
handled according to scoring manuals for each respective patient questionnaire (Fayers 2001; 
Oemar and Janssen 2013; Cleeland 2009). 
As the main analysis and to best utilize the repeated PRO assessments, a repeated measures 
model for longitudinal data will be used to compare the two treatment arms in sub-scales 
obtained from EORTC QLQ-C30 and the VAS score of EQ-5D-5L over time. This 
longitudinal model will include terms for treatment, the randomization stratification factors, 
time (duration in weeks counting from the time of baseline measurement to the time of a 
particular post baseline measurement), baseline value as main effects, and an interaction term 
for treatment by time. Time will be considered as a continuous variable in this analysis. As a 
first approach, an unstructured correlation matrix will be used to model the correlation within 
patients. The structure of the correlation matrix will be investigated and simplified using 
likelihood ratio tests if appropriate. Time is considered as a continuous variable in the 
analysis. The data for selected time points will be fitted using a linear model using treatment, 
stratification factors, baseline value as covariates. The differences in least square means 
between the experimental 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 up to EOT 
assessment will be included.  
Analysis of the time to definitive 10% deterioration in the primary and the secondary PRO 
variables of interest will be performed. 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, start of new 
anti-neoplastic therapy, lost to follow-up, end of treatment or withdrawal of consent, the time 
to deterioration will be censored at the date of 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 details in 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 


Novartis 
Confidential 
Page 47 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
stratified log-rank test (strata based on IRT data) at 2 sided 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 without10% deterioration at 2 month 
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. Sensitivity analysis of time to definitive deterioration with different cut-
off definitions (e.g. 5%, 15%) may also be considered if the number of events per arm is 
judged sufficient to draw relevant conclusions. 
Descriptive statistics (n, mean, median, SD, min, max) will be used to summarize the 
individual item and subscale scores from the EORTC QLQ-C30, EQ-5D-5L, and worst pain 
item (question 3), pain severity index and pain interference indices of the BPI-SF 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 
change from baseline analyses.  
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 ‘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 4.03. 
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) 


Novartis 
Confidential 
Page 48 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 by treatment group:  
• Summary of deaths and adverse events 
• Adverse events, irrespective of causality, by primary system organ class, preferred 
term and maximum grade  
• Adverse events with suspected relationship to study treatment by primary system 
organ class, preferred term and maximum grade  
• 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 


Novartis 
Confidential 
Page 49 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
• Grade 3 or 4 adverse events, irrespective of causality, by primary system organ class, 
preferred term and maximum grade 
• Grade 3 or 4 adverse events with suspected relationship to study treatment by primary 
system organ class ,preferred term and maximum grade 
• 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  
• Non-serious adverse events (at least x% incidence rate in either treatment arms) 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 interest will also be summarized. See Section 3.9.1.5 for the grouping details. 
3.9.1.5 
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 
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.).  


Novartis 
Confidential 
Page 50 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 3-6 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 3-6 
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 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): 
• Box plots of laboratory values by scheduled time point and treatment arm. 


Novartis 
Confidential 
Page 51 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
• 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).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 summarized for neutrophil, and ALT/AST, using 
the Kaplan-Meier method. Median time to first occurrence and 95% CI will be provided. In 
addition, Kaplan-Meier plots will be generated. Simple descriptive statistics, median, min and 
max as well as 25th percentile and 75th percentile, will be presented. 
 
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 


Novartis 
Confidential 
Page 52 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
assessment for the lab parameter. Note that patients who have grade X or worse toxicity at the 
baseline or missing baseline evaluation will be excluded from this analysis.  
Duration of grade X or worse laboratory toxicity (for neutrophil, X=2; for ALT or AST, X=3) 
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 worse 
event) + 1 
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. 
In addition, failure curves (ascending Kaplan-Meier curves) for time to first occurrence of AE 
will be constructed by treatment arm. Median together with 95% confidence interval as well 
as 25th percentile and 75th percentile will be presented for each treatment arm. 
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 


Novartis 
Confidential 
Page 53 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
The following summaries will be produced for each vital sign parameter: 
• 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 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 3-6 
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%  


Novartis 
Confidential 
Page 54 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
> 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 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.  
Time to grade 2 or worse QTcF prolongation will be analyzed using the Kaplan-Meier method 
and the median time to grade 2 or worse QTcF prolongation will be presented along with a 
95% confidence interval if there are sufficient events for each treatment group. 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 the baseline or missing 
baseline evaluation will be excluded from this analysis.  
 
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 
Urinary Analysis 
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. 
 
3.9.7 
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. 


Novartis 
Confidential 
Page 55 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration. 
Subgroup analyses will be explored as described in Section 3.14.1. 
3.10 
Pharmacokinetic (PK) analyses 
3.10.1 
General principle 
All PK analyses will be based on  PAS set, unless otherwise specified. 
Evaluable pre-dose concentrations satisfy the below conditions: 
• Sample was collected before the current dose 
• In addition, for pre-dose concentrations collected on Day 15 of any cycle 
o Patient had at least 10 consecutive days of ribociclib dosing (either 10 doses at 
600 mg or 10 doses at 400 mg or 10 doses at 200 mg) immediately prior to the 
pre-dose collection. Ten consecutive doses are expected to provide adequate 
time to reach steady state for ribociclib at 600 mg and after dose reduction. 
o The PK collection was done at 24 ± 2 hours after the previous dose on Day 14 
of the corresponding cycle. 
o Patient did not vomit within the first 4 hours following the last dose (confirmed 
using the records of date/time of PK sample collection and dosing). 
o the concentration has not been flagged for exclusion by the pharmacokineticist 
Evaluable post dose 2h, 4h, 6h concentrations on Day 15 of any cycle satisfy the below 
conditions:  
• Patient had at least 10 consecutive days of ribociclib dosing (either 10 doses at 600 mg 
or 10 doses at 400 mg or 10 doses at 200 mg) immediately prior to the PK collection. 
• The PK collection was done within ± 15 minutes window of 2 hours after the Day 15 
dosing for the post 2h concentration 
• The PK collection was done within ± 30 minutes window of 4, 6 hours after the Day 
15 dosing 
• Patient did not vomit within the first 4 hours following the current dose.  
• the concentration has not been flagged for exclusion by the pharmacokineticist 
Only evaluable PK concentrations which are not flagged for exclusion will be used for 
figures, summaries, and statistical analysis. Concentration listings will include all 
concentrations, with flags indicating those excluded from analyses. 
3.10.2 
PK concentrations 
PK concentrations of ribociclib and LEQ803 at C2D1 will be summarized for fulvestrant+ 
ribociclib arm.   


Novartis 
Confidential 
Page 56 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
In addition, ribociclib and LEQ803 steady state concentrations (i.e., Cycle 1 Day 15 and 
Cycle 2 Day 15 concentrations) will be also summarized by ribociclib dose level, visit, and 
timepoint. Patients will be classified into the following dose groups at each visit (C1D15 and 
C2D15) and timepoint: 
• RIBO600: consists of all patients who provided evaluable concentrations after 
receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to 
the PK collection without a dose change or interruption. 
• RIBO400: consists of all patients who provided evaluable concentrations after 
receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to 
the PK collection without a dose change or interruption. 
• RIBO200: consists of all patients who provided evaluable concentrations after 
receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to 
the PK collection without a dose change or interruption. 
Additional separate summaries of ribociclib and LEQ803 will be produced for Asian and non-
Asian patients (based on race) at each visit (C1D15 and C2D15) by ribociclib dose level and 
timepoint. 
Descriptive statistics of concentrations will include n, m (number of non-zero concentrations), 
mean, CV%, SD, median, geometric mean, geometric CV%, minimum and maximum). 
Coefficient of variation CV% is calculated as below:  
100*(SD/arithmetic mean) 
Geometric CV% is calculated as follows from non-zero values:  
( )
(
) 1
ˆ
exp
100
%
2 −
⋅
=
σ
CV
 
where 
2ˆσ  denotes the variance of the log-transformed values. 
All individual plasma ribociclib (and also LEQ803) concentration data will be listed for 
fulvestrant + ribociclib arm using the Full analysis set. The meal record will be listed using 
Full Analysis Set.  
3.10.3 
Analysis of relationship between efficacy or safety endpoints and 
exposure 
3.10.3.1 Exposure vs. PFS and TTR 
The relationship between ribociclib exposure and PFS/TTR will be explored using the 
Kaplan-Meier method. Kaplan-Meier plots of the distribution of PFS and TTR by category of 
average Ctrough at steady state (denoted as Ctrough_avg_ss) will be presented, along with the 
median time for each category if estimable. For each patient, Ctrough_avg_ss will be 
calculated as the geometric mean of evaluable Ctrough values from C1D15 and C2D15.  For 
the patients with only one evaluable Ctrough, the Ctrough_avg_ss will be that evaluable 
Ctrough itself. The Ctrough_avg_ss categories are defined as follows: < 25%, 25% to < 50%, 
50% to < 75%, and ≥ 75%. The data will be analyzed using PAS.  


Novartis 
Confidential 
Page 57 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
3.10.3.2 Exposure vs. QTcF 
The relationship between ribociclib concentration and the mean change from baseline QTcF 
(i.e., ∆QTcF) will be explored graphically: the arithmetic mean ∆QTcF and geo-metric mean 
ribociclib concentration will be displayed together against nominal time (time in x-axis, 
ΔQTcF and concentration in y-axis) using the PAS. The mean will be taken with respect to all 
the measurements from all patients at the same given nominal time. If a patient does not have 
both QTcF and evaluable PK measurement at a certain time point, then this patient will not be 
included in the plot for that time point. 
In addition, the relationship between ribociclib dose level and QTcF will also be explored 
using the safety set. Patients will be classified into the following dose groups at each 
scheduled QTcF collection time point on C1D15 and C2D15. 
• RIBO600: consists of all patients who received at least 10 consecutive daily ribociclib 
doses of 600 mg without a dose change or interruption immediately prior to the 
corresponding QTcF collection timepoint.  
• RIBO400: consists of all patients who received at least 10 consecutive daily ribociclib 
doses of 400 mg without a dose change or interruption immediately prior to the 
corresponding QTcF collection timepoint. 
• RIBO200: consists of all patients who received at least 10 consecutive daily ribociclib 
doses of 200 mg without a dose change or interruption immediately prior to the 
corresponding QTcF collection timepoint.  
Summary statistics of the raw QTcF data and change from baseline will be presented by visit, 
time point and dose group using the safety set. Only scheduled QTcF on C1D15 and C2D15 
will be included in the analysis.  
 
3.10.3.3 Exposure vs. liver function 
Box plots for ribociclib Ctrough_avg_ss  will be presented by worst post_baseline LFT lab 
category (for TBIL, AST, ALT, ALP separately) using the PAS set. The categories are 
defined as: 
• TBIL (“≤ 2xULN” vs. “>2xULN”),  
• AST (“≤ 5xULN” vs. “>5xULN”),  
• ALT (“≤ 5xULN” vs. “>5xULN”),  
• ALP (“≤ 1.5xULN” vs. “>1.5xULN”) 
 
3.10.4 
Handling missing and invalid values 
Plasma samples will be assayed for ribociclib concentrations by Novartis or Novartis 
designated laboratory using validated LC-MS/MS methods with a LLOQ of approximately 
1.00 ng/mL for ribociclib.  
All concentrations below the LLOQ will be displayed in listings as zero with a flag and 
handled as zero in any calculations of summary statistics, but handled as missing for the 


Novartis 
Confidential 
Page 58 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
calculation of the geometric means and their CV%.  The number of non-zero concentrations 
will also be reported in the summary statistics. 
Missing values for any PK data will not be imputed and will be treated as missing. 


Novartis 
Confidential 
Page 59 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 


Novartis 
Confidential 
Page 60 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
 


Novartis 
Confidential 
Page 61 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 


Novartis 
Confidential 
Page 62 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
3.14 
Interim analyses 
3.14.1 
Primary Endpoint: PFS 
No Planned interim analysis for PFS.  
3.14.2 
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 (fulvestrant + 
ribociclib). A hierarchical testing procedure will be adopted in this study and the treatment 
effect on OS will be tested only if the primary efficacy endpoint PFS is statistically 
significant.  A maximum of 3 analyses are planned for OS: at the time of analysis for PFS 
(provided PFS is significant), at which point a total of  161 deaths are expected, after 263 
events have been documented, and a final analysis for OS when 361 deaths are expected 
(expected 56 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 (fulvestrant + 
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 3-9 considering the hierarchical 
testing strategy of PFS and OS. The probabilities shown in Table 3-9 are conditional on PFS 
being statistically significant. 
Statistical properties of the group sequential design are summarized in Table 3-9. 


Novartis 
Confidential 
Page 63 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Table 3-9 
Projected 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 
0.71 
26 
364 (100%) 
95 
161(46%) 
14 
39 
-- 
-- 
263(75%) 
60 
56 
-- 
-- 
351(100%) 
85 
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). 
, 


Novartis 
Confidential 
Page 64 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 


Novartis 
Confidential 
Page 65 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
3.16 
Sample size calculation 
The median time to progression (TTP) for fulvestrant in first line post-menopausal advanced 
breast cancer patients is estimated to be between 8 month (Howell 2004) and 23 months in 
FIRST trial (Robertson et al 2012). For sample size calculation, the median PFS for 1st line 
patients is assumed to be 18 month. The median PFS for fulvestrant in relapsed advanced 
breast cancer is estimated to be between 4.8 months (SoFEA trial, Johnston et al 2013) and 
6.5 months (CONFIRM trial, Di Leo et al 2010). Since the study population is closer to the 
population in CONFIRM trial, for sample size calculation, the median PFS for fulvestrant in 
second line is assumed to be 6.5 months. It is assumed that 40% and 60% of the patients will 


Novartis 
Confidential 
Page 66 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
be from first line and second line respectively. The median PFS in the control arm (fulvestrant 
+ placebo) is estimated via simulation to be around 9 months. It is hypothesized that the 
addition of ribociclib will result in a clinically meaningful 33% reduction in the hazard rate of 
PFS, corresponding to an increase in median PFS to 13.4 months. A maximum of 364 PFS 
events will be required to detect a hazard ratio of 0.67 with 95% power using the log-rank test 
at one-sided cumulative 2.5% level of significance. Assuming that enrollment will continue 
for approximately 19 months at a uniform rate and 10% dropout rate by the time of PFS final 
analysis, a total of 660 patients should be randomized to the two treatment groups in 2:1 ratio 
to observe 364 events at approximately 7 months following the randomization of the last 
patient, i.e., 26 months from the randomization date of the first patient in this study. The 
sample size calculation was conducted with software package East 6.3. The sample size 
calculations are based on the estimates from data available from prior studies. A mid-study 
sample size re-assessment based on blinded pooled data may be performed prior to any 
efficacy analysis if data from the study indicate substantial deviation from the study 
assumptions. 
The primary objective of the study is to compare investigator assessed PFS between arms in 
the overall population (both 1st line and 2nd line patients). If the primary analysis is 
statistically significant, treatment effect will be evaluated in 1st and 2nd line patients (i.e. 
previous endocrine therapy stratification factor A and B as defined in section 1.1) separately. 
Based on the estimated median PFS and proportion of patients in 1st line and 2nd line 
respectively, it is expected that the accumulation of events in 1st line will be slower than 2nd 
line patients. To ensure enough information coming from 1st line patients, the final analysis 
will be done after approximately 125 events in the first line patients or approximately 364 
events in both arms whichever comes later.  
Audit size for BIRC assessed 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 0 (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).  
 
3.17 
Power for analysis of secondary variable 
OS will be compared between the two treatment arms, provided that the primary endpoint, 
PFS, is statistically significant. The power statements for overall survival below are therefore 
conditioned on significant primary PFS result. Estimate of first line median OS with 
fulvestrant alone is not published. However the median OS with fulvestrant alone in first line 
setting is expected to be between 34 months (letrozole alone, Mouridsen 2003) and 38 months 
(anastrozole alone, FACT trial, Bergh et al 2012) based on results from endocrine based 
monotherapy studies. For sample size calculation, we assume the median OS for fulvestrant 


Novartis 
Confidential 
Page 67 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
alone in first line to be 38 month. Median OS for fulvestrant in relapsed post-menopausal 
advanced breast cancer patients is estimated to be between 19 months (SoFEA trial, Johnston 
et al 2013) and 26 months (CONFIRM trial, Di Leo et al 2014). For sample size calculation, 
the median OS for fulvestrant in second line is assumed to be 26 months. Based on the 
expected split of first line and second line patients mentioned above, the median overall 
survival of control arm is estimated via simulation to be approximately 30 months. It is 
hypothesized that adding ribociclib to fulvestrant will result in a 29% reduction in the hazard 
rate for OS (corresponding to an increase in median survival to 42 months). To detect a 
hazard ratio of 0.71 with 85% cumulative power, a maximum of 351 deaths need to be 
observed, (using a log-rank test and a 3-look [superiority only] group sequential design at 
one-sided cumulative 2.5% level of significance). The sample size calculation was conducted 
with software package East 6.3. 
Based on the number of patients planned to be randomized and 10% dropout rate by the time 
of OS final analysis, it is estimated that these 351 deaths will be observed at approximately 56 
months after the randomization of the first patient. Therefore the estimated time for the final 
OS evaluation will be 30 months after the primary analysis of the PFS endpoint. 
3.18 
Sample size considerations for PK analysis 
Sparse PK sampling will be performed on approximately 150 patients. Assuming a 2:1 ratio 
between the ribociclib and placebo arm, sparse plasma concentrations for ribociclib will be 
available in approximately 100 patients. Trough PK sampling will be performed in all 
remaining patients. PK data collected from this study may also be combined with data from 
other studies to support a population PK analysis of ribociclib using non-linear mixed effect 
modeling; details will be provided in a separate analysis plan. The choice of sampling time 
points was selected to ensure capture of Cmax. The aim of this analysis is to analyze the 
pharmacokinetics of ribociclib in a sample size as large as possible. This sample is anticipated 
to represent the covariate distributions in the targeted population. No specific hypothesis will 
be tested and therefore no specific sample size calculation has been performed. The decisions 
on number of sparse PK samples and number of patients needed are driven by feasibility. 
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 the following 
time-to-event variables: 
• Progression-free survival 
• Overall survival 


Novartis 
Confidential 
Page 68 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
• 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 (e.g., global health status/QoL, physical 
functioning, emotional functioning, social functioning scales of the EORTC QLQ-
C30, and the VAS of the EQ-5D-5L)           
• Time to onset of safety events   
• Duration of safety events  
• Time to first chemotherapy or death      
• Time to first chemotherapy      
• Duration of response 
• 
                                                         
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. 
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, i.e., 
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 (fulvestrant+ ribociclib arm vs. fulvestrant + placebo arm) of 
PFS.  
The stratified log-rank test (strata based on the randomization factor from IRT) will be 
implemented as follows: For each of the K=4 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, 3 and 4) will be estimated from this analysis.  


Novartis 
Confidential 
Page 69 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
The final test statistics will then be reconstructed using the formula: Z=[S1+ 
S2+S3+S4]/√[var(S1) + var (S2)+ var (S3)+ var (S4)]. 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 
An estimate of the survival function in each treatment group will be constructed using 
Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST with 
METHOD=KM option. The 
PROC 
LIFETEST statement will 
use 
the 
option 
CONFTYPE=LOGLOG. 
Median survival for each 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. 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+ 𝜆𝜆̂(𝜃𝜃
෢𝐿𝐿𝐴𝐴̅ −𝜃𝜃෠𝐿𝐿𝐿𝐿) 
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  
and it depends on the variance estimators of  𝜃𝜃෠𝐶𝐶𝐶𝐶 (𝑉𝑉෠𝐶𝐶𝐶𝐶)and 𝜃𝜃෠𝐿𝐿(𝑉𝑉෠𝐿𝐿) (the estimator of log-HR 
based on the local assessment in all patients), the proportion of patients in the audited 
subset(𝛿𝛿), and 𝜌𝜌ො, 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 10000 times, giving rise to 10000 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, 𝑉𝑉෠𝐶𝐶𝐶𝐶{1 − 𝜌𝜌ො2(1 −𝛿𝛿)}. 


Novartis 
Confidential 
Page 70 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
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 assessment 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 analyses of OS will be based on group sequential 
methodology with efficacy stopping boundaries defined by type I error spending functions. 
This approach is flexible in dealing with any deviations from the targeted event totals, or 
unexpected changes to the plan. 
If the exact number of events observed at the interim and final analyses deviates from the 
target numbers described in the protocol, the actual critical boundaries will be derived using 
the pre-specified error spending functions and the actual numbers of events observed.  
• At interim analyses, information fractions will be computed as the ratio of the number 
of events observed at the considered interim analysis relative to the number targeted 
for the final analysis, as described in the sample size section of the protocol.  
• At the final analysis, 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 and smaller than 5% for a two-sided test).  
4.3.1 
Alpha-spending function 
The stopping boundaries to be used for OS 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: 
 
)
/
(
2
2
)
(
2
/
t
Z
t
α
α
Φ
−
=


Novartis 
Confidential 
Page 71 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
This function generates stopping boundaries that closely resemble the O’Brien-Fleming 
boundaries (O’Brien and Fleming, 1979).  
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 
primary 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.  Date of censoring is the same as defined for the 
PFS and OS analysis. 
In addition, the time from PFS/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. 
 
 


Novartis 
Confidential 
Page 72 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
5 
References 
Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J and Burger HU. Blinded 
independent central review of progression in cancer clinical trials: results from a meta-
analysis. European Journal of Cancer 2011; 47: 1772-1778. 
Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, 
Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and 
anastrozole in combination compared with anastrozole alone as first-line therapy for patients 
with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-
25. doi: 10.1200/JCO.2011.38.1095. Epub 2012 Feb 27. 
Bretz F, Posch M, Glimm E, et al (2011). Graphical approaches for multiple comparison 
procedures using weighted Bonferroni, Simes or parametric tests. Biometrical Journal; 53, 
894-913.  
Bretz, F., Maurer, W., and Hommel, G. (2009) Test and power considerations for multiple 
endpoint analyses using sequentially rejective graphical procedures. Statistics in Medicine 30, 
1489-1501.  
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41.    
Buzdar AU, Jonat W, Howell A, et al: Anastrozole versus megestrol acetate in the treatment 
of postmenopausal women with advanced breast carcinoma: Results of a survival update 
based on a combined analysis of data from two mature phase III trials. Arimidex Study 
Group. Cancer 83:1142-1152, 1998 
Cleeland CS (2009) The Brief Pain Inventory. User Guide. Houston, Texas. 
Clopper, C.; Pearson, E.S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413 
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
Di Leo A, Malorni L. Polyendocrine treatment in estrogen receptor-positive breast cancer: a 
"FACT" yet to be proven. J Clin Oncol. 2012 Jun 1;30(16):1897-900. 
Dodd E L, Korn L E, Freidlin B, Gray R, Bhattacharya S. An audit strategy for 
progression-free survival. Biometrics, Vol 67, Issue 3; 1092-99, 2011. 
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, 
Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, 
Tjabbes T, Chaudri HA, Hornberger U, Trunet PF. Letrozole, a new oral aromatase inhibitor 
for advanced breast cancer: double-blind randomized trial showing a dose effect and 
improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998 
Feb;16(2):453-61. 
Dmitrienko A., Molenberghs G., Chuang-Stein Ch., Offen W. (2005). Analysis of clinical 
trials using SAS. SAS Institute Inc., SAS press  


Novartis 
Confidential 
Page 73 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Dowsett M, Pfister C, Johnston RD, et al. Impact of tamoxifen on the pharmacokinetics and 
endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast 
cancer. Clin Can Res 1999;5:2338-2343. 
Dowsett M, Tobias JS, Howell A et al.  (1999) 79(2):311-315. The effect of anastrozole on 
the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer. Br J 
Cancer. 1999;79(2):311-315 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of Life Group 
(2001) The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European 
Organisation for Research and Treatment of Cancer, Brussels 2001 
FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies. 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncol
ogicdrugsadvisorycommittee/ucm311141.pdf  
Finn, Rs ; Crown, JP ; Lang, I ; Boer, K ; Bondarenko, Im ; Kulyk, So ; Ettl, J ; Patel, R ; 
Pinter, T ; Schmidt, M ; Shparyk, Y ; Thummala, Ar ; Voytko, Nl ; Fowst, C ; Huang, X ; 
Kim, St ; Randolph, S ; Slamon, Dj. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-
positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised 
phase 2 study. Lancet Oncology, 2015 Jan, Vol.16(1), pp.25-35 
Fleming TR, Harrington DP, O’Brien PC (1984). Designs for group sequential tests. 
Controlled Clinical Trials 5: 348-361. 
Fleming TR, Rothmann MD, Lu HL (2009). Issues in Using Progression-Free Survival When 
Evaluating Oncology Products. Journal of Clinical Oncology 27, 2874-2880 
Glimm, E., Maurer, W., and Bretz, F. (2010) Hierarchical testing of multiple endpoints in 
group-sequential trials. Statistics in Medicine 29, 219-228 
Hernan M., Brumback B., Robins J. Marginal structural models to estimate the causal effect 
of zidovudine on the survival of HIV-positive men. Epidemiology, 11(5), 561-570 (2000). 
Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris 
C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the 
treatment of advanced breast cancer in postmenopausal women previously untreated with 
endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 
1;22(9):1605-13. 
Hung HM, Wang SJ and O’Neil R (2007) Statistical considerations for testing multiple 
endpoints in group sequential or adaptive clinical trials. Journal of Biopharmaceutical 
Statistics 17: 1201-1210.   
Hwang, I.K. Shih, W.J. and DeCani, J.S. (1990). Group sequential designs using a family of 
type I error probability spending functions. Statistics in Medicine 9, 1439-1445 


Novartis 
Confidential 
Page 74 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Johnston S., Kilburn L.S., Ellis P. et al (2012) Fulvestrant alone or with concomitant 
anastrozole vs Exemestane following progression on non-steroidal aromatase inhibitor: first 
results of the SoFEa trial. EJC Volume 47, Supplement 2. 
Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, Im YH, Braybrooke 
JP, Brunt AM, Cheung KL, Jyothirmayi R, Robinson A, Wardley AM, Wheatley D, Howell 
A, Coombes G, Sergenson N, Sin HJ, Folkerd E, Dowsett M, Bliss JM; SoFEA investigators. 
Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-
steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive 
locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 
randomised trial. Lancet Oncol. 2013 Sep;14(10):989-98. 
Jonat W, Kaufmann M, Blamey RW, Howell A, Collins JP, Coates A, Eiermann W, Janicke 
F, Njordenskold B, Forbes JF, Kolvenbag GJCM (1995), A randomized study to compare the 
effect of the Luteinising Hormone Releasing Hormone (LHRH) analogue Goserelin with or 
without Tamoxifen in pre- and perimenopausal patients with advanced breast cancer. 
European Journal of Cancer, 31A(2), 137-142 
Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L and Sylvester R (2001), 
Combined Tamoxifen and Luteinizaing Hormone-Releasing Hormone (LHRH) agonist  
versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four 
randomized trials. Journal of Clinical Oncology, 19: 343-353 
Lan, K. K. G. & Demets, D. L. (1983). Discrete sequential boundaries for clinical trials. 
Biometrika 70, 659-63 
Lien EA1, Anker G, Lønning PE, Solheim E, Ueland PM. Decreased serum concentrations of 
tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res. 1990 Sep 
15;50(18):5851-7 
Mouridsen H, Gershanovich M, Sun Y, et al (2003) Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis 
of survival and update of efficacy from the International Letrozole Breast Cancer Group. J 
Clin Oncol; 21: 2101-09 
Mouridsen H, Gershanovich M, Sun Y, et al (2001) Superior efficacy of letrozole versus 
tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: 
results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol; 
19: 2596-606 
O'Brien PC, Fleming TR (1979). A multiple testing procedure for clinical trials, Biometrics. 
35(3):549-56. 
Oemar M, Jannsen B. (2013) EQ-5D-5L User Guide: Basic information on how to use the 
EQ-5D-5L instrument. Version 2.0, October 2013. © EuroQol Group 2013.  
Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, 
Therasse P. Phase III study comparing exemestane with tamoxifen as first-line hormonal 
treatment of metastatic breast cancer in postmenopausal women: the European Organisation 
for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008 
Oct 20;26(30):4883-90. doi: 10.1200/JCO.2007.14.4659. Epub 2008 Sep 15. 


Novartis 
Confidential 
Page 75 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Rabin R, Oemar M, Oppe M (2011) EQ-5D-5L User Guide: Basic information on how to use 
the EQ-5D-5L instrument. Version 1.0, April 2011. © EuroQol Group 2011 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics. 1993 Nov;4(5):353-65 
Robertson JFR, Lindemann JPO, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the 
first-line treatment of advanced breast cancer: follow-up analysis from the randomized 
‘FIRST’ study. Breast Cancer Res Treat (2012) 136:503–511. 
Robertson, Jfr ; Lindemann, J ; Garnett, S ; Anderson, E ; Nicholson, Ri ; Kuter, I ; Gee, Jmw. 
A Good Drug Made Better: The Fulvestrant Dose-Response Story. Clinical Breast Cancer, 
2014 Dec, Vol.14(6), pp.381-389  
Schuirmann DJ (1987). A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 
15(6):657-80. 
Tang Z (2015). Optimal futility interim design: a predictive probability of success approach 
with time to event end point. Journal of Biopharmaceutical Statistics, 25(6), 1312-1319. 
Zhang JJ, Chen H, He K, Tang S, Justice R, Keegan P, Pazdur R and Sridhara R. Evaluation 
of blinded independent central review of tumor progression in oncology clinical trials: a meta-
analysis. Therapeutic innovation & regulatory science: 2012, 47(2): 167-174. 


Novartis 
Confidential 
Page 76 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301 
 
Appendix 1 
CTC grades for laboratory values in Novartis Oncology  
 


Novartis 
Confidential 
Page 77 
SAP amendment 1  
24-Jul-2018 (10:31) 
CLEE011F2301