COMPLEEMENT-1: An Open-label, Multicenter, Phase IIIb Study to Assess the Safety and Efficacy of Ribociclib (LEE011) in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With Hormone Receptor-positive (HR+) HER2-negative (HER2-) Advanced Breast Cancer (aBC) With no Prior Hormonal Therapy for Advanced Disease
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................14
Amendment 04 (23-Jan-2020)...........................................................................................20
Amendment 03 (24-Sep-2018)..........................................................................................23
Amendment 02 (16-Aug-2017).........................................................................................25
Amendment 01 (19-Dec-2016)..........................................................................................29
1
Background........................................................................................................................33
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............33
1.1.1
Role of the CDK4/6 pathway in breast cancer......................................33
1.1.2
Role of estrogen pathway in breast cancer............................................35
1.2
Introduction to investigational treatment(s) and other study treatment(s).............37
1.2.1
Overview of Ribociclib.........................................................................37
1.2.2
Overview of Letrozole ..........................................................................40
1.2.3
Low potential for interaction between ribociclib and letrozole ............41
1.2.4
Overview of LHRH agonists.................................................................41
2
Rationale............................................................................................................................42
2.1
Study rationale and purpose...................................................................................42
2.2
Rationale for the study design ...............................................................................43
2.3
Rationale for dose and regimen selection..............................................................43
2.4
Rationale for choice of comparator drugs .............................................................44
2.5
Risks and benefits..................................................................................................44
3
Objectives and endpoints...................................................................................................45
4
Study design ......................................................................................................................47
4.1
Description of study design ...................................................................................47
4.2
Timing of interim analyses and design adaptations...............................................49
4.3
Definition of end of study......................................................................................49
4.4
Early study termination..........................................................................................50
5
Population..........................................................................................................................50
5.1
Patient population..................................................................................................50
5.2
Inclusion criteria ....................................................................................................50
5.3
Exclusion criteria...................................................................................................52

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Treatment...........................................................................................................................54
6.1
Study treatment......................................................................................................54
6.1.1
Dosing regimen.....................................................................................55
6.1.2
Ancillary treatments..............................................................................57
6.1.3
Rescue medication ................................................................................57
6.1.4
Guidelines for continuation of treatment ..............................................57
6.1.5
Treatment duration................................................................................57
6.2
Dose escalation guidelines.....................................................................................57
6.3
Dose modifications................................................................................................57
6.3.1
Dose modification and dose delay ........................................................57
6.3.2
Follow-up for toxicities.........................................................................65
6.4
Concomitant medications ......................................................................................65
6.4.1
Permitted concomitant therapy .............................................................65
6.4.2
Permitted concomitant therapy requiring caution.................................66
6.4.3
Prohibited concomitant therapy ............................................................67
6.4.4
Drugs with QT prolongation.................................................................67
6.5
Patient numbering and treatment assignment........................................................68
6.5.1
Patient numbering .................................................................................68
6.5.2
Treatment assignment ...........................................................................68
6.5.3
Treatment blinding................................................................................68
6.6
Study drug preparation and dispensation...............................................................68
6.6.1
Study treatment packaging and labeling ...............................................69
6.6.2
Drug supply and storage........................................................................69
6.6.3
Study drug compliance and accountability ...........................................70
6.6.4
Disposal and destruction .......................................................................70
7
Visit schedule and assessments .........................................................................................70
7.1
Study flow and visit schedule................................................................................70
7.1.1
Molecular pre-screening........................................................................80
7.1.2
Screening...............................................................................................80
7.1.3
Run-in period ........................................................................................82
7.1.4
Treatment period...................................................................................82
7.1.5
Discontinuation of study treatment .......................................................82
7.1.6
Withdrawal of consent ..........................................................................84
7.1.7
Follow up for safety evaluations...........................................................85
7.1.8
Lost to follow-up...................................................................................85
7.2
Assessment types...................................................................................................85

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7.2.1
Efficacy assessments.............................................................................85
7.2.2
Safety and tolerability assessments.......................................................87
7.2.3
Patient reported outcomes.....................................................................90
8
Safety monitoring and reporting........................................................................................91
8.1
Adverse events.......................................................................................................91
8.1.1
Definitions and reporting ......................................................................91
8.1.2
Laboratory test abnormalities................................................................93
8.2
Serious adverse events...........................................................................................93
8.2.1
Definitions.............................................................................................93
8.2.2
Reporting...............................................................................................94
8.3
Emergency unblinding of treatment assignment ...................................................95
8.4
Pregnancies............................................................................................................95
8.5
Warnings and precautions......................................................................................95
8.6
Data Monitoring Committee..................................................................................95
8.7
Steering Committee ...............................................................................................95
9
Data collection and management.......................................................................................96
9.1
Data confidentiality ...............................................................................................96
9.2
Site monitoring ......................................................................................................96
9.3
Data collection.......................................................................................................97
9.3.1
IRT data collection................................................................................97
9.3.2
FACT-B questionnaire data collection..................................................97
9.4
Database management and quality control............................................................97
10 Statistical methods and data analysis ................................................................................98
10.1
Analysis sets ..........................................................................................................98
10.1.1
Full Analysis Set ...................................................................................99
10.1.2
Safety set in Core Phase........................................................................99
10.1.3
Safety Set in Extension Phase...............................................................99
10.1.4
Per-Protocol set .....................................................................................99
10.1.5
Dose-determining analysis set...............................................................99
10.1.6
Pharmacokinetic analysis set.................................................................99
10.1.7
Other analysis sets.................................................................................99
10.2
Patient demographics/other baseline characteristics .............................................99
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................99
10.4
Primary objective.................................................................................................100
10.4.1
Variable...............................................................................................100
10.4.2
Statistical hypothesis, model, and method of analysis........................100

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10.4.3
Handling of missing values/censoring/discontinuations.....................100
10.4.4
Supportive and Sensitivity analyses....................................................100
10.5
Secondary objectives ...........................................................................................101
10.5.1
Secondary objective(s)........................................................................101
10.5.2
Other secondary efficacy objectives ...................................................101
10.5.3
Safety objectives .................................................................................101
10.5.4
Patient-reported outcomes...................................................................103
10.6
Exploratory objectives.........................................................................................104
10.7
Interim analysis....................................................................................................104
10.8
Sample size calculation........................................................................................104
10.9
Power for analysis of key secondary variables....................................................105
11 Ethical considerations and administrative procedures ....................................................105
11.1
Regulatory and ethical compliance......................................................................105
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................105
11.3
Informed consent procedures...............................................................................105
11.4
Discontinuation of the study................................................................................106
11.5
Publication of study protocol and results.............................................................106
11.6
Study documentation, record keeping and retention of documents.....................106
11.7
Confidentiality of study documents and patient records .....................................107
11.8
Audits and inspections.........................................................................................107
11.9
Financial disclosures............................................................................................107
12 Protocol adherence ..........................................................................................................108
12.1
Amendments to the protocol................................................................................108
13 References (available upon request)................................................................................109
14 Appendices ......................................................................................................................113
14.1
Appendix 1 - Concomitant Medications..............................................................113
14.2
Appendix 2 – Patient Reported Outcomes FACT-B ...........................................117
14.3
Appendix 3 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....120
14.3.1
Introduction.........................................................................................122
14.3.2
Efficacy assessments...........................................................................122
14.3.3
Definitions...........................................................................................122
14.3.4
Disease measurability..........................................................................122
14.3.5
Eligibility based on measurable disease..............................................123
14.3.6
Methods of tumor measurement - general guidelines.........................123
14.3.7
Baseline documentation of target and non-target lesions ...................125

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Follow-up evaluation of target and non-target lesions........................126
14.3.9
Follow-up and recording of lesions.....................................................126
14.3.10
Non-nodal lesions................................................................................126
14.3.11
Nodal lesions.......................................................................................127
14.3.12
Determination of target lesion response..............................................127
14.3.13
Determination of non-target lesion response ......................................129
14.3.14
New lesions .........................................................................................130
14.3.15
Evaluation of overall lesion response .................................................130
14.3.16
Efficacy definitions .............................................................................131
14.3.17
Best overall response...........................................................................131
14.3.18
Time to event variables .......................................................................134
14.3.19
Progression-free survival ....................................................................134
14.3.20
Overall survival...................................................................................134
14.3.21
Time to progression.............................................................................134
14.3.22
PFS2....................................................................................................135
14.3.23
Time to treatment failure.....................................................................135
14.3.24
Duration of response ...........................................................................135
14.3.25
Time to response .................................................................................136
14.3.26
Definition of start and end dates for time to event variables ..............137
14.3.27
Handling of patients with non-measurable disease only at baseline...138
14.3.28
Sensitivity analyses .............................................................................139
14.3.29
Data handling and programming rules................................................141
14.3.30
Study/project specific decisions..........................................................142
14.3.31
End of treatment phase completion.....................................................142
14.3.32
End of post-treatment follow-up (study phase completion)................142
14.3.33
Medical validation of programmed overall lesion response ...............143
14.3.34
Programming rules..............................................................................143
14.3.35
Calculation of ‘time to event’ variables..............................................144
14.3.36
Incomplete assessment dates...............................................................144
14.3.37
Incomplete dates for last known date patient alive or death ...............144
14.3.38
Non-target lesion response..................................................................144
14.3.39
Study/project specific programming...................................................144
14.3.40
Censoring reason.................................................................................144
14.3.41
References (available upon request) ...................................................145
14.4
Appendix 4 - Bone Marrow Reserve in Adults ...................................................146

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List of figures
Figure 1-1
Regulation of cell cycle checkpoint control..........................................35
Figure 4-1
Study design..........................................................................................48
Figure 6-1
Men / Premenopausal regimen..............................................................55
Figure 6-2
Postmenopausal regimen.......................................................................56
List of tables
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal 
BC patients............................................................................................36
Table 3-1
Objectives and related endpoints ..........................................................46
Table 6-1
Dose and treatment schedule.................................................................55
Table 6-2
Ribociclib Dose Modification Guidelines.............................................58
Table 6-3
Ribociclib dose reduction/interruption and management 
recommendations for hematological adverse drug reactions 
(CTCAE v4.03).....................................................................................59
Table 6-4
Ribociclib dose reduction/interruption and management 
recommendation for hepatic toxicities (CTCAE v4.03) .......................60
Table 6-5
Ribociclib dose adjustment and management recommendation for 
QTcF prolongation................................................................................63
Table 6-6
Ribociclib dose adjustment and management recommendation for   
ILD/pneumonitis ...................................................................................64
Table 6-7
Ribociclib dose reduction/interruption and management 
recommendation for all other adverse reactions ...................................64
Table 6-8
Packaging and labeling .........................................................................69
Table 6-9
Supply and storage of study treatments ................................................69
Table 7-1
Visit evaluation schedule (Core Phase).................................................72
Table 7-2
Visit evaluation schedule (Extension Phase) ........................................78
Table 7-3
Imaging Assessment Collection Guidance............................................85
Table 7-4
ECOG performance status.....................................................................88
Table 7-5
Local Clinical laboratory parameters collection plan ...........................89
Table 7-6
Patient reported outcomes collection plan ............................................91
Table 10-1
Confidence Intervals associated with AEs of interest for subgroups..104
Table 14-1
List of prohibited medications during study drug treatment...............113
Table 14-2
List of medications to be used with caution during study drug 
treatment..............................................................................................115
Table 14-3
Response criteria for target lesions .....................................................127
Table 14-4
Response criteria for non-target lesions..............................................129
Table 14-5
Overall lesion response at each assessment ........................................131

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Table 14-6
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................138
Table 14-7
Options for event dates used in PFS, TTP, duration of response........139
Table 14-8
Bone Marrow Reserve in Adults.........................................................146

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List of abbreviations
aBC
AE
Advanced Breast Cancer
Adverse Event
AI
Aromatase Inhibitors
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
ALP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
aBC
Advanced Breast Cancer
BC
Breast Cancer
BCRP
Breast Cancer resistance protein
BSEP
CBD
Bile export salt pump
Cannabidiol
CBR
Clinical Benefit Rate
CCND1
Cyclin D1
CDK4/6
Cyclin-Dependent Kinases 4 and 6
CMO&PS
CL
Chief Medical Officer and Patient Safety
Clearance
CNS
Central Nervous System
Cmax
Maximum Plasma Concentration
COA
Clinical Outcome Assessment
eCOA
Electronic Clinical Outcome Assessment
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DDI
Drug-Drug Interaction
DFS
Disease Free Survival
DHEA
Dehydroepiandrosterone
DI
Dose Intensity
DILI
Drug-Induced Liver Injury
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
EDC
Electronic Case Report Form
Electronic Data Capture
EOT
End of Treatment
ER
Estrogen Receptor
ET
Endocrine Therapy
FACT-B
Functional Assessment of Cancer Therapy - Breast
FAS
Full Analysis Set

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FDA
Food and Drug Administration
FMO3
Flavin-containing Monooxygenase 3 
FPFV
First Patient First Visit
FSH
Follicle Stimulating Hormone
G3/4
Grade 3/4
GCP
Good Clinical Practice
GI
Gastrointestinal
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HR+
Hormone Receptor Positive
IA
Interim Analysis
IB
Investigator’s Brochure
IC50
Inhibitory Concentration, where 50% inhibition is observed
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
ILD
Immunohistochemistry
Interstitial Lung Disease
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
LFT
Liver Function Test
LHRHa
Luteinizing Hormone-Releasing Hormone agonist
LLN
Lower Limit of Normal
LPFV
Last Patient First Visit
MATE1
Multidrug And Toxin Extrusion protein-1
NCCN
National Comprehensive Cancer Network
NSAI
Nonsteroidal Aromatase Inhibitors
NSCLC
Non-Small Cell Lung Cancer
OCT2
Organic Cation Transporter 2
OFS
Ovarian Function Suppression
ORR
Overall Response Rate
OS
Overall Survival
PAS
PRO Analysis Set
PD
P-gP
Progression of Disease
Permeability-glycoprotein
PFS
Progression Free Survival
PgR
Progesterone receptor
PHI
Protected Health Information
PK
Pharmacokinetics
pRb
Retinoblastoma Protein
PR
Partial Response
PRO
Patient-Reported Outcomes

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PS
PSDS
Performance Status
Post-Study Drug Supply
PT
PTA
Prothrombin Time
Post Trial Access
PVC
Premature Ventricular Contractions
QD
Quaque Die (every day)
QTcF
QT corrected interval using Fridericia
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
Rb
Retinoblastoma Protein
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RT
RadioTherapy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Stable Disease
SERM
Selective ER Modulators
SmPC
SUSAR
Summary of Product Characteristics
Suspected Unexpected Serious Adverse Reaction
T1/2
Half-life
TBIL
Total Bilirubin
TdP
TEN
THC
Torsades de Pointes
Toxic Epidermal Necrolysis
tetrahydrocannabinol
TTP
Time To Progression
ULN
Upper Limit of Normal
US
United States
VES
Visit Evaluation Schedule
WBC
White Blood Cell

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Glossary of terms
Assessment
A procedure used to generate data required by the study
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
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 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
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.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason.
Subject Number
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
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.

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Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Withdrawal of Consent
Withdrawal of consent occurs only when a patient does not want to participate in 
the study any longer, and does not want any further visits or assessments, and 
does not want any further study related contact

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Protocol summary
Title
An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of 
ribociclib (LEE011) in combination with letrozole for the treatment of men and 
pre/postmenopausal women with hormone receptor-positive (HR+) HER2-
negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy 
for advanced disease
Brief title
Study to assess the safety and efficacy of ribociclib (LEE011) in combination with 
letrozole for the treatment of men and pre/postmenopausal women with HR+ 
HER2- aBC in a broader population
Sponsor and
Clinical Phase
Novartis
Phase IIIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this Phase IIIb study is to collect additional safety and efficacy 
data for the combination of ribociclib + letrozole in a broader population of 
patients with HR+HER2- aBC in comparison with other Phase III studies with 
ribociclib.
Primary Objective(s) and 
Key Secondary Objective
To evaluate the safety and tolerability of ribociclib with letrozole in men and 
pre/postmenopausal women with HR+, HER2- aBC who received no prior 
hormonal therapy for advanced disease
Note: Throughout this document, perimenopausal and premenopausal status will 
be grouped together and referred as “Premenopausal”
Secondary Objectives
●
To assess the clinical efficacy of ribociclib + letrozole measured by Time-to-
Progression (TTP) and tumor response by overall response rate (ORR) and 
clinical benefit rate (CBR)
●
To assess treatment impact on patient reported outcome (PRO) measured by 
variations of Functional Assessment of Cancer Therapy - Breast (FACT-B)
questionnaire scores
●
To evaluate long-term safety of ribociclib + letrozole during Extension Phase
●
To evaluate clinical benefit of ribociclib + letrozole as assessed by 
investigator during Extension Phase
Study design
This open-label, single arm, multi-center Phase IIIb study will evaluate the overall 
safety and tolerability and clinical efficacy of ribociclib in combination with 
letrozole in men and pre/postmenopausal women with HR+, HER2- aBC and no 
prior hormonal treatment for advanced disease. A total of approximately 3,000 
patients will be enrolled for treatment with Letrozole (2.5 mg once daily) + 
Ribociclib (LEE011) 600 mg (day 1 to 21 in a 28 day cycle); goserelin (3.6mg as 
injectable subcutaneous implant every 28 days) or leuprolide (7.5mg 
intramuscular injection every 28 days) will be used in men and premenopausal 
women patients.
The study will be composed of 2 phases: Core Phase (from FPFV to 18 months 
after LPFV) and Extension Phase (18 months from LPLV of the Core Phase ). 
During the Core Phase, safety and efficacy data (including ePRO in selected 
countries) will be collected. In the event that patients are still deriving benefit at 
the end of the Core phase and ribociclib is not approved or available and 
reimbursed, patients may be transitioned to the Extension Phase and continue to 
receive study treatment until progression, intolerance, death or physician/patient 
decision. Only safety and clinical benefit (as assessed by investigator) data will 
be collected in the Extension Phase
During the Extension Phase, if ribociclib is approved and reimbursed, patients 
will be transitioned to prescription or drug access/support program(s) according 
to local laws and regulations. 
The study will end after completion of the Extension Phase and all remaining 
patients will discontinue from the study. Patients who complete this Extension 
Phase, and continue to derive clinical benefit from the treatment based on the 
investigator’s evaluation will receive ribociclib from prescription (if approved and 

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reimbursed), another Post-Trial Access (PTA) program, or other drug 
access/support program(s).
Population
This study includes men and pre/postmenopausal women with HR+, HER2- aBC 
who had not received any prior hormonal agent for treatment of advanced 
disease

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Inclusion criteria
1.
Patient is an adult, male or female ≥ 18 years old at the time of informed 
consent
2.
Male or female with advanced (locoregionally recurrent or metastatic) breast 
cancer not amenable to curative therapy.
3.
In the case of women, both pre/perimenopausal and postmenopausal 
patients are allowed to be included in this study; menopausal status is 
relevant for the requirement of goserelin or leuprolide to be used 
concomitantly with ribociclib and letrozole.
a)
Postmenopausal status is defined either by:
i) Prior bilateral oophorectomy
OR
ii) Age ≥60
OR
iii) Age <60 and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH 
and estradiol in the postmenopausal range per local normal range. If 
patient is taking tamoxifen or toremifene and age <60, then FSH and 
plasma estradiol levels should be in post-menopausal range per local 
normal range.
Note: For women with therapy-induced amenorrhea, serial measurements 
of FSH and/or estradiol are needed to ensure menopausal status.
b)
Premenopausal status is defined as either:
i) Patient had last menstrual period within the last 12 months
OR
ii) If on tamoxifen or toremifene within the past 14 days, plasma 
estradiol and FSH must be in the premenopausal range per local 
normal range
OR
iii) In case of therapy induced amenorrhea, plasma estradiol and/or FSH 
must be in the premenopausal range per local normal range.
c)
Perimenopausal status is define as neither premenopausal nor 
postmenopausal
Note: Throughout this document, perimenopausal and premenopausal status 
is grouped together and referred as “Premenopausal”
4.
Patient has a histologically and/or cytologically confirmed diagnosis of 
estrogen-receptor positive and/or progesterone receptor positive breast 
cancer by local laboratory. A confirmatory biopsy is not required.
5.
Patient has HER2-negative breast cancer 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.
6.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance 
status ≤2
7.
Patient has adequate bone marrow and organ function as defined by ALL of
the following laboratory values (as assessed by local laboratory):
●
Absolute neutrophil count ≥ 1.5 × 109/L
●
Platelets ≥ 100 × 109/L
●
Hemoglobin ≥ 9.0 g/dL
●
Potassium, sodium, calcium corrected for serum albumin and 
magnesium within normal limits or corrected to within normal limits with 
supplements before first dose of the study medication
●
INR ≤1.5
●
Serum creatinine <1.5 mg/dl or creatinine clearance ≥ 50 mL/min

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●
In absence of liver metastases, alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) should be < 2.5 × ULN. If the patient 
has liver metastases, ALT and AST should be < 5 × ULN.
●
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.
8. Patient must have a 12-lead ECG with ALL of the following parameters at 
screening:
●
QTcF interval at screening < 450 msec (using Fridericia’s correction)
●
Resting heart rate ≥ 50 bpm
9. Patient must be able to swallow ribociclib and letrozole tablets
10. Patient has signed informed consent obtained before any trial-related 
activities and according to local guidelines
11. Patients must be able to communicate with the investigator and comply with 
the requirements of the study procedures
Exclusion criteria
1.
Patient has a known hypersensitivity to any of the excipients of ribociclib or 
letrozole, including peanut and soy
2.
Patient who received any CDK4/6 inhibitor
3.
Patient who received any prior systemic hormonal therapy for advanced 
breast cancer; no more than one prior regimen of chemotherapy for the 
treatment of metastatic disease is permitted
Note:
●
Patients who received (neo) adjuvant therapy for breast cancer are 
eligible. If the prior neo (adjuvant) therapy included letrozole or 
anastrozole the disease free interval must be greater than 12 months 
from the completion of treatment until study entry.
●
Patients who received ≤ 28 days of letrozole or anastrozole for 
advanced disease prior to inclusion in this trial are eligible.
4.
Patient is concurrently using other anti-cancer therapy
5.
Patient has had major surgery within 14 days prior to starting study drug or 
has not recovered from major side effects
6.
Patient who has not had resolution of all acute toxic effects of prior anti-
cancer therapy to NCI CTCAE version 4.03 Grade ≤1 (except alopecia or 
other toxicities not considered a safety risk for the patient at investigator's 
discretion)
7.
Patient who has received extended-field radiotherapy ≤ 4 weeks or limited 
field radiotherapy for palliation ≤ 2 weeks prior to start of treatment, 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 RE 
1961) of the bone marrow has been previously irradiated are also excluded.
(see Appendix 14.4)
8.
Patient has a concurrent malignancy or malignancy within 3 years prior to 
starting study drug, with the exception of adequately treated, basal or 
squamous cell carcinoma, non-melanomatous skin cancer or curatively 
resected cervical cancer
9.
Patient with central nervous system (CNS) metastases unless they meet 
ALL of the following criteria:
●
At least 4 weeks from prior therapy for CNS disease completion 
(including radiation and/or surgery) to starting the study treatment.
●
Clinically stable CNS lesions at the time of study treatment initiation and 
not receiving steroids and/or enzyme-inducing anti-epileptic medications 
for the management of brain metastases for at least 2 weeks.
10. Patient has impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of the study drugs (e.g., uncontrolled 

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ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection)
11. Patient has a known history of HIV infection (testing not mandatory)
12. 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.)
13. Clinically significant, uncontrolled heart disease and/or cardiac 
repolarization abnormalities, including but not limited to any of the following:
●
History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty, 
or stenting) or symptomatic pericarditis within 6 months prior to 
screening
●
History of documented congestive heart failure (New York Heart 
Association functional classification III-IV)
●
Documented cardiomyopathy
●
Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), 
complete left bundle branch block, high-grade AV block (e.g. bifascicular 
block, Mobitz type II and third-degree AV block)
●
Long QT syndrome or family history of idiopathic sudden death or 
congenital long QT syndrome, or any of the following:
i.
Risk factors for Torsades de Pointe (TdP) including uncorrected
hypokalemia or hypomagnesemia, history of cardiac failure, or 
history of clinically significant/symptomatic bradycardia.
ii.
Concomitant use of medication(s) with a known risk to prolong the 
QT interval and/or known to cause Torsades de Pointe that cannot
be discontinued (within 5 half-lives or 7 days prior to starting study 
drug) or replaced by safe alternative medication
iii. Inability to determine the QTcF (Fridericia’s correction) interval on 
screening
●
Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
14. Patient is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to starting Cycle 1 Day 1:
●
Concomitant medications, herbal supplements, and/or fruits (e.g. 
grapefruit, pumeloes, star fruit, Seville oranges) and their juices that are 
known strong inducers or inhibitors of CYP3A4/5 (See Appendix 14.1)
●
Medications that have a narrow therapeutic window and are 
predominantly metabolized through CYP3A4/5
15. 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)
16. Participation in a prior investigational study within 30 days prior to 
enrollment or within 5-half-lives of the investigational product, whichever is 
longer
17.   Pregnant or nursing (lactating) women
Note: Women of child-bearing potential is defined as all women 
physiologically capable of becoming pregnant, unless they are using highly 
effective methods of contraception during dosing and for 21 days after 
stopping your study medication.
Highly effective contraception methods include:
●
Total abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, 

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symptothermal, post-ovulation methods), and withdrawal are not acceptable 
methods of contraception
●
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy), total hysterectomy (surgical removal of the uterus 
and cervix) or tubal ligation (getting the “tubes tied”) at least 6 weeks 
before taking study treatment. In case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up 
hormone level assessment
●
Male partner sterilization (at least 6 months prior to screening). For 
female patients on the study the vasectomized male partner should be the 
sole partner for that patient

Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
Note: Use of oral (estrogen and progesterone), transdermal, injected,
implantedhormone containing intrauterine (IUS) or any other hormonal
methods of contraception is not allowed in this study
Investigational and 
reference therapy
Ribociclib 600mg oral daily (3 weeks on/ 1 week off) in combination with letrozole 
2.5 mg oral once daily; goserelin 3.6mg (as injectable subcutaneous implant 
every 28 days) or leuprolide 7.5mg (as injectable intramuscular depot every 28 
days) will be used in men and premenopausal women patients 
Safety assessments
●
Physical examinations
●
ECOG performance status
●
Weight and vital signs
●
12 lead ECGs (assessed locally)
●
Laboratory assessments including hematology, chemistry and INR (assessed 
by local lab)
●
Adverse Events (AEs) collection
Efficacy assessments
Clinical efficacy will be assessed by the investigator
Tumor assessments will be performed according to the current standard of care 
(every 12 weeks until disease progression is recommended)
Other assessments
Patient Reported Outcomes FACT-B Questionnaire (See Appendix 14.2)
Data analysis
The data will be summarized with respect to demographic and baseline 
characteristics, and safety observations and efficacy measurements. Categorical 
data will be presented as frequencies and percentages. For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented.
Time to progression (TTP) is defined as time from date of start of treatment to 
the date of event defined as the first documented progression or death due to 
underlying cancer (Appendix 14.3: Novartis RECIST Guideline v 3.2). ORR and 
CBR will be calculated and summarized based on investigators’ assessment 
(according to RECIST 1.1).
For PROs, descriptive statistics will be used to summarize the subscale and 
overall scores at each scheduled assessment time point. Additionally, change 
from baseline at the time of each assessment will be summarized.
Key words
HR-positive, HER2-negative, advanced breast cancer, LEE011, ribociclib, 
letrozole, goserelin, leuprolide, CDK, CDK4, CDK6, CDK4/6, Phase IIIb, ER-
positive, PR-positive, premenopausal, postmenopausal, male breast cancer

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Amendment 04 (23-Jan-2020)
Amendment Rationale
The study was initiated in November, 2016 and 3,246 subjects were treated. The Core Phase 
was completed (Last Patient Last Treatment occurred on 09-Oct-2019 and Last Patient Last 
Visit occurred on 08-Nov-2019). A total of 415 subjects have been transitioned to the Extension 
Phase of the study.
The current amendment is intended to incorporate the updated safety information on  ribociclib 
in alignment with LEE011 (Ribociclib) Investigator’s Brochure (IB), Edition 14 (release date: 
28-Nov-2019) and to define the duration of the Extension Phase and transition plan for patients 
during and at the end of the study .

Interstitial Lung Disease (ILD)/pneumonitis has been observed with CDK4/6 inhibitor 
treatment as a class effect and was requested by FDA to be added to US label (Please refer 
to IB Edition 14 for more information). A new Table 6-6, Ribociclib dose adjustment and 
management recommendation for ILD/pneumonitis has been added 

Toxic Epidermal Necrolysis (TEN) has been reported in the post-marketing setting in a 
well-documented literature case report. No case was observed in the clinical trials.  (Please 
refer to IB Edition 14 for more information). Protocol section 6.3.1.3.5, Guidance for all 
other adverse reactions was updated with clear guidance to discontinue ribociclib if TEN is 
diagnosed

Updated recommended tables relating to Hepatic and Cardiac QTc Monitoring

Clarified Contraceptive methods allowed during study

Updated the list of prohibited medications during study treatment, and co-medication 
considerations

Updated the list of medications to be used with caution during study drug treatment

Updated the language regarding Extension Phase duration and transition plan

Editorial and typographical changes throughout the document
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:

Protocol Summary Exclusion criterion 17 clarified the information provided on acceptable 
male and female contraception methods by:
a.
Removal of the needed combination of an IUD/IUS with an occlusive cap or condom 
with spermicidal foam/gel/film/vaginal suppository
b. Additional methods of hormone contraceptives not allowed in the study

Section 4.3 was updated to clarify the end of the Extension Phase and transition plan

Table 6-3 was updated by removal of Grade 3 ANC without fever or signs of infection on 
Day 14 of the first 2 cycles

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
Table 6-3 Title was updated with CTCAE v4.03 grading

Table 6-4 Title was updated with CTCAE v4.03 grading and clarification of bi-weekly to 
every two weeks

Table 6-5 was updated with instructions on how to manage Grade 2 QTc prolongation with 
instructions to repeat ECG within one hour of first QTcF ≥481 ms

Section 6.3.1.3.4 and Table 6-6 Ribociclib dose adjustment and management 
recommendation for ILD/pneumonitis was added in.

Former section 6.3.1.3.4 Guidance for all other adverse reactions was renumbered to 
6.3.1.3.5

Former Table 6-6 was renumbered to Table 6-7 Ribociclib dose reduction/interruption and 
management recommendation for all other adverse reactions

Table 6-7 Ribociclib dose reduction/interruption and management recommendation for all 
other adverse reactions include language referring to Toxic Epidermal Necrosis (TEN)
was modified

Section 6.4.1 updated the text with with prohibited medications and the list of use with 
cautions with citations for Appendices

Section 6.4.1.3 Palliative Radiotherapy wording clarified that RT should not be used on 
target lesions and the total cumulative doses should not encompass > 25% of irradiated 
bone marrow

Section 6.4.1.3 text moved to the Section 6.4.4 ie, ‘Refer to the ribociclib [Investigator’s 
Brochure] and letrozole, goserelin, and leuprolide drug package insert and Appendix 14.1
for information on possible interactions with other drugs’

Former Table 6-7 was renumbered to Table 6-8 Package and labeling

Former Table 6-8 was renumbered to Table 6-9 Supply and Storage of Study Treatment

Table 7-2 Extension Phase Visit Evaluation Schedule was revised to label visits E-C1D1, 
E-C4D1, E-C7D1, and E-C1D1 and subsequent cycles and goserelin/leuprolide dose 
administration updated to monthly

Section 7.1.5 was updated to describe discontinuation of study treatment from the Extension 
Phase

Section 8.4 Pregnancies was updated to remove the timeframe for outcome collection for 
pregnant partners of male patients

Section 14.1 - Appendix 1 cited source changed from ‘Oncology Clinical Pharmacology 
guidance’ to ‘Novartis PK Science Memorandum’ and the release updated to Jan 2018

Table 14-1 was updated with the most current prohibited medications

Table 14-2 was updated with the most current medications to be used with caution
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.

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The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 03 (24-Sep-2018)
Amendment Rationale
The study was initiated in November, 2016 and enrollment has been completed (last Patient 
First Visit occurred on March 22, 2018). 3255 patients have been enrolled in the study.
The current amendment is intended to incorporate updated ribociclib program information.
A summary of the key changes in this amendment is listed below:

Updated the language regarding early study termination by the sponsor

Updated withdrawal of consent language with the new Global Data Protection 
Requirements

Updated 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 QTc prolongation.

Updated the list of prohibited medications during study treatment, and co-medication 
considerations

Updated the list of medications to be used with caution during study drug treatment

Clarified that paper PROs may be used if ePRO is unavailable

Editorial and typographical changes throughout the document
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:

Protocol Summary inclusion criterion 1 removed the need for men to use a condom while 
taking drug and for 21 days after stopping medication, whether they are vasectomized or 
not.

Protocol Summary exclusion criterion 17 expanded the information provided on acceptable 
female contraception methods

Section 4.4 updated the language regarding the reasons why the study may be terminated 
early by the sponsor and what actions are needed in that case

Section 5.2 inclusion criterion 1 removed the need for men to use a condom while taking 
drug and for 21 days after stopping medication, whether they are vasectomized or not.

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
Section 5.3 exclusion criterion 17 expanded the information provided on acceptable female 
contraception methods

Sections 6.1.1.1 and 6.4.3 updated to clarify that herbal or dietary supplements with a known 
risk of QT prolongation are not permitted

Section 6.4.1.4 updated to indicate that potential drug interactions are possible between 
ribociclib and antiemetics.

Section 6.4.2 clarified the information provided regarding renal transporters MATE1, OCT2 
and BCRP.

Section 6.4.3 was updated to clarify that both herbal medications and dietary supplements 
that are strong inhibitors of CYP3A4/5 or those known to cause QT prolongation are 
prohibited.

Section 7.1 and table 7.5 were updated to clarify that absolute lymphocyte count is required 
when reporting hematology-related lab results

Section 7.1.6 was updated with updated language regarding actions needed when a patient 
withdraws their consent to participate in the trial

Section 7.2.3 was updated to clarify the timing of the PRO administration

Section 8.1.3 was removed due to redundancy as AESI review information is also included 
in section 10.4.1

Section 9.3.2 was updated to allow for use of paper PROs when the ePRO is unavailable, 
and to clarify that questionnaires should be administered in the patient’s local language

Table 6-5 was updated with instructions on how to manage QTcF prolongation

Table 14-1 was updated with the most current prohibited medications

Table 14-2 was updated with the most current medications to be used with caution
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 02 (16-Aug-2017)
Amendment rationale
The study was initiated in November, 2016 and enrollment is currently ongoing. As of Aug 8, 
2017, 1008 patients have been enrolled in the study.
The current amendment is intended to update the existing information on ribociclib and clarify 
specific aspects of amendment 01, based on feedback and communications received from 
investigators and the Study Steering Committee. This will result in enhanced clarity for patient 
eligibility and quality of data collection.
A summary of the key changes in this amendment is listed below:

Information from the pivotal study CLEE011A2301 (MONALEESA-2) supporting the use 
of ribociclib + letrozole in aBC has been updated to strengthen the study rationale

Standard language around contraception was updated in the inclusion/exclusion criteria

Recruitment duration was adjusted according to the expected recruitment figures and 
required follow-up to adequately address the primary and secondary objectives of the study

Clarifications on assessments performed during the Core Phase and the Extension Phase

Expansion of another monthly-based dosing LHRH agonist (leuprolide) in addition to 
goserelin, based on NCCN Breast Cancer Guidelines 2017

Removal of requirement for prior anti-cancer therapy 5 half-lives washout period, given the 
low probability of drug-drug interactions and the urgency to treat patients with advanced 
breast cancer who are progressing

Clarified radiotherapy windows and rationale

Additional clarification and updated wording on prohibition of herbal products

Updated wording on allowance of local/regional sub-studies/analysis studies

Clarification about ribociclib administration and assessments schedule due to drug 
interruptions from adverse events

Clarification of the sample size calculation. Three thousand (3,000) patients are planned to 
be enrolled in this study to detect rare AEs (frequency ~0.1%) with high probability. This 
will allow for a greater precision when reporting rare, but clinically meaningful AEs (e.g. 
febrile neutropenia, QT prolongation, renal insufficiency, thromboembolic events, etc.) and 
will allow for a meaningful safety analysis of specific patient subgroups of particular 
interest
Amendment 02 also includes minor editorial changes and additional clarifications to address 
investigators’ questions 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:

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
Cover page authorship was removed according to Novartis Oncology Protocol template, 
version 06-Apr-2017

Summary section of the protocol has been updated to maintain consistency with the main 
body of the protocol

Section 1.1.1 updated current preclinical and clinical data supporting CDK4/6 pathway in 
breast cancer

Section 1.1.3 role of Cyclin D kinases inhibitor in breast cancer was deleted as updated 
information was provided in Section 1.1.1

Section 1.2.1 overview of ribociclib was updated with newly reported results on non-clinical 
data, clinical safety, clinical efficacy, clinical pharmacokinetics, and clinical experience

Section 1.2.4 summary of results from study CLEE011X2107 and Section 1.2.5 summary 
of results from study CLEE011A2301 was removed as the updated information has been 
provided in the updated Section 1.2

Section 1.2.6 was updated with LHRH agonists information and was renumbered as Section 
1.2.4

Section 1.2.7 was removed

Section 2.4 (previous) was deleted and merged with Section 2.3: rationale for dose and 
regimen selection updated; added leuprolide to the combination of ribociclib+letrozole to 
achieve adequate hormonal suppression in men/premenopausal women

Section 2.6 renumbered as Section 2.5: added ribociclib approval by US FDA on Mar 13, 
2017

Section 4.1 updated to allow the use of leuprolide; removed expected Core Phase duration 
of 36 months; allowed local/regional sub-studies/analysis to be conducted in patient 
population enrolled in LEE011A2404 study; Figure 4-1 study design was updated to allow 
the use of leuprolide for ovarian suppression

Section 4.3 revised definition of end of study

Section 5.2 inclusion criterion 4 clarified that a confirmatory biopsy is not required

Section 5.2 inclusion criterion 7 clarified the laboratory values required for total bilirubin 
and direct bilirubin

Section 5.3 exclusion criterion 3 removed requirement of stopping any prior (neo)adjuvant 
anti-cancer therapy or prior chemotherapy for metastatic disease at least 5 half-lives or 7 
days before study entry

Section 5.3 exclusion criterion 7 clarified the criterion on prior radiotherapy

Section 5.3 exclusion criterion 14 clarified prohibition of herbal products

Section 5.3 exclusion criterion 17 updated highly effective contraception methods

Section 6.1, Section 6.1.1, Table 6-1, Figure 6-1, and Section 6.1.1.1 updated with 
leuprolide dose and treatment information

Section 6.1.5 Treatment Duration was revised to remove the 18 months of recruitment 
period after FPFV

Section 6.3.1 clarified dose modifications and discontinuations guides for ribociclib, 
letrozole, and goserelin/leuprolide

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
Section 6.3.1.2 updated dose information and monitoring of post-menopausal status of 
patient given LHRH agonists

Section 6.3.1.3 Table 6-2 Dose Modification Guideline: Letrozole and Goserelin columns 
were removed from table; clarified seven consecutive rest days needed prior to reinitiating
ribociclib

Section 6.3.1.3.1 Added Recommendations on Adjustment of Ribociclib Treatment Cycles 
in the Case of Dose Interruptions/ Reinitiation

Section 6.3.1.3.2 Follow up on potential drug-induced liver injury (DILI) cases was 
renumbered from former Section 6.3.1.3.1

Section 6.3.1.3.3 Additional follow-up for QTc prolongation was renumbered from former 
Section 6.3.1.3.2

Table 6-3 clarified dose adjustment and management recommendation on Absolute 
Neutrophil Count (ANC) Grade 4 toxicity

Table 6-4 modified dose reduction/interruption and management recommendation for 
Grade 2 and 3 hepatotoxicity and note section

Section 6.1.3.4 adjustment of starting dose in special populations was removed as this 
protocol is not intended to investigate the combination of ribociclib + letrozole in the special 
populations

Section 6.4.1 clarified requirement of documenting dose schedule change of concomitant 
medications

Section 6.4.1.2 clarified that the prophylactic use of WBC growth factors with ribociclib is 
not recommended as ASCO guidelines recommendations regarding the use of WBC growth 
factors is for chemotherapy induced neutropenia

Section 6.4.1.4 added the use of antiemetic medications

Section 6.4.2 updated the use of permitted concomitant therapy requiring caution

Section 6.4.3 clarified the use of prohibited concomitant therapy

Section 6.4.4 updated the use of drugs with QT prolongation as concomitant medications

Section 6.6 added leuprolide information on drug dispensing, packaging and labeling, and 
drug supply and storage

Section 7.1 clarified direct bilirubin required to be assessed at screening and during 
treatment only if clinically indicated; clarified that study visits should be adjusted according 
to treatment cycle in the case of ribociclib being withheld

Section 7.1.2 updated to allow bloodwork completed during regular work-up as standard 
practice within 5 calendar days prior to signing ICF to be considered as screening 
assessments

Section 7.1.4 updated with leuprolide information

Section 7.1.5 clarified patients’ withdrawal/discontinuation criteria and EOT visit schedule

Section 7.2.2.5.4 renamed section Pregnancy and Hormonal Levels and clarified FSH and 
Estradiol local collection (not collected on eCRFs) at screening for confirmation on 
menopausal status

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
Table 7-1 Visit Evaluation Schedule updated Chemistry and Coagulation reference link to 
Table 7-5; added leuprolide to table; for hematology and chemistry assessments during 
screening, added text “-14 days to Day 1”. This 14 day period was already part of the 
protocol in Section 7.2.2.5

Table 7-5 clarified direct bilirubin required only if clinically indicated, added note to clarify 
that electrolytes are required to be monitored but not entered on the eCRF

Table 7-6 clarified FACT-B questionnaires collection plan to include End of Treatment visit

Sections 8.2.2 and 8.4 replaced “Novartis Drug Safety and Epidemiology (DS&E)” with 
“Novartis Chief Medical Office and Patient Safety (CMO&PS)”

Section 8.4 replaced “must” with “should” for collection of pregnancy outcomes of female 
partners’ of male participants

Section 10.1.3 added to clarify safety set in Extension Phase

Section 10.3 clarified safety set analysis in Core Phase and Extension Phase respectively

Section 10.5.3.1 clarified safety set used for safety analysis in Core Phase and Extension 
Phase respectively during pre-treatment, on-treatment, and post-treatment period

Section 10.7 clarified interim analysis plan

Section 10.8 clarified sample size calculation

Table 10-1 added to show confidence intervals associated with AEs of interest for subgroups

Section 14.1 Prohibited Concomitant Medications and Concomitant Medication use with 
Caution medications were updated; Website www.qtdrugs.org
was updated to 
www.crediblemeds.org

References section updated
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 01 (19-Dec-2016)
Amendment rationale
The study was initiated in Nov, 2016 and enrollment is currently ongoing with First Patient 
First Visit (FPFV) on 30-Nov-2016.
The current amendment is intended to update the existing information about ribociclib, clarify 
specific aspects of the original protocol and expand the patient population to also include 
premenopausal women in use of ovarian suppression with goserelin. A summary of the key 
changes proposed in this amendment is listed below:

Ribociclib information was updated based on the data available on the current IB version 
(v10, release date: Oct-10-2016; safety cut-off date: Jul-5-2016)

Detailed information from the pivotal study CLEE011A2301 (MONALEESA-2) 
supporting the use of ribociclib + letrozole in aBC has been included to strengthen the study 
rationale

Premenopausal patients (receiving concomitant ovarian suppression with goserelin) are 
allowed to be included in the study, based on current treatment guidelines suggesting similar 
treatment strategies in premenopausal patients with ovarian suppression as post-menopausal 
patients and data from another CDKi (palbociclib) demonstrating similar efficacy of CDKi 
+ ET in prepost-menopausal patients (PALOMA-3 Study). Standard language around 
contraception was added to the inclusion/exclusion criteria as of result of this change

Male patients entering the study will also be required to use goserelin concurrently with 
ribociclib + letrozole based on the current standard of care in this patient population and to 
avoid potential increase of FSH and testosterone (increasing potential substrates for 
aromatization) which could be associated with prolonged administration of AIs

Recruitment duration and follow-up duration were adjusted according to the expected 
recruitment period and required follow-up to adequately address the primary and secondary 
objectives of the study

Recruitment will be completed 18 months after FPFV or when 3,000 patients are 
enrolled, whichever occurs first

Core Phase of the study will be completed 18 months after LPFV

Core Phase (from FPFV to 18 months after Last Patient First Visit (LPFV)) and Extension 
Phase (18 months after LPFV to Last Patient Last Visit (LPLV)) of the study is defined

Clarifications on assessments performed during the Core Phase and the Extension Phase

Clarifications around the use of denosumab and bisphosphonates, which are now allowed 
together with ribociclib + letrozole according to investigator’s judgment

Adjustments of VES requiring study visits every 2 months after 6 months of treatment 
(starting on C6), and every 3 months after 12 months of treatment (starting on C12).
Amendment 01 also includes minor editorial changes and additional clarifications to address 
investigators’ questions as described in the list of changes below.

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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.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Throughout the document: Addition of language to refer to most recent version of the 
LEE011 Investigator’s Brochure and minor text editorial changes

Throughout the document: Premenopausal and perimenopausal status is grouped together 
and referred as “Premenopausal”

Throughout the document: Typographical and grammatical corrections

Section 1: Updated based on new data from ongoing and completed trials with LEE011.

Section 1.1.2: Updated to include data on clinical benefit of AIs in combination with ovarian 
function suppression (OFS) in premenopausal patients with breast cancer in neoadjuvant, 
adjuvant and advanced settings; Rationale for inclusion of male patients is further clarified.

Section 1.2.5: Added to provide CLEE011A2301 (MONALEESA-2) trial key efficacy and 
safety results of pre-planned interim analysis.

Section 1.2.6 and Section 1.2.7: Added to provide information on Goserelin (Zoladex®) 
overview and drug-drug-interactions.

Section 2: Added rationale on inclusion of premenopausal patients with appropriate ovarian 
suppression (with the use of goserelin) in this trial. Study rationale was updated with 
CLEE011A2301 (MONALEESA-2) positive interim result to reinforce the activity of the 
combination of ribociclib and letrozole.

Section 2.4: Addition of rationale for the standard dose of goserelin.

Section 2.5: Addition of rationale for non-comparative design.

Section 2.6: Risks and benefits section was updated in relation to CLEE011A2301 
(MONALEESA-2) positive interim result and addition of goserelin to premenopausal/ male 
patients.

Section 3 Table 3-1: updated to add secondary objective for Extension Phase and the 
associated end points.

Section 4.1: Updated to define Core and Extension Phase of the study; added Extension 
Phase to allow patients who still derive benefit of ribociclib-based treatment however 
without access to ribociclib to continue to receive treatment until EOT; updated to clarify 
that goserelin is added to the treatment regimen in men/premenopausal women patients. 
Clarification was provided to allow country to stop recruitment after the planned number of 
patients is reached in respective country during the study.

Figure 4-1: Updated to add Extension Phase of the study; updated to add goserelin to the 
study treatment (ribociclib+letrozole+goserelin) for male and premenopausal patients. 
“Study treatment” was updated as appropriate throughout the document.

Section 4.3: Definition of end of study was revised to clarify on recruitment period (18 
months) and end of Core Phase (18 months after LPFV).

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
Section 5.2: Inclusion criterion #3 was updated to include pre/perimenopausal women with 
premenopausal status defined; additionally, postmenopausal status is further clarified in the 
case of age < 60 if patient is taking tamoxifen or toremifene.

Section 5.3: Exclusion criterion #17 was added to require premenopausal women to use 
highly effective contraception method during the study.

Section 6.1 and Section 6.1.1: Updated to add goserelin to study treatment for men and 
premenopausal women. Figure 6-1 dosing regimen was updated to include goserelin.

Section 6.1.5: Treatment duration was updated and further clarified in relation to Core Phase 
and Extension Phase of the study.

Section 6.3.1: Clarified that dose reduction is not permitted for letrozole and goserelin. 
Robociclib dose modification guidelines were clarified to ensure seven (7) consecutive rest 
days and avoid overdose.

Section 6.3.1.3.4: Updated dose modification guidelines on adjustment of starting dose in 
renal impairment and hepatic impairment populations.

Table 6-2: Goserelin was added to Table 6-2 Dose Modification Guidelines

Table 6-3: Ribociclib dose reduction/interruption guidelines updated for G3 neutropenia on 
Day 14 of the first 2 cycles.

Section 6.4.1.1: Clarified that the use of denosumab and bisphosphonates together with 
ribociclib+ letrozole is allowed according to investigator’s judgement.

Section 6.6: Updated to include goserelin information on study drug preparation and 
dispensation, study treatment packaging and labeling, and drug supply and storage.

Table 7-1 Visit Evaluation Schedule (VES) was updated as Core Phase VES. Other 
clarifications and updates include: clarifications of pregnancy test requirement, adjustments 
on the schedule of ribociclib IRT dispensing, ePRO, vital sign and weight, ECOG, and 
physical exam assessment schedules were adjusted to monthly for C1-C5, every 2 months 
for C6-C11, and every 3 months from C12 onwards; updates on the requirement of EOT 
visit completion within 7 days from the last ribociclib based treatment.

Section 7.1.4: Added Extension Phase.

Section 7.1.5: Added discontinuation information on Core Phase. Table 7-2: Added 
Extension Phase VES.

Section 7.1.7: Follow-up for safety evaluation was updated to clarify the requirement after
EOT of Core and Extension Phase.

Section 7.2.1: Clarification on no central review of imaging assessments; Confirmation of 
Clinical Benefit is required during the Extension Phase.

Section 7.2.2: Addition of safety assessments required during Extension Phase.

Section 7.2.3: Clarified that FACT-B is collected electronically in selected countries and it 
is not collected on male patients.

Section 7.2.2.5.4: Pregnancy section is added.

Table 7-5: Pregnancy test is added.

Section 10: Updated to add data summary at Extension Phase and details in subgroup 
analysis.

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
Section 10.4.1: Updated to clarify the variables to evaluate the primary objective.

Section 10.5.1: updated to add secondary objective for Extension Phase.
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.
Some changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Role of the CDK4/6 pathway in breast cancer
While endocrine therapy (ET) is effective in treatment of HR-positive advanced BC, 
approximately 30-50% of patients may not respond to it due to a primary resistance. Moreover, 
many advanced BC patients with initial response to ET will acquire secondary resistance to 
these agents (Bachelot et al 2012; Nichols 2015). Co-targeting the estrogen receptor (ER) with 
other key intracellular proliferation and cell survival signaling pathways, such as mechanisms 
responsible for cell cycle regulation and progression, may enhance first-line endocrine 
responsiveness of BC tumors by preventing or delaying the development of acquired resistance 
for endocrine treatments.
Cell cycle progression is regulated by cyclin-dependent serine-threonine protein kinases 
(CDKs). Extracellular growth and adhesion signals increase the level and function of cyclin D 
proteins within the cell. In turn, the cyclin D proteins associate with and activate CDK4 and 
CDK6 (Musgrove et al 2011). CDK4 and CDK6 phosphorylation leads to inactivation of the 
retinoblastoma protein (Rb) and thus releases E2F, which in turn leads to the transcription 
initiation of proteins involved in cell cycle propagation and proliferation (Figure 1-1). The 
luminal A and B subtypes of BC (85% of which are ER-positive and HER2-negative) have high 
rates of cyclin D/CDK activation; in the luminal A and B subtypes, cyclin D1 (CCND1) 
amplifications were observed in 29% and 58%, and CDK4 amplifications were observed in 14% 
and 25%, respectively (Holm et al 2012; The Cancer Genome Atlas Network 2012). Luminal 
A subtype tumors also have loss of CDKN2A, which encodes p16INK4A, a CDK inhibitor 
(Beroukhim et al 2010). The luminal subtypes also maintain expression of Rb, which is essential 
for benefit from treatment with a CDK4/6 inhibitor (Thangavel et al 2011).
Dysregulation of cell cycle checkpoints is common in BC, and in all cancers in general, and 
may have clinical and therapeutic significance. For example, patients with HR-positive BC 
exhibiting a gene expression signature of Rb loss had a shorter recurrence-free survival 
following adjuvant tamoxifen (Bosco et al 2007). A tumor gene expression signature of E2F 
activation is also associated with higher residual tumor cell proliferation following neoadjuvant 
AI therapy. Therefore, activation of the CDK4/6-Rb-E2F pathway promotes endocrine 
resistance, and treatment with a CDK4/6 inhibitor or knockdown of CDK4 expression leads to 
reactivation of Rb, binding back of E2F and subsequent cell cycle arrest, thus abrogating 
endocrine-resistant cell proliferation.
Selective inhibitors of CDK4/6, such as palbociclib and ribociclib, inhibit proliferation and 
induce apoptosis in preclinical models of endocrine-resistant breast cancer (Miller et al 2011;
Thangavel et al 2011; ribociclib [Investigator’s Brochure]. Both palbociclib and ribociclib 
demonstrated synergy with endocrine treatments in preclinical studies and efficacy in clinical 
studies in patients with HR-positive, HER2-negative advanced BC (Finn et al 2009; ribociclib 
[Investigator’s Brochure]). Addition of palbociclib to letrozole improved median progression-
free survival (PFS) from 10.2 months to 20.2 months (hazard ratio 0.49, 95% CI: 0.32-0.75, 
p=0.0004) in a randomized, open-label, multicenter phase II study (Finn et al 2015) and from 

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14.5 to 24.8 months (hazard ratio 0.58, 95% CI: 0.46-0.72, p=0.0001) in a phase III study in 
systemic non-adjuvant treatment-naïve postmenopausal women with ER-positive, HER2-
negative advanced BC (Finn et al 2016). In addition, in a phase III study in 521 pre- and 
postmenopausal patients with advanced HR-positive, HER2-negative BC that had relapsed or 
progressed during prior ET, addition of palbociclib to fulvestrant (with ovarian suppression in 
premenopausal women in both arms) improved median PFS from 3.8 months to 9.2 months 
(hazard ratio 0.42; 95% CI: 0.32-0.56; p<0.001) (Turner et al 2015).
In the subgroup analysis of this study, the palbociclib-containing regimen has similar efficacy 
in pre-/perimenopausal vs post-menopausal women and PFS results were not significantly 
associated with plasma estrogen (E2) levels (Loibl et al 2016), supporting use of palbociclib in 
pre-/perimenopausal women.
Efficacy and safety of the combination of ribociclib and letrozole as first line treatment was 
evaluated in 668 postmenopausal women with HR-positive, HER2-negative advanced BC in a 
phase III study (CLEE011A2301). Ribociclib significantly improved PFS (hazard ratio 0.56, 
95% CI: 0.43-0.72, p = 0.00000329) (Hortobagyi et al 2016).
Refer to the most recent ribociclib [Investigator’s Brochure] for more details.
An update to this study with an additional 11 months of follow-up reported a consistent 
improvement in PFS in comparison with the interim analysis. Median PFS was prolonged by 
9.3 mo, from 16.0 mo (95% CI: 13.4–18.2) in the placebo + letrozole arm to 25.3 mo (95% CI: 
23.0–30.3) in the ribociclib + letrozole arm (hazard ratio 0.568, 95% CI: 0.457-0.704, 
p=0.0000000963). 24-mo PFS rates were 54.7% vs 35.9%. The investigator-reported overall 
response rate was 42.5% (95% CI: 37.2%-47.8%) in the ribociclib arm and 28.7% (95% CI: 
23.9%-33.6%) in the placebo arm (in the full analysis set); and 54.5% (95% CI: 48.4%, 60.6.%) 
and 38.8% (95% CI: 32.7%, 44.9%) in patients with measurable disease at baseline (Hotobagyi 
et al, ASCO 2017).
Considering demonstrated efficacy of CDK4/6 inhibitors in the HR-positive, HER2-negative 
advanced BC, co-targeting the CDK4/6-Rb-E2F pathway with CDK4/6 inhibitors may be a 
viable strategy to enhance endocrine responsiveness and prevent or delay the development of 
acquired resistance.

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Figure 1-1
Regulation of cell cycle checkpoint control
Adapted from Lange and Yee 2011.
Refer to ribociclib [Investigator’s Brochure] for more details.
1.1.2
Role of estrogen pathway in breast cancer
Expression of the estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most 
important prognostic factors in invasive breast cancer and is detected in approximately 70% of 
cases. Estrogen deprivation therapy is the core treatment modality in patients with hormone 
receptor positive (HR+) advanced breast cancer.
Endocrine therapy options for postmenopausal women with ER+ advanced breast cancer 
(locally advanced, recurrent, or metastatic breast cancer) include selective ER modulators or 
SERM (tamoxifen), ER antagonists (fulvestrant), nonsteroidal aromatase inhibitors (NSAI; 
anastrozole and letrozole) and steroidal aromatase inhibitors (exemestane). Blocking estrogen 
signaling with tamoxifen has been the main approach in treatment 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 
2.2017).
In premenopausal patients without previous exposure to an antiestrogen, initial treatment of 
advanced/metastatic disease involves the use of a selective ER modulator alone or ovarian 
suppression/ablation plus endocrine therapy as for postmenopausal women. In premenopausal 
women who received a prior endocrine therapy within 12 months, the preferred therapy involves 
ovarian ablation or suppression + endocrine therapy - such as aromatase inhibitors (AIs) - as 
for post-menopausal patients. (NCCN Breast Cancer Guidelines, version 2.2017).
Based on the clinical benefit shown in postmenopausal patients, AIs in combination with 
ovarian function suppression (OFS) have been investigated in premenopausal patients with 

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breast cancer in neoadjuvant, adjuvant and advanced settings. Results from the randomized 
phase III trials SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and 
EXemestane Trial) showed that adjuvant treatment with exemestane+OFS as compared with 
tamoxifen+OFS, significantly reduced recurrence in premenopausal women with HR+ early 
breast cancer. Results from both trials (N=5,738) showed statistically significant differences in 
disease free survival (DFS) at 5 years (91.1% in exemestane + OFS vs 87.3% in tamoxifen + 
OFS) and rate of freedom from breast cancer at 5 years (92.8% in exemestane+OFS vs 88.8% 
in tamoxifen+OFS) (Pagani 2014). Studies exploring the combination of third generation AIs 
and goserelin in metastatic premenopausal BC patients are shown below in Table 1-1. 
(Montagna 2013)
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal BC 
patients
Study
N
AI+goserelin (G)
ORR 
(CR+PR) (%)
CB 
(CR+PR+SD) 
(%)
TTP 
(months)
First line 
endocrine 
therapy
(Forward 2004)
16
Anastrozole+G
6.2
75
N/R
No
(Cheung 2010)
36
13
Anastrozole+G
Exemestane+G*
36
N/R
67
38
12
N/R
Yes
No
(Carlson 2010)
35
Anastrozole+G
37
72
8.3
Yes
(Park 2010)
35
Letrozole+G
46
77
9.5
Yes
(Yao 2011)
52
Letrozole+G
21
71
10
Yes/No
(Roche 2009)
33
Anastrozole+G
55
64
13
Yes
(Nishimura 2012)
37
Anastrozole+G
19
62
7.2
Yes/No
ORR=Objective response rate, CR=Complete response, PR=Partial response, CB=Clinical benefit, SD=Stable 
disease, PD=Progressive disease, TTP=Time to progression, N/R=Not reported
*In study by Cheung et al, patients received treatment with exemestane after they received treatment with 
anastrozole.
Although data are limited (Montagna 2013), clinical benefit of the combination of AIs and OFS 
in premenopausal women with advanced ER+ breast cancer has been shown in small phase II 
studies with letrozole and anastrozole. In one study (Cheung 2010), patients received 
exemestane, but only after they had received anastrozole, so the effect of single–agent 
exemestane has not been well characterized. Lastly, novel therapeutic approaches targeting 
promising pathways should be explored to further improve efficacy in premenopausal women 
with advanced HR+ breast cancer.
Male breast cancer is rare, with less than 1% of all breast carcinomas occurring in men 
(Giordano 2005). The pathology is similar to that of female breast cancer, and infiltrating ductal 
cancer is the most common tumor type. Male breast cancers have high rates of hormone-
receptor expression, with approximately 90% of male breast cancers expressing estrogen 
receptor, and 81% expressing progesterone receptor.
In general, the approach to the treatment of metastatic breast cancer is similar in male and 
female patients with breast cancer, with hormonal therapy being the often the first approach. 
Although, historically, surgical ablative therapies such as orchiectomy, adrenalectomy, and 
hypophysectomy have been used effectively to control metastatic breast cancer in male patients, 
these surgical procedures are rarely used today and have been supplanted by additive hormonal 
therapies. Tamoxifen has established efficacy in metastatic male breast cancer, with an 

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approximate 50% response rate, and is considered an acceptable treatment option. Luteinizing 
hormone–releasing hormone agonists, with or without antiandrogens, have also been reported 
to be effective in male breast cancer. There have been case reports of responses to a wide variety 
of hormonal therapies including progestins, androgens, steroids, aminoglutethamide, estrogens, 
and letrozole.
Since the hormonal environment in male patients differs from that observed in female patients, 
the role of AIs in male patients may be different (Doyen J 2010). In men, 80% of circulating 
estrogens are derived from peripheral aromatization of testicular and adrenal androgens, with 
direct production from the testes accounting for the remaining 20%. Studies in men patients had 
demonstrated that non-steroidal AIs lead to a decrease in plasma E2 levels, but these levels can 
still be detectable in some patients, potentially because of the baseline levels of peripheral 
androgens (with are subtracts for aromatization) and the testicular production of estrogens, 
which is not inhibited by NSAIs. Additionally, the use of NSAIs can be associated with 
feedback loop leading to increase of LH and FSH, which can lead of additional production of 
androgens, with increased availability of subtracts for aromatization. All these elements 
converge to a suboptimal suppression of estrogen production in male patients submitted to 
treatment with monotherapy AI, and create a rational for the combined use of these agents 
together with LHRH.
The use of aromatase inhibitors together with LHRH was studied as first- or second-line therapy 
for male patients with HR+ metastatic breast cancer (Giordano SH 2005); 19 patients were 
evaluated with promising results: 2 patients (10.5 %) had complete response, 7 patients (36.8 %) 
experienced a partial response, 7 patients (36.8 %) had stable disease lasting ≥6 months, and 3 
patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median 
progression-free survival was 12.5 months (95 % CI 8.2–16.9), median overall survival was 
35.8 months (95 % CI 24.4–49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. 
Safety profile was expected and manageable, with no grade 3/4 adverse events
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Ribociclib
Ribociclib is an orally bioavailable and highly selective small molecule inhibitor with highly 
specific nanomolar inhibitory activity against CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme 
complexes with IC50’s of 0.01 and 0.039 µM in biochemical assays, respectively.
1.2.1.1
Non-clinical data
Ribociclib inhibits the phosphorylation of Rb at CDK4/6-binding sites with an average IC50 of 
60 nM in Jeko-1 MCL cells that overexpress cyclin D1. 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.
Cardiac safety studies in vivo demonstrated QT prolongation with the potential to induce 
premature ventricular contractions (PVCs) at higher exposure levels. The effects of ribociclib 
on the bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal 
mucosa (atrophy), the kidney (concurrent degeneration and regeneration of tubular epithelial 

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cells), 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. The hepatobiliary system (proliferative changes, cholestasis, sand-like gallbladder 
calculi and inspissated bile) was identified as an additional target organs of toxicity that are not 
likely related to the primary pharmacology of ribociclib. Generally, all these effects of ribociclib 
demonstrated either reversibility or a clear trend towards reversibility. Ribociclib did not show 
an indication for a genotoxic potential. Reproductive studies in animals have demonstrated that 
ribociclib is embryotoxic, fetotoxic and teratogenic.
In vitro, ribociclib was a reversible inhibitor of human cytochrome P450 (CYP) enzymes 
CYP1A2, CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. Under 
therapeutic conditions, inhibition of CYP3A4 is likely to occur, while inhibition of CYP1A2 or 
CYP2E1 is not expected. The in vitro inhibitory potency of ribociclib for the transporters breast 
cancer resistance protein (BCRP), organic cation transporter 2 (OCT2), multidrug and toxin 
extrusion protein-1 (MATE1), and bile salt export pump (BSEP) 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). 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.
Refer to the most recent ribociclib [Investigator’s Brochure] for additional details.
1.2.1.2
Clinical experience
Ribociclib is currently being investigated in patients with breast cancer and other solid tumors 
in multiple clinical trials at different phases of development. Refer to the most recent ribociclib 
[Investigator’s Brochure] for details on clinical studies with ribociclib.
1.2.1.2.1 Clinical safety of ribociclib
Clinical safety of ribociclib with endocrine agents such as letrozole, tamoxifen, exemestane and 
fulvestrant has been evaluated in several phase I and III combination trials. The recommended 
dose of ribociclib in combination with these agents was declared as 600 mg qd on a 3 weeks 
on/1 week off schedule.
The safety profile of ribociclib in combination with letrozole was investigated in a randomized 
clinical trial of ribociclib and letrozole versus placebo and letrozole (CLEE011A2301) in 668 
treatment-naive postmenopausal women with HR-positive, HER2-negative, advanced BC. 
Most common treatment-emergent AEs reported in the ribociclib arm in this study occurring 
in >30% of patients were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue 
(36.5%), diarrhea (35.0%), alopecia (33.2%) and leukopenia (32.9%). The most common grade 
3 or 4 AEs reported in ≥5 % of patients in the ribociclib arm were neutropenia (59.3%), 
leukopenia (21.6%), hypertension (9.9%), increased alanine aminotransferase (9.3%), 
lymphopenia (6.9%) and increased aspartate aminotransferase (5.7%). Febrile neutropenia 
occurred in 1.5% of the patients in the ribociclib arm. Blood creatinine increases were reported 
in 6.9% of patients. Four patients (1.2%) met the biochemical and clinical criteria for Hy’s Law 
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discontinuation. Eleven patients (3.3%) presented on treatment QTcF prolongation >480 msec. 
Serious AEs were reported in 21.3% of patients in the ribociclib arm with 7.5% of serious AEs 
deemed by investigators as treatment-related. There were 3 fatal events in the ribociclib arm 
(disease progression, sudden death, unknown cause) with 1 AE (sudden death) reported as 
treatment-related in a patient that had grade 3 hypokalemia and grade 2 QTcF prolongation (483 
msec). Neutropenia, QT interval prolongation and hepatobiliary toxicity are considered to be
important identified risks for ribociclib which appear to be manageable and reversible with 
adequate monitoring, interruption and/or reduction of ribociclib dosing.
For a comprehensive review of safety profile of ribociclib in combination with endocrine agents 
refer to the most recent ribociclib [Investigator’s Brochure].
1.2.1.2.2 Clinical efficacy with ribociclib
In a phase III randomized clinical trial of ribociclib and letrozole versus placebo and letrozole 
(CLEE011A2301) in 668 treatment-naive postmenopausal women with HR-positive, HER2-
negative, advanced BC, ribociclib improved PFS (hazard ratio 0.56, 95% CI: 0.43-0.72, 
p=0.00000329). The investigator-reported overall response rate was 40.7% (95% CI: 35.4%-
46.0%) in the ribociclib arm and 27.5% (95% CI: 22.8%-32.3%) in the placebo arm 
(p=0.000155) in the full analysis set; and 52.7% (95% CI: 46.6%, 58.9%) and 37.1% (95% CI: 
31.1%, 43.2%) (p=0.00028) in patients with measurable disease at baseline (Hortobagyi et al 
2016).
An update to this study with an additional 11 months of follow-up reported a consistent 
improvement in PFS in comparison with the interim analysis. Median PFS was prolonged by 
9.3 mo, from 16.0 mo (95% CI: 13.4–18.2) in the placebo + letrozole arm to 25.3 mo (95% CI: 
23.0–30.3) in the ribociclib + letrozole arm (hazard ratio 0.568, 95% CI: 0.457-0.704, 
p=0.0000000963). 24-mo PFS rates were 54.7% vs 35.9%. The investigator-reported overall 
response rate was 42.5% (95% CI: 37.2%-47.8%) in the ribociclib arm and 28.7% (95% CI: 
23.9%-33.6%) in the placebo arm (in the full analysis set); and 54.5% (95% CI: 48.4%, 60.6.%) 
and 38.8% (95% CI: 32.7%, 44.9%) in patients with measurable disease at baseline (Hortobyagi 
et al, ASCO 2017).
Refer to the most recent ribociclib [Investigator’s Brochure] for additional details on efficacy 
profile of ribociclib.
1.2.1.2.3 Clinical Pharmacokinetics of ribociclib
Following oral dosing of the capsule formulation at 600 mg, ribociclib is rapidly absorbed with 
median Tmax of 2.40 h (range: 0.683 to 7.82 h). Steady-state plasma Cmax ranges from 606-
6170 ng/mL (geometric mean: 1820 ng/mL or 4.1 µM) and AUC0-24h ranges from 6770-90600 
ng*h/mL (geometric mean: 23800 ng*h/mL). The effective T1/2 of ribociclib is 32.0 h (range: 
8.06 to 97.9 h). Inter-patient variability in Cmax and AUC is 62% and 66%, respectively, as 
assessed by geometric coefficient of variation. LEQ803, an active metabolite of ribociclib, has 
similar PK characteristics as parent drug. At the 600 mg dose level, LEQ803 accounts for 
approximately 8% of parent exposure after single and multiple doses. Neither ribociclib nor 
LEQ803 accumulate substantially following repeated daily administration.

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suppress ovarian function in premenopausal women in this study as the 3-month depot 
formulations do not reliably suppress estrogen levels in all patients (Gradishar et al 2016).
The most common AEs occurring of women treated with LHRH agonists included hot flushes, 
headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast 
atrophy, seborrhea and peripheral edema.
The most common AE occurring of men treated with LHRH agonists include a transitory 
elevation in testosterone levels can occur in men after the first few doses, followed by the 
expected decrease of these hormonal levels; as a result, the most commonly observed adverse 
reactions, which occurred in at least 1 out of every 10 men (10%) who participated in clinical 
trials, are hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms 
(for example, urinary urgency, cystitis, blood in your urine). Some patients may experience a 
temporary increase in bone pain.
Refer to the most recent regional prescribing information and/or clinical guidelines for more 
information on LHRH agonists.
2
Rationale
2.1
Study rationale and purpose
Approximately 75% of breast cancers express estrogen receptor (ER) and/or progesterone 
receptor (PgR) and are dependent of estrogen for growth. Studies of ER+ breast cancer cell 
lines indicate that estrogens and antiestrogens act in early to mid-G1 phase, via cyclin D1 
expression. G1/S transition is under the control of CDKs, particularly CDK4, CDK6 and CDK2. 
CDK4 and CDK6 are activated by binding to D-type cyclins and act early in G1 phase. The 
interplay between the ER pathway and the cell cycle control machinery – particularly the control 
of G1-S transition mediated by cyclin d and CDK 4/6 – provides a strong rational for the 
combined use of interventions designed to control both nodes as a way to stop the HR+ breast 
cancer proliferation. This mechanistic approach is corroborated by preclinical evidence of 
synergistic activity of CDK inhibitors and hormonal agents against HR+ breast cancer in cell 
lines and animal models and also clinical superiority with the combination (CDKi + hormonal 
agents) vs. endocrine therapy alone in recent phase II/III trials (PALOMA-1/2/3 with 
palbociclib; MONALEESA-2 with ribociclib).
Ribociclib (LEE011) is an oral selective inhibitor of CDK 4/6 which has demonstrated activity 
in HR+BC cell lines in combination with multiple hormonal partners, as well as in clinical 
studies. While studies in combination with fulvestrant (MONALEESA-3) and NSAI/tamoxifen 
in premenopausal patients (MONALEESA-7) are ongoing, the phase III trial MONALEESA-2 
(ribociclib + letrozole vs. letrozole) was declared as a positive study in an interim assessment, 
with clinically and statistically meaningful benefit observed with the combination (ribociclib + 
letrozole) vs letrozole monotherapy in major endpoints (PFS and tumor response); the 
combination treatment had demonstrated a manageable safety profile based on dose 
interruptions and/or reductions. These results reinforce the activity of this combination for the 
treatment of HR+ advanced breast cancer. This trial will support the first authorization granted 
in the United States (US).

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The purpose of this study is to further evaluate the overall safety and tolerability and clinical 
efficacy of ribociclib in combination with letrozole in a large cohort of patients with HR+, 
HER2- aBC who have not received prior hormonal treatment for advanced disease.
This study will collect additional safety, tolerability, and efficacy data in a larger and broader 
patient population including certain clinical situations not included in the phase III trials (e.g., 
patients treated with prior chemotherapy for advanced disease, ECOG PS 2.) Premenopausal 
patients with appropriate ovarian suppression achieved with the use of goserelin, will be 
included in this trial, since the treatment of these patients is quite similar to what 
postmenopausal women typically receive. In this trial, perimenopausal patients can be included 
(see Section 5 for definition) and should be treated with goserelin as premenopausal patients. 
The results from the phase III PALOMA-3 trial with palbociclib + fulvestrant had demonstrated 
similar superior efficacy vs. fulvestrant monotherapy in both premenopausal (+goserelin) and 
post-menopausal patients (premenopausal, N=72; median Progression Free Survival (mPFS): 
9.5 months (95% CI: 7.4-NE); post-menopausal, N=275; mPFS: 9.9 months (95% CI 8.5-11.0)
(Cristofanilli, Lancet Oncology 2016). The trial will also include males with HR+, HER2- aBC, 
which will generate data about the use of this combination in a very rare patient population with 
the rational to explore the activity of letrozole + LHRH agonists (as hormonal suppressant)
together with ribociclib, given the observed benefit of CDKi when added to standard hormonal 
therapy in women with HR+ advanced breast cancer.
The results from this trial will provide a relevant set of information to the medical community 
about the activity of ribociclib + letrozole in HR+ aBC and potentially generate additional 
hypothesis to be explored in future trials.
2.2
Rationale for the study design
This is an open-label, single arm, multi-center Phase IIIb study to evaluate the overall safety 
and tolerability and clinical efficacy of ribociclib in combination with letrozole in men and 
pre/postmenopausal women with HR+, HER2- advanced breast cancer who have not received 
prior hormonal treatment for advanced disease.
The study design will allow an adequate characterization of the safety profile of this 
combination (primary objective); efficacy parameters will also be collected in all patients
during study participation, which will provide additional information about the combination 
activity in a broader patient population with aBC.
2.3
Rationale for dose and regimen selection
The dose (oral administration of 600 mg daily) and regimen (Days 1-21 of a 28 day cycle) of 
ribociclib was selected for this study, since this dose and regimen were shown to be tolerable 
and efficacious when combined with ET in clinical trials in patients with HR-positive, HER2-
negative advanced BC (see Section 1.2.1).
Data from ribociclib [MONALEESA-2] trial (Hortobagyi 2016) and palbociclib ([PALOMA-
1] and [PALOMA-2] studies) demonstrated clinical benefit, when used in combination with the 
non-steroidal aromatase inhibitor letrozole, significantly prolonging progression free survival 
in postmenopausal women with HR+, HER2-negative advanced breast cancer when compared 
with letrozole alone (Finn 2015, Finn 2016, Hortobagyi 2016).

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In this study, we propose to use the same approach, combining ribociclib with letrozole 
(+LHRH agonists to achieve adequate hormonal suppression in men/premenopausal women)
in HR+, HER2-negative men and pre/postmenopausal women with advanced breast cancer who 
have received no prior therapy for advanced disease.
The standard doses of goserelin (3.6 mg subcutaneously every 28 days) and leuprolide (7.5 mg 
intramuscularly every 28 days) will be used in this study as goserelin or leuprolide are not 
expected to affect the metabolism of nor be affected by co- administration of other drugs.
2.4
Rationale for choice of comparator drugs
This is a non-comparative study. The purpose of this trial is to further evaluate the overall 
safety/tolerability and clinical efficacy of ribociclib in combination with letrozole in a more 
diverse population in comparison with the existing phase III study with this combination. Given 
the positive results from MONALEESA-2 (and also available data with other CDK 4/6 
inhibitors), the combination of ribociclib (a CDK 4/6 inhibitor) + letrozole demonstrated 
superior efficacy in comparison with monotherapy with letrozole, and this treatment is now an 
accepted standard of care for the treatment of HR+ aBC.
For this reason, the trial is designed as a single-arm, non-comparative study to allow all patients 
on the study to be treated with this regimen while relevant information about its safety and 
efficacy will be collected and analyzed.
2.5
Risks and benefits
The treatment landscape in HR+, HER2- aBC has evolved during recent years, with the 
characterization that CDK 4/6 inhibitors may play an important role in controlling the disease 
and prolonging PFS in comparison to NSAI alone. Many treatment guidelines have already 
incorporated CDKi as a treatment choice and palbociclib (the first commercially available 
CDKi) is already approved in many countries around the world. On March 13, 2017 , the US 
Food and Drug Administration approved Kisqali® (ribociclib), a cyclin-dependent kinase 4/6 
inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the 
treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal 
growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Ribociclib, a selective CDK 4/6 inhibitor, has been evaluated in patients with HR+ HER2- aBC, 
supported by strong preclinical data showing activity against HR+ luminal breast cancer cell 
lines and synergistic activity with hormonal agents in preclinical models. Study 
[CLEE011X2107] was the first one to demonstrate activity of ribociclib in combination with 
letrozole in aBC patients that were treatment-naïve for their advanced disease, with adequate 
tumor control based on ORR and CBR. Treatment was generally well-tolerated and emerging 
toxicities were appropriately managed with dose reductions/interruptions. The pivotal phase III 
trial ([MONALEESA-2]) comparing ribociclib + letrozole with letrozole in a similar patient 
population as [CLEE011X2107] was declared positive in a preplanned interim analysis with 
clinically and statistically meaningful benefit observed with the combination (ribociclib + 
letrozole) vs letrozole monotherapy in major endpoints (PFS and tumor response); the 
combination treatment had demonstrated a manageable safety profile based on dose 
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This proposed trial is intended to expand the available information about ribociclib in HR+, 
HER2- aBC either in terms of safety as well as efficacy. The population to be included in this 
trial is slightly broader than those included in the pivotal phase III trials (e.g. PS 0-2, prior 
treatment with chemotherapy for advanced disease, premenopausal women and men), which 
will allow the generation of data in a larger patient population in comparison with other Phase 
III trials.
Patients included in this trial will potentially benefit from an effective treatment, based on the 
results from phase I and phase III trials; since all patients included in this trial will receive the 
combination of ribociclib + letrozole, no ethical issues are expected from this perspective. 
Patients will continue to receive treatment until disease progression, death, unacceptable 
toxicity, physician’s decision, subject/guardian’s decision, protocol deviation, study 
termination by sponsor, lost to follow-up, technical problems or until 18 months after LPFV in 
the Core Phase, whichever event occurs first. Patients may be transitioned to the Extension 
Phase and continue to receive the drugs until progression, intolerance, death or 
physician/patient decision.
Ribociclib + letrozole treatment is associated with potential AEs, including reversible 
cytopenias (neutropenia, anemia and thrombocytopenia), GI toxicities (nausea, vomiting, and 
diarrhea), fatigue, alopecia, elevation in liver enzymes and QT prolongation; some of them can 
be serious. These toxicities can be managed with appropriate monitoring, dose 
reductions/interruptions and symptom-related treatments. These risks can be appropriately 
mitigated in this protocol with clear guidance about eligibility criteria, monitoring of potential 
toxicities and strategies for therapy management (including instructions related to dose 
adjustments/interruptions).
The addition of goserelin or leuprolide to premenopausal women / male patients is not expected 
to affect the metabolism of nor be affected by co-administration of the other drugs (ribociclib 
and letrozole), so no additional safety risks are expected with this combination.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To evaluate the safety and tolerability of ribociclib + letrozole in men 
and pre / postmenopausal women with HR+, HER2- aBC who 
received no prior hormonal therapy for advanced disease
Note: Throughout this document , perimenopausal and 
premenopausal status is grouped together and referred as 
“Premenopausal”
●
AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib 
+ letrozole
Refer to Section 10.4
Secondary
To assess the clinical efficacy and patient reported outcomes of 
ribociclib + letrozole in the patient population as described above
To evaluate long-term safety of ribociclib + letrozole during Extension 
Phase
To evaluate clinical benefit of ribociclib + letrozole as assessed by 
investigator during Extension Phase
●
Time-to-Progression (TTP) (RECIST 1.1), based on 
investigators’ assessment
●
Overall response rate (ORR) as defined by RECIST 1.1 for 
patients with measurable disease
●
Clinical Benefit Rate (CBR) as defined by RECIST 1.1 
(including patients with CR, PR, SD, NCRNPD >24 weeks)
●
Patient Reported Outcome (PRO) using FACT-B 
questionnaire
●
Frequency and severity of AEs & SAEs during Extension 
Phase
●
Proportion of patients with clinical benefit as assessed by 
investigator during Extension Phase
Refer to Section 10.5.1

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4
Study design
4.1
Description of study design
This is an open-label, single arm, multi-center Phase IIIb study to evaluate the overall safety 
and tolerability and clinical efficacy of ribociclib in combination with letrozole in men and 
pre/postmenopausal women with HR+, HER2- aBC and no prior hormonal treatment for 
advanced disease. Gonadal suppression is achieved with either goserelin or leuprolide in men
and premenopausal women patients.
The study will be composed of 2 phases:

Core Phase: from FPFV to 18 months after LPFV. During the Core Phase, safety and 
efficacy data (including PROs in selected countries) will be collected;

Extension Phase: from the end of the Core Phase to LPLV. In the event study patients are 
still deriving benefit at the end of the Core Phase and ribociclib is not approved or 
available and reimbursed, patients may be transitioned to this Extension Phase and 
continue to receive the drugs until progression, intolerance, death or physician/patient 
decision; only safety and clinical benefit (as assessed by investigator) data will be 
collected.
Approximately 3,000 patients across a diverse number of sites, countries, and regions are 
expected to be enrolled in this trial. Study treatment of the Core Phase will be provided until 
disease progression, death, unacceptable toxicities, physician’s decision, subject/guardian’s 
decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems 
or until 18 months after LPFV, whichever event occurs first (See Figure 4-1).
Enrollment in this trial is not competitive, with the purpose to include a diverse patient 
population in terms of sites, countries and regions. Each participating country will be assigned 
a predefined number of patients (based on number of participating sites and available patient 
population); once this number is achieved, countries may stop enrollment while the study will 
continue to enroll in other countries/regions. Safety data collected will include all AEs and 
SAEs including grade 3/4 AEs, events of special interest (Neutropenia including febrile 
neutropenia, QT prolongation, hepatobililary toxicity), AEs leading to permanent treatment 
discontinuation or death, vital signs, physical examination, variation of the ECOG performance 
status, and selected hematology/chemistry parameters at study visits while the patient remains 
on study and for 30 days after discontinuation.
Time to Tumor Progression (TTP) and overall tumor response (ORR/CBR) will be assessed by 
the investigator using RECIST v1.1 criteria. Tumor assessments should be performed every 
12 weeks (recommended timeframe) or according to the current standard of care (as per 
local requirements) during treatment phase and at end of treatment (EOT). It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
antineoplastic therapy.
Local/regional sub-studies/analysis can be conducted in the patient population enrolled in 
[CLEE011A2404] (CompLEEment-1) study. These sub-studies can be designed to explore 
additional aspects of ribociclib treatment in HR+HER2- advanced breast cancer, which are not 

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assessed in the current CLEE011A2404 protocol. Examples of sub-studies include biomarker 
analysis (correlative science studies), additional patient-reported outcome (PRO) evaluations or 
any other relevant assessments that are not currently evaluated during CLEE011A2404 study. 
Sub-study protocols must follow the current Novartis process for review and approval of 
sponsored clinical trials, and should be reviewed and approved by the relevant regulatory 
authorities and Ethics Committees before implementation.
Figure 4-1
Study design

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4.2
Timing of interim analyses and design adaptations
Interim analyses (IA) may be performed periodically. The first IA is planned to be performed 
about 12 months after FPFV, and periodically, if needed, to fulfill regulatory requests, safety 
updates, or for publication purposes.
4.3
Definition of end of study
Study recruitment will stop when approximately 3,000 patients are enrolled.
The planned overall study duration of the Core Phase will be from FPFV to 18 months after 
LPFV. At the time of Core Phase end if patients are still deriving clinical benefit and ribociclib 
is not approved or available and reimbursed, patients may be transitioned to the Extension Phase 
trial period and continue to receive the drugs until progression, intolerance, death or 
physician/patient decision, but only safety and clinical benefit as assessed by investigator will 
be collected during the Extension Phase.
The duration of the Extension Phase will be 18 months from LPLV of the Core Phase. During 
the Extension Phase, if ribociclib is approved and reimbursed, patients will be transitioned to 
prescription or drug access/support program(s) according to local laws and regulations. 
The study will end after completion of the Extension Phase and all remaining patients will 
discontinue from the study. Patients who complete the Extension Phase, and continue to derive 
clinical benefit from the treatment based on the investigator’s evaluation will receive ribociclib 
from prescription (if approved and reimbursed), another Post-Trial Access (PTA) program, or 
other drug access/support program(s).
Post-Trial Access (PTA) means the provision of treatment to trial participants following their 
completion of trial participation. PTA will be provided until one of the following is met:  patient 
no longer derives clinical benefit, investigator discontinues treatment, launch or reimbursement 
(where applicable), treatment fails to achieve registration in the trial participant’s country, or 
the clinical program is discontinued for any other reason.  
The mechanism of PTA for this Extension Phase is provision of the Novartis investigational 
product in a non-trial setting (known as post-study drug supply [PSDS]) when no further safety 
or efficacy data are required, or any other mechanism appropriate for the country.  
This PTA mechanism must comply with local laws and regulations in the participating trial 
countries.  If Novartis discontinues the PSDS for this trial, Novartis will work with investigators 
to transition patients onto locally available alternative treatment, or standard of care.
The expected median follow-up at the time of study completion will be around 24 months, 
which is sufficient to provide adequate information about the safety and efficacy of ribociclib 
+ letrozole in the population under investigation. According to data from Study 
CLEE011A2301 (MONALEESA-2), Grade 3/4 (G3/4) AE of special interest (neutropenia, QT 
prolongation and liver enzyme elevations) were observed during the first cycles of treatment 
(QTc prolongation observed during the first 2 cycles; 83.8% of the LFT elevations had been 
observed during the first 6 cycles; 85% of the G3/4 neutropenia events were observed during 
the first 12 months of treatment), so a minimal period of 18 months of follow-up seems 
sufficient to capture these events as part of the primary endpoint of the study. Additionally, 

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patients entering in the Extension Phase will continue to have safety/tolerability monitored, 
which will generate relevant data about the long-term safety of this regimen.
4.4
Early study termination
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
5
Population
5.1
Patient population
This trial will be conducted in men and pre/postmenopausal women with HR+, HER2- aBC 
who have not received any prior hormonal agent for the treatment of advanced disease.
Approximately 3,000 patients are expected to be enrolled in this trial.
Patients enrolled in this protocol are not permitted to participate in additional parallel 
investigational drug(s) studies while on treatment.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient is an adult, male or female ≥ 18 years old at the time of informed consent
2. Male or female advanced (locoregionally recurrent or metastatic) breast cancer not 
amenable to curative therapy.
3. In the case of women, both pre/perimenopausal and postmenopausal patients are allowed to 
be included in this study; menopausal status is relevant for the requirement of goserelin or 
leuprolide to be used concomitantly with ribociclib and letrozole.
a. Postmenopausal status is defined either by:
1. Prior bilateral oophorectomy
OR
2. Age ≥60
OR

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3. Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the 
postmenopausal range per local normal range. If patient is taking tamoxifen or 
toremifene and age < 60, then FSH and plasma estradiol levels should be in post-
menopausal range per local normal range (NCCN Guidelines Version 2.2017).
Note: For women with therapy-induced amenorrhea, serial measurements of FSH 
and/or estradiol are needed to ensure menopausal status.
b. Premenopausal status is defined as either:
1. Patient had last menstrual period within the last 12 months,
OR
2. If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH
must be in the premenopausal range per local normal range,
OR
3. In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in
the premenopausal range per local normal range.
c. Perimenopausal status is define as neither premenopausal nor postmenopausal
Note: Throughout this document, perimenopausal and premenopausal status is
grouped together and referred as “Premenopausal”
4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor 
positive and/or progesterone receptor positive breast cancer by local laboratory. A 
confirmatory biopsy is not required.
5. Patient has HER2-negative breast cancer 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.
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
7. Patient has adequate bone marrow and organ function as defined by ALL of the following 
laboratory values (as assessed by local laboratory):

Absolute neutrophil count ≥ 1.5 × 109/L

Platelets ≥ 100 × 109/L

Hemoglobin ≥ 9.0 g/dL

Potassium, sodium, calcium corrected for serum albumin and magnesium within 
normal limits or corrected to within normal limits with supplements before first dose of 
the study medication

INR ≤1.5

Serum creatinine < 1.5 mg/dl or creatinine clearance ≥ 50 mL/min

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver metastases, 
ALT and AST should be < 5 × ULN.

Total 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
8. Patient must have a 12-lead ECG with ALL of the following parameters at screening:

QTcF interval at screening < 450 msec (using Fridericia’s correction)

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
Resting heart rate ≥ 50 bpm
9. Patient must be able to swallow ribociclib and letrozole tablets
10. Patient has signed informed consent obtained before any trial-related activities and 
according to local guidelines
11. Patients must be able to communicate with the investigator and comply with the 
requirements of the study procedures
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
including peanuts and soy
2. Patient who received any CDK4/6 inhibitor
3. Patient who received any prior systemic hormonal therapy for advanced breast cancer; no 
more than one prior regimen of chemotherapy for the treatment of metastatic disease is 
permitted
Note:

Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior 
neo (adjuvant) therapy included letrozole or anastrozole the disease free interval must 
be greater than 12 months from the completion of treatment until study entry.

Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior 
to inclusion in this trial are eligible.
4. Patient is concurrently using other anti-cancer therapy
5. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects
6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to 
NCI CTCAE version 4.03 Grade ≤1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator's discretion)
7. Patient who has received extended-field radiotherapy ≤ 4 weeks or limited field 
radiotheraphy for palliation ≤ 2 weeks prior to start of treatment, and who has not recovered 
to grade 1 or better from related side effects of such therapy (with the exception of alopecia
or other toxicities not considered a safety risk for the patient at the investigator’s discretion). 
Patients from whom ≥ 25% (Ellis RE 1961) of the bone marrow has been previously
irradiated are also excluded. See Appendix 14.4
8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study 
drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer.
9. Patient with central nervous system (CNS) metastases unless they meet ALL of the 
following criteria:

At least 4 weeks from prior therapy for CNS disease completion (including radiation 
and/or surgery) to starting the study treatment

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
Clinically stable CNS lesions at the time of study treatment initiation and not receiving 
steroids and/or enzyme-inducing anti-epileptic medications for the management of 
brain metastases for at least 2 weeks
10. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
11. Patient has a known history of HIV infection (testing not mandatory)
12. 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.)
13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, 
including but not limited to any of the following:

History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic 
pericarditis within 6 months prior to screening

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Documented cardiomyopathy

Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and 
third-degree AV block)

Long QT syndrome or family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following:
1. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia
2. Concomitant use of medication(s) with a known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 
half-lives or 7 days prior to starting study drug) or replaced by safe alternative 
medication
3. Inability to determine the QTcF (Fridericia’s correction) interval on screening

Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
14. Patient is currently receiving any of the following medications and cannot be discontinued 
7 days prior to Cycle 1 Day 1:

Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pomelos, 
star fruit, Seville oranges) and their juices that are known strong inducers or inhibitors 
of CYP3A4/5 (See Appendix 14.1)

Medications that have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5

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15. 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)
16. Participation in a prior investigational study within 30 days prior to enrollment or within 5-
half-lives of the investigational product, whichever is longer
17. Pregnant or nursing (lactating) women
Note: Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 21 days after stopping the study medication.
Highly effective contraception methods include:

Total abstinence when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment.

Male partner sterilization (at least 6 months prior to screening). For female patients on 
the study the vasectomized male partner should be the sole partner for that patient.

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Note: Use of oral (estrogen and progesterone), transdermal, injected, implanted hormone
containing intrauterine systems (IUS) or any other hormonal methods of contraception is 
not allowed in this study
6
Treatment
6.1
Study treatment
For this protocol, the term “investigational drug” refers to the Novartis study drug ribociclib. 
The other drugs to be used in this study are letrozole and either goserelin or leuprolide (for men 
/ premenopausal women). “Study treatment” in this protocol refers to the combination of drugs
and includes investigational drug (ribociclib) as well as letrozole and goserelin or leuprolide (if 
applicable).
Ribociclib will be supplied by Novartis or its designee as 200 mg tablets as individual patient 
supply packaged bottles. Letrozole (Femara or generic equivalent), goserelin and leuprolide
will be procured locally by Country Pharma Organization or local institution as it is 
commercially available in each participating country according to local practices and 
regulations. 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 in the eCRF.

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6.1.1
Dosing regimen
Ribociclib (LEE011) will be given orally once a day on days 1-21 of each 28- day cycle. On 
days 22-28 ribociclib will not be given (“rest days”). Letrozole will be given orally as per SmPC 
once a day on a continuous daily schedule (days 1-28 of each 28- day cycle). There will be no 
“rest” in the letrozole schedule. For men and premenopausal women, either goserelin will be 
given as an injectable subcutaneous implant or leuprolide will be given as an intramuscular 
injection. Either goserelin or leuprolide is recommended to be administered on day 1 starting at 
Cycle 1 and then every 28 days. Goserelin or leuprolide must be given as the monthly injection
dosage form, as the 3-month depot dosage forms do not reliably suppress hormonal levels in all 
patients (NCCN ver. 2 2017). If a patient is already receiving goserelin or leuprolide before 
C1D1, a 28 days schedule should be maintained based on the pre-existing dosing schedule.
See Table 6-1 and Figure 6-1 for details.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Ribociclib
Tablet for oral use
600 mg (3 tablets of 200 
mg)
Daily on D1-D21
(28 day cycles)
Letrozole
Tablet for oral use
2.5mg
Continuous Daily 
Goserelin
Injectable Subcutaneous 
implant
3.6 mg
Every 28 days
(only for men and 
premenopausal women)
Leuprolide
Injectable Intramuscular
Depot
7.5 mg
Every 28 days
(only for men and 
premenopausal women)
Figure 6-1
Men / Premenopausal regimen

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Figure 6-2
Postmenopausal regimen
The study treatment will be administered as a flat-fixed dose (Starting doses: Ribociclib 600
mg QD 3 weeks on/1 week off; letrozole 2.5 mg QD continuously), and not by body weight or 
body surface area.
The investigator or responsible site personnel should instruct the patient to take the study 
treatment as per protocol (emphasizing the importance of compliance). Drug accountability 
must be performed on a regular basis. Patients will be instructed to return unused study 
treatment to the site at the end of each cycle. The site personnel will ensure that the appropriate 
dose of each study treatment is provided at each visit.
6.1.1.1
Ribociclib and Letrozole Dosing
Ribociclib and letrozole should be taken as follows:

Ribociclib is dosed for the first 21 days out of the 28- day cycle.

Patients should be instructed to take the study treatment combination of ribociclib and 
letrozole together with a large glass of water (~250 mL or ~8 oz) at the same time each 
day. Evening doses are strongly not recommended.

Ribociclib and letrozole can be administered with or without food.

Patients should be instructed to swallow the ribociclib and letrozole tablets whole and not 
chew, crush or open them.

For men and premenopausal women, either goserelin or leuprolide must be administered by 
injection every 28 days in accordance with the local prescribing information.

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.

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, pummelos, star-fruit, 
Seville oranges or products containing the juice of each during the entire study and 
preferably 7 days before the first dose of study medication, due to potential CYP3A4 
interaction with the study medications. These foods are known as CYP3A4 inhibitors and 
have a potential to increase exposure to ribociclib.

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Note: 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. If the potential for interactions are unknown, then the herbal / dietary 
supplements should be avoided. (See Appendix 14.1)
6.1.2
Ancillary treatments
Not Applicable.
6.1.3
Rescue medication
Not Applicable.
6.1.4
Guidelines for continuation of treatment
Refer to Section 6.3 Dosing Modification for guidelines for continuation of treatment.
6.1.5
Treatment duration
The planned overall study duration of the Core Phase will be from FPFV to 18 months after 
LPFV.
The study treatment during the Core Phase will be provided until disease progression, death, 
unacceptable toxicities, physician’s decision, subject/guardian’s decision, protocol deviation,
study termination by sponsor, lost to follow-up, technical problems or up to 18 months after 
LPFV.
At the time of Core Phase end, if patients are still deriving benefit and ribociclib is not approved
or available and reimbursed, patients may be transitioned to the Extension Phase and continue 
to receive the drugs until progression, intolerance, death or physician/patient decision, but only 
safety and clinical benefit as assessed by investigator will be collected.
6.2
Dose escalation guidelines
Not Applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment. These dose modifications are summarized in Table 6-2, Table 6-3, Table 
6-4, Table 6-5, Table 6-6, and Table 6-7. No dose re-escalation is permitted.
Clinical judgment of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. However, for events requiring a discontinuation in 
Table 6-3, Table 6-4, Table 6-5, Table 6-6, and Table 6-7 or listed in Section 7.1.5., treatment 
must be discontinued. If dosing was interrupted for >28 days due to ribociclib related toxicity, 
ribociclib must be discontinued.

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Dose reductions are not permitted for letrozole, goserelin or leuprolide.
Any changes to ribociclib dose or interruption of the study treatment must be recorded on the 
Dosage Administration Record eCRF. All patients will be followed for (S)AEs for 30 days 
following the last dose of ribociclib.
6.3.1.1
Letrozole
The established clinical dose of letrozole (2.5 mg/day) will be used and no dose modification 
of letrozole is planned in this study. The letrozole SmPC should be consulted regarding full 
prescribing information, monitoring, and management of adverse events.
In the case where letrozole is required to be permanently discontinued the patient must be 
discontinued from study.
6.3.1.2
Goserelin and leuprolide
The established clinical dose of goserelin or leuprolide will be used in men and premenopausal 
women patients and no dose modification is planned in this study. Patients receiving LHRH 
agonists will be monitored regularly per local institutional clinical guidelines to confirm a post-
menopausal status, according to local laboratory ranges of FSH and estradiol levels.
Refer to the most recent regional prescribing information and/or clinical guidelines for more 
information on LHRH agonists.
6.3.1.3
Ribociclib
Ribociclib should not be used as monotherapy.
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of ribociclib therapy. Refer to Table 6-2 for guidance.
Table 6-2
Ribociclib Dose Modification Guidelines
Ribociclib
Dose
Number of tablets and strength
Starting dose
600 mg
3 x 200 mg tablets
First dose reduction
400 mg
2 x 200 mg tablets
Second dose reduction
200 mg
1 x 200 mg tablets
Recommendations for dose reduction, interruption or discontinuation of ribociclib in the 
management of study drug related adverse reactions are summarized in Table 6-3, Table 6-4, 
Table 6-5, Table 6-6, and Table 6-7.
Clinical judgment of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. However, for events requiring a discontinuation in 
Table 6-3, Table 6-4, Table 6-5,  Table 6-6, and Table 6-7 or listed in Section 7.1, treatment 
must be discontinued.
If a patient inadvertently doses ribociclib on a rest day (e.g. days 22-28 of any given cycle), 
ribociclib should be interrupted to ensure 7 consecutive rest days and avoid overdose. The visit 
schedule will be adjusted accordingly.

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6.3.1.3.1 Recommendations on Adjustment of Ribociclib Treatment Cycles in the 
Case of Dose Interruptions/ Reinitiation
Delayed start of a cycle:
In the case of ribociclib being withheld at Cycle (x) D1 based on investigator’s judgement, the 
patient should reinitiate ribociclib on a 3 week ON/ 1 week OFF schedule once the assessment(s) 
are within acceptable levels according to Section 6.3 Dose Modifications. The visit schedule 
should be adjusted based on the ribociclib treatment schedule.
Mid-cycle dose interruption:
In the case of ribociclib being withheld for < 7 days during any cycle, patient should reinitiate 
ribociclib to complete the 21 calendar day treatment (3 weeks ON) followed by 1 week OFF 
schedule.
In the case of ribociclib being withheld for ≥ 7 days during any cycle, patient should reinitiate 
ribociclib to a new 28 calendar day treatment schedule (3 weeks ON/ 1 week OFF) once the 
assessment(s) are within acceptable levels according to Section 6.3 Dose Modifications. The 
visit schedule should be adjusted based on the ribociclib treatment schedule.
Table 6-3
Ribociclib dose reduction/interruption and management 
recommendations for hematological adverse drug reactions (CTCAE 
v4.03)
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 at the same dose.
Grade 3 (≥25 x 109/L - <50 x 109/L)
Dose interruption until recovery to grade 1.
Re-initiate ribociclib at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to grade 1 and reduce ribociclib to the next lower 
dose level.
Grade 4(<25 x 109/L)
Dose interruption until recovery to grade 1.
Re-initiate ribociclib at the next lower dose level.
If toxicity recurs at grade 4: discontinue ribociclib
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 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 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 at the next lower dose level.

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Toxicity/Grade
Dose Adjustment and Management Recommendations
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.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue ribociclib.
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 at the same dose.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue ribociclib.
Table 6-4
Ribociclib dose reduction/interruption and management 
recommendation for hepatic toxicities (CTCAE v4.03)
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN)
(confirmed 48-72h later)
Maintain dose level with LFTs monitored every two weeks
Grade 2 (> 1.5 – 3.0 x ULN) 
Dose interruption of ribociclib 
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
If toxicity recurs after two dose reductions, or recovery to ≤ 
grade 1 is > 28 days, discontinue ribociclib
Grade 3 (> 3.0 – 10.0 x ULN) 
Dose interruption of ribociclib, until
resolved to ≤ grade 1 , then lower 1 dose level of ribociclib
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 
Grade 4 (> 10.0 x ULN)
Discontinue ribociclib 
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’s Syndrome, 
other pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs.
For patients with Gilbert’s Syndrome, these dose modifications apply to changes in direct bilirubin only.
Bilirubin will be fractionated if elevated.

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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 every two weeks in 
case of increase from baseline grade 0 to 1
Increase from baseline grade 0 or 1 to grade 2 
(> 3.0 – 5.0 x ULN)
Dose interruption of ribociclib 
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
Increase from baseline grade 0 or 1 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
Repeat liver enzyme and bilirubin tests twice weekly for 2 
weeks after dose resumption
If recovery to ≤ baseline grade is > 28 days, discontinue 
ribociclib
If toxicity recurs, discontinue ribociclib
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
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.
Grade 4 (> 20.0 x ULN)
Discontinue ribociclib 
AST or ALT and concurrent Bilirubin
For patients with normal ALT and AST and 
total bilirubin at baseline: AST or ALT >3.0 x 
ULN combined with total bilirubin > 2 x ULN 
without evidence of cholestasis
Or
For patient with elevated AST or ALT or total 
bilirubin at baseline: baseline: [AST or ALT >2 
x baseline AND >3.0x 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
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose 
interruption/reduction. They include but are not limited to: concomitant medications, herbal preparations or 
dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive liver metastasis, and 
alcohol intake. 

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6.3.1.3.2 Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of 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], , combined with [TBIL > 2 
x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: Alkaline Phosphatase (ALP) elevation > 2.0 x ULN with R value < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic
(R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury.
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat Liver Function Tests 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) or INR and GGT. For patients with 
Gilbert’s Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies 
to changes in direct bilirubin only.
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves:

Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values.

Obtaining a more detailed history of current symptoms.

Obtaining a more detailed history of prior and/or concurrent diseases, including history of 
any pre-existing liver conditions or risk factors.

Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets.

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.

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
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.

Consider a liver biopsy as clinically indicated to assess pathological change and degree of 
potential liver injury
All cases of DILI 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 meeting the definition of SAE (Section 8.2.1), and must be 
reported as SAE using the term “potential drug-induced liver injury”. All events must be 
followed up with the outcome clearly documented. Results of tests as well as other clinically 
important information will be recorded in the eCRF.
6.3.1.3.3 Additional follow-up for QTc prolongation
Table 6-5
Ribociclib dose adjustment and management recommendation for 
QTcF prolongation
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++ correct for albumin, 
Phos, Mg++). If outside of the normal range, interrupt ribociclib 
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.
1
QTcF 450-480 ms
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment 
required.
2
QTcF 481-500 ms
Interrupt ribociclib. 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 with dose reduced by 1 dose level. Refer to Table 6-2 for dosing 
schedule.
If QTcF ≥ 481 ms recurs, ribociclib should be reduced again by 1 dose level.
Repeat ECG 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. 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 will be reduced by 1 dose level. 
Refer to Table 6-2 for dosing schedule.

If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For All 
Grades,” discontinue ribociclib.
Repeat ECG 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.

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Grade
Dose Modification
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. 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.
6.3.1.3.4 Additional follow-up for Interstitial Lung Disease (ILD)/pneumonitis (CTCAE 
v4.03)
Table 6-6
Ribociclib 
dose 
adjustment 
and 
management 
recommendation 
for   
ILD/pneumonitis
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 
6.3.1.3.5 Guidance for all other adverse reactions
Consider performing an analysis of serum potassium, calcium, and magnesium for all adverse 
reactions that are potentially associated with electrolyte imbalance. If electrolyte values are 
outside of the normal range, interrupt ribociclib administration, correct electrolytes with 
supplements or appropriate therapy as soon as possible, and repeat electrolyte testing until 
documented normalization of the electrolytes.
For all other adverse events, including Toxic Epidermal Necrolysis (TEN), which is a grade-4
event by CTCAE, please follow recommendations in Table 6-7.
Table 6-7
Ribociclib dose reduction/interruption 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 at the same dose.
If the same toxicity recurs at grade 2, interrupt ribociclib until recovery to grade 1. Re-initiate 
ribociclib at the next lower dose level.

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6.3.2
Follow-up for toxicities
Patients who complete treatment or whose treatment is interrupted or permanently discontinued 
due to an adverse event or clinically significant laboratory value, must be followed at least once 
a week (or more frequently if required by institutional practices, or if clinically indicated) for 4 
weeks, and subsequently at approximately 4-week intervals, until resolution or stabilization of 
the event, whichever comes first. Appropriate clinical experts such as ophthalmologist, 
endocrinologist, dermatologist, psychiatrists etc. should be consulted as deemed necessary.
All patients will be followed up for adverse events and serious adverse events for 30 days 
following the last dose of study treatment. Patients stopping study treatment but still receiving 
ribociclib outside of this trial (e.g., commercial supply) will be followed up for safety up to 30 
days independently of resolution/stabilization of AEs. Further reports of AEs after 30 days of 
EOT should follow local pharmacovigilance practices.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed.
Please consult the list of prohibited medications and the list of use with caution medications for 
further guidance (see Table 14-1 and Table 14-2 in Appendix 14.1).
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Prior and Concomitant 
Medications or the Surgical and Medical Procedures eCRF.
If patients take concomitant medications chronically, any change in the dose or schedule of any 
concomitant medication throughout the study period should be clearly documented
6.4.1.1
Bisphosphonates and denosumab
Bisphosphonates and denosumab are generally allowed with the following comments:

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.

Chronic concomitant bisphosphonate/denosumab therapy for the prevention of bone 
metastasis is permitted.
3
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor.
Re-initiate ribociclib at the next lower dose level.
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade 1 and reduce 
ribociclib dose the next lower dose level.
If toxicity recurs at grade 3, discontinue ribociclib.
4
Discontinue ribociclib and treat with appropriate medical therapy.

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Patients taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible.
6.4.1.2
Hematopoietic growth factors
Prophylactic use of WBC growth factors with ribociclib is not recommended.
6.4.1.3
Palliative radiotherapy
Palliative radiation is permitted. It should not be delivered to target lesion. Cumulative courses 
of RT should not encompass  >25% of irradiated bone marrow (see Appendix 14.4).
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use must 
be clearly documented and progression must be ruled out.
No dose modification of study treatment is needed during palliative radiotherapy.
6.4.1.4
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, 2017; Roila F et al 2016).
Potential drug interaction between ribociclib and antiemetic medications should always be 
taken into consideration. Example of a prohibited antiemetic medication is ondansetron that in 
combination with ribociclib may precipitate TdP. Refer to Appendix 1 for list of medications 
that are prohibited or allowed to be used with ribociclib.
6.4.2
Permitted concomitant therapy requiring caution
Medications to be used with caution during combined ribociclib and letrozole (+/- goserelin or 
leuprolide) in this study are listed below (see Table 14-2 in Appendix 14.1). 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 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)

Strong inhibitors of BSEP (Bile Salt Export Pump) (based on in vitro data 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 (has a potential to 
increase exposure to substrates of these transporters, although no animal or clinical data 
are available to support these statements)

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
Sensitive substrates of transporter BCRP (has a potential to increase exposure to 
substrates of these transporters, although no animal or clinical data are available to 
support these statements)

Substrates metabolized predominantly by CYP2C19 or CYP2A6 with a narrow 
therapeutic index (that could be affected by letrozole)
6.4.2.1
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)
6.4.3
Prohibited concomitant therapy
The following medications are prohibited during study treatment in the study 
(see Table 14-1 in Appendix 14.1). 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 (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 all these preparations at least 7 days prior to first dose of study 
treatment.
6.4.4
Drugs with QT prolongation
As far as possible, avoid co-administering medications with a “Known”, “Possible” or 
“Conditional” risk of TdP (www.crediblemeds.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
must be interrupted (see Table 6-5). If during the course of the study, concomitant 
administration of a drug with “Possible risk” or “Conditional risk” of TdP is required, based on 

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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.crediblemeds.org). Medications with a 
known risk for QT prolongation are prohibited during study treatment.
Refer to the ribociclib [Investigator’s Brochure] and letrozole, goserelin, and leuprolide drug 
package insert in addition to Appendix 14.1 for information on possible interactions with other 
drugs.
6.5
Patient numbering and treatment assignment
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for 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.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT system. If the patient fails to meet 
eligibility criteria for any reason, the reason will be entered into the Screening Phase Disposition 
eCRF page. The patient will be entered as screen failure in the IRT system.
Once Subject No. is assigned, it 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.
6.5.2
Treatment assignment
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be assigned via IRT 
to treatment. 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 the patient to the 
ribociclib treatment and will specify a unique medication number for the first package of study 
ribociclib to be dispensed to the patient.
6.5.3
Treatment blinding
Not applicable; this is an open label study.
6.6
Study drug preparation and dispensation
Patients will be provided with an adequate supply of study drug for self-administration at home, 
including instructions for administration, until at least their next scheduled study visit. Patients 
will receive ribociclib on an outpatient basis. The investigator shall provide the patient with 
instructions for ribociclib administration according to the protocol.
Letrozole, and either goserelin (if applicable) or leuprolide (if applicable) should be dispensed 
and administered according to the local prescribing information and practice.

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The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF(s).
6.6.1
Study treatment packaging and labeling
Ribociclib will be provided as global clinical open-labeled supply and will be packed and 
labeled under the responsibility of Novartis, Drug Supply Management.
Letrozole, goserelin and leuprolide will be sourced as local commercial supply (in the locally 
approved formulation and packaging configuration) and labeled in the country when possible.
Study treatment labels (see Table 6-8) will comply with the legal requirements of each country 
and will include storage conditions, and a unique medication. Responsible site personnel will 
identify the study treatment package(s) to dispense by the medication number(s) assigned by 
IRT to the patient. Site personnel will add the patient number on the label. If the label has 2
parts (base plus tear-off label), immediately before dispensing the package to the patient, site 
personnel will detach the outer part of the label from the package and affix it to the patient’s 
source document (Drug Label Form) for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient.
Table 6-8
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Ribociclib
Tablets in bottles
Labeled as ‘LEE011”
Study treatment packaging has a 2-part label.
Letrozole
Refer to local product information
Refer to local product information
Goserelin
Refer to local product information
Refer to local product information.
Leuprolide
Refer to local product information
Refer to local product information.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatments should be stored according to the 
instructions specified on the drug labels (Table 6-9) and in the [Investigator’s Brochure].
Table 6-9
Supply and storage of study treatment
Study treatments
Supply
Storage
Ribociclib
Centrally supplied by Novartis
Refer to study treatment label
Letrozole
Locally
Refer to local product information
Goserelin
Locally
Refer to local product information
Leuprolide
Locally
Refer to local product information

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6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
clinical database (D) or remain in source documents only (S) (“Category” column).
Note:

During screening visits, lab assessments including white blood cell (WBC) count, absolute 
neutrophil count (ANC), absolute lymphocyte count, hemoglobin, platelets, INR, ALT, 
AST, total bilirubin (or direct bilirubin if Gilbert’s Syndrome), serum creatinine, 
electrolytes (potassium, sodium, calcium corrected for serum albumin, and magnesium) are 
required to be collected within 14 days of C1D1 for eligibility assessment.

During treatment phase, only selected labs assessments are required to be collected in the
clinical database at the patient scheduled visits: WBC, ANC, absolute lymphocyte count, 

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hemoglobin, platelets, AST, ALT, ALP, total bilirubin, and direct bilirubin (if clinically 
indicated). Electrolytes should be monitored at the beginning of each cycle before resuming 
ribociclib dose during the first 6 cycles and as clinically indicated thereafter. The results 
should not be captured in clinical database. Eventual abnormal electrolyte lab results should 
be reported as AEs at the investigator’s discretion.

ECG will be performed at screening (within 5 days of C1D1), C1D15, C2D1, then as 
clinically indicated, and EOT.

If treatment is withheld at any time during the study, all study visits, safety assessments, 
and efficacy assessments should be adjusted accordingly to match the treatment cycles.

For all visits, there is a +/-3 day window on assessments to take into account scheduling 
over public holidays, if not explicitly specified otherwise.

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Table 7-1
Visit evaluation schedule (Core Phase)
Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Screening
Study Informed 
Consent
D
7
×
IRT Screening 
(after ICF 
signature)
D
7.1.2
×
Patient History
Demography
D
7.1.2
×
Inclusion / 
Exclusion criteria
D
5.1
×
Medical History
D
7.1.2
×
Diagnosis and 
extent of cancer
D
7.1.2
×
Prior 
antineoplastic 
therapy-
medication
D
7.1.2
×

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Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Prior 
antineoplastic 
therapy-
radiotherapy
D
7.1.2
x
Prior 
antineoplastic 
therapy- surgery
D
7.1.2
x
Prior and 
concomitant 
medication
D
7.1.2
×
Continuous – up to 30 days after last dose
Surgical and 
Medical 
procedures
D
7.1.2
×
Continuous – up to 30 days after last dose
IRT
Eligibility 
checklist (within 
IRT)
S
7.1.2
×
IRT - ribociclib 
administration
S
7
×
×
×
×
×
×
2 cycle
supply 
(e.g. 6, 8, 
10) 
×
3 cycle 
supply (12, 
15, 18…)
×

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Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Physical Examination
Physical 
examination
S
7.2.2.1
×
×
×
×
×
×
×
Every 2 
cycles
(6, 8, 10) 
×
Every 3
cycles
(12,15, 
18…)
×
ECOG 
performance 
status
D
7.2.2.4
×
×
×
×
×
×
×
Every 2 
cycles
(6, 8,10)
×
Every 3 
cycles (12, 
15, 18...)
×
Height
D
7.2.2.3
×
Weight
D
7.2.2.3
×
×
× 
×
Every 2 
cycles
(6, 8,10)
×
Every 3
cycles (12, 
15, 18…)
×
Vital signs
D
7.2.2.2
×
×
×
×
×
x
×
Every 2 
cycles (6, 
8,10)
×
Every 3 
cycles (12, 
15, 18…)
× 

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Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Laboratory assessments (local)
Hematology 
(selected 
parameters: 
WBC, ANC, 
lymphocytes, 
platelets, 
hemoglobin)
D
7.2.2.5.1
× (-14 
Days to 
Day 1)
×
×
×
×
×
×
×
(cycle 6 
only), 
then as 
clinically 
indicated)
as clinically 
indicated
×
Chemistry 
(see Table 7-5)
D
7.2.2.5.2
× (-14 
Days to 
day 1)
×
×
×
×
×
×
×
(cycle 6 
only), 
then as 
clinically 
indicated)
as clinically 
indicated
×
Coagulation
(see Table 7-5)
D
7.2.2.5.3
×
As clinically indicated
×
Tumor Assessment
Tumor 
Assessment
D
7.2.1
×
Recommendation: every 12 weeks from start of study treatment can be 
performed at different intervals according to the local standard of care
×

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Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Cardiac Assessment
ECG (standard 
12 lead)
D
7.2.2.6
×
(-5 Days to 
Day 1)
×
×
As clinically indicated
×
Safety
Serum 
Pregnancy test
(only 
premenopausal 
patients) 
D
7.2.2.5.4
x
x
Urine pregnancy 
test (only 
premenopausal 
patients)
D
7.2.2.5.4
x
every cycle
Adverse events
D
8.1
×
Continuous – up to 30 days after last dose of study treatment
Patient Reported Outcome
FACT-B (female 
patients only)
D
7.2.3
×
×
×
×
×
×
Every 2 
cycles (6, 
8, 10)
x
Every 3 
cycles (12, 
15, 18…)
×

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Category
Reference to 
Protocol 
Section
Screening 
Phase
Core Treatment Phase
End of study 
treatment 
(EOT) within 7
days from the 
last dose of 
study
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
Screening 
(-28 Days 
to Day 1)
C1D1
C1D15
C2D1
C2D15
C3D1
C4D1
C5D1
C6D1-C11D1
C12D1 and 
subsequent 
cycles (up to 
cycle 36)
Treatment
Letrozole
D
6
×
(Daily)
Ribociclib
D
6
×
(Daily: Day 1-21)
Goserelin (men 
/premenopausal 
women only)
D
6
x
x
x
x
x
x
every 
cycle
x
every cycle
Leuprolide (men 
/premenopausal 
women only)
D
6
x
x
x
x
x
x
every 
cycle
x
every cycle
Discontinuation
Antineoplastic 
therapies since 
discontinuation 
of study 
treatment
D
7
×
End of phase 
disposition
D
7
×
×

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Table 7-2
Visit evaluation schedule (Extension Phase)
Category
Reference 
to Protocol 
Section
Extension Treatment Phase
End of study 
treatment 
(EOT) within 7 
days from the 
last dose of 
study 
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
E-C1D1
  E-C4D1
  E-C7D1
E-C10D1 and  
subsequent 
cycles
Concomitant medication 
(only if related to (s)AE)
D
7.1.2
X
Continuous – up to 30 days after last dose
Surgical and Medical 
procedures (only if 
related to (s)AE)
D
7.1.2
X
Continuous – up to 30 days after last dose
IRT
IRT – ribociclib 
administration
S
7
X
Every 3 cycles dispense 3 cycle supply (Cycle 1, 4, 7, 10…)
Safety
Adverse events
D
8.1
X
Continuous – up to 30 days after last dose of study treatment
Pregnancy Serum Test
(only premenopausal 
patients)
S/D
7.2.2.5.4
X
Pregnancy urine test
(only premenopausal 
patients)
S/D
7.2.2.5.4
X
every cycle
Confirmation of Clinical 
Benefit (assessed by 
investigator)
D
7
X
Every 3 cycles (1, 4, 7, 10…)

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Category
Reference 
to Protocol 
Section
Extension Treatment Phase
End of study 
treatment 
(EOT) within 7 
days from the 
last dose of 
study 
treatment
Safety follow 
up within 30 
days of last 
dose of study 
treatment
Visit name
E-C1D1
  E-C4D1
  E-C7D1
E-C10D1 and  
subsequent 
cycles
Treatment
Letrozole
D
6
X
(Daily)
Ribociclib
D
6
X
(Daily: Day 1-21)
Goserelin 
(men/premenopausal 
only)
D
6
X
(Monthly)
Leuprolide 
(men/premenopausal 
only)
D
6
X
(Monthly)
Discontinuation
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7
X
End of phase disposition
D
7
X

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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to start of study treatment or within 5 days of start of study treatment for selected assessments 
(i.e., ECG; see Table 7-1 for list of assessments to be performed).
Note: Any screening assessment that is done outside the screening window (Day -28 to Day 
1 or Day -5 to Day 1 for ECG assessment as applicable) must be repeated prior to C1D1.
If patient meets all inclusion and no exclusion criteria, the screening labs can be used for 
baseline if patient is dosed within 14 days of the screening visit. If patient cannot be dosed 
within 14 days of screening, then the labs should be repeated the day before patient starts dosing 
(see baseline visit in Table 7-1)
Any blood work already completed during the regular work-up of the patient within 5 calendar 
days before signing the main study ICF can be considered as the screening assessments for this 
study. Tests not considered standard practice should only be performed after the patient has 
signed ICF.
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 assignment). In this case the Subject No. assigned 
to the patient initially will be used and the patient will be identified with this number throughout 
his/her entire participation to the study.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of study treatment, including before signing the main study ICF can be 
considered as the baseline images for this study.
7.1.2.1
Eligibility screening
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.

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7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page.
The following eCRF pages will be collected on screen failures:

Demographic information

Informed consent

Inclusion/Exclusion

Death

Withdrawal of consent, if applicable, must also be completed. 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 for SAE reporting 
details). If the patient fails to be enrolled, the IRT must be notified within 2 days of the 
screen fail that the patient was not enrolled.
7.1.2.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Date of birth and initials (where permitted), sex, race, ethnicity)

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.

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 taken within 30 days before the first dose is administered must be recorded 
on the Prior and Concomitant medication eCRF page and updated on a continual basis if 
there are any new changes to the medications.

Surgeries and Medical Procedures prior to Informed Consent are recorded on the Medical 
History eCRF. The Surgical and Medical Procedures after signing Informed Consent are 
recorded on Surgical and Medical Procedures eCRF.

Patient-reported outcome Functional Assessment of Cancer Therapy – Breast (FACT-B)
questionnaire (See Section 7.2.3).
Furthermore the following assessments will be performed:

Vital signs

Height, weight

Physical examination

Performance status (ECOG)

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
Laboratory evaluations (hematology, INR, chemistry)

ECG

Radiological assessments (e.g. CT Scan)
7.1.3
Run-in period
Not Applicable.
7.1.4
Treatment period
Core Phase
Patients will be treated with ribociclib + letrozole (goserelin or leuprolide will be added to this 
combination in men and premenopausal women) until disease progression, unacceptable 
toxicity, death, or discontinuation from the study treatment due to any other reason. For details 
of assessments, refer to Table 7-1.
Extension Phase
Patients will be treated with ribociclib + letrozole (goserelin or leuprolide will be added to this 
combination in premenopausal patients and men) until disease progression, unacceptable 
toxicity, death, or discontinuation from the study treatment due to any other reason. For details 
of assessments, refer to Table 7-2.
7.1.5
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 (Core or Extension Phase), 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 eCRF pages. They may be considered withdrawn if they state an intention to 
withdraw, fail to return for visits, or become lost to follow-up for any other reason.

The investigator may discontinue study treatment (Core or Extension Phase) for a given 
patient if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.

Patients will discontinue from the Core Phase 18 months after LPFV. In the event study 
patients are still deriving benefit at the end of the Core Phase and ribociclib is not 
approved or available and reimbursed, patients may be transitioned to the Extension Phase 
and continue to receive the study treatment until progression, intolerance, death, or 
physician/patient decision; only safety and clinical benefit as assessed by investigator will 
be collected.

During the Extension Phase, if ribociclib is approved and reimbursed, patients will be 
transitioned to prescription or drug access/support program(s) according to local laws and 
regulations.

The study will end after completion of the Extension Phase and all remaining patients will 
discontinue from the study. Patients who complete this Extension Phase, and continue to 
derive clinical benefit from the treatment based on the investigator’s evaluation will

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receive ribociclib from prescription (if approved and reimbursed), another Post-Trial 
Access (PTA) program, or other drug access/support program(s).
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time.
Patients may be withdrawn from the study treatment if any of the following occur:

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
Adverse Event

Lost to follow-up

Physician decision

Progressive Disease

Protocol deviation

Study terminated by sponsor

Technical problems
Patients must be withdrawn from the study treatment if any of the following occur:

Pregnancy

Death

Subject/Guardian decision
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 6.3

Use of prohibited medication. Please refer to Section 6.4.3

Any other protocol deviation that results in a significant risk to the patient’s safety.
Patients who discontinue study treatment should undergo an End of Treatment (EOT) visit 
followed by a 30-day safety follow-up.
At EOT visit, all the assessments as listed in Table 7-1 will be performed. If the decision to 
discontinue the patient occurs at a regularly scheduled visit, that visit may serve as the EOT 
visit rather than having the patient return for an additional visit.
The investigator or his/her delegate must also contact the IRT to register the patient’s 
discontinuation from study treatment within 2 days of EOT visit.
7.1.6
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the
assessment table. Novartis will continue to keep and use collected study information (including 

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any data resulting from the analysis of a patient’s samples until their time of withdrawal) 
according to applicable law.
7.1.7
Follow up for safety evaluations
All patients who complete the Core Phase of the study but do not transition to the Extension 
Phase must have safety evaluations completed within 30 days after the last dose of study 
treatment (ribociclib + letrozole + either goserelin or leuprolide). Patients who continue to the 
Extension Phase will complete safety evaluations within 30 days after the last dose of study 
treatment of the Extension Phase.
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF.
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 eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments
Tumor response will be assessed locally according to the Novartis guideline version 3.2 
(Appendix 14.3) based on RECIST 1.1 (Eisenhauer et al 2009). The imaging assessment 
collection plan is presented in Table 7-3. There will be no central review of imaging assessments.
Table 7-3
Imaging Assessment Collection Guidance
Procedure
Screening: day−28 to day 1
Treatment phase*
End of treatment*
CT or MRI (Chest, 
Abdomen, Pelvis)
Mandated
Recommend every 12 weeks 
or at different intervals 
according to local standards 
of care during treatment 
phase
Mandated
Brain CT or MRI
Only if suspected brain 
metastases
As clinically indicated
As clinically indicated
Whole body bone 
scan**
Mandated
As clinically indicated
As clinically indicated
Bone X-ray, CT or 
MRI
Only if skeletal abnormalities 
identified by whole body bone 
scan (or skeletal survey) at 
screening, which are not 
visible in the chest, abdomen, 
pelvis CT/MRI.
If bone lesion at screening, 
recommend every 12 weeks 
or at different intervals 
according to local standards 
of care during treatment 
phase
Mandated only if bone 
lesion at screening

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Procedure
Screening: day−28 to day 1
Treatment phase*
End of treatment*
Skin visual 
inspection and 
measurement 
Only if skin lesions at 
screening
Recommend every 12 weeks 
or at different intervals 
according to local standards 
of care during treatment 
phase
Mandated if skin 
lesions at screening
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 baseline, 
recommend 12 weeks or at 
different intervals according to 
local standards of care during 
treatment phase
Mandated if lesion at
screening
*Tumor evaluation at EOT is required for patients who discontinue study treatment before the first scheduled 
post-baseline tumor assessment (week 12) and for patients whose previous tumor assessment did not 
demonstrate PD and was done more than 28 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).
Baseline/Screening imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after study 
treatment cannot be considered baseline images. The following assessments are required at 
screening/baseline:

Chest, abdomen and pelvis CT or MRI

Brain CT or MRI, if clinically indicated

Whole body bone scan

Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI

Skin visual inspection and measurement (only if skin lesions at screening)

CT or MRI of other metastatic sites (e.g. neck), if clinically indicated
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
If brain metastases are suspected at baseline, brain MRI or CT should be completed. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then MRI without 
contrast or CT with/without contrast is acceptable.
A whole body bone scan should be performed per institutional standard of care [e.g., Tc-99 
bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-
PET) or sodium fluoride (NaF) PET]. Localized CT, MRI or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen and pelvis CT/MRI.

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If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed.
If skin lesions are present at screening, lesion will be measured and visually monitored.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 7-3 should be performed at the timepoints specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 7-1). Imaging assessments for response evaluation will be performed 
in recommended timeframe of every 12 weeks or at different intervals according to the local 
standard of care after screening/baseline, until disease progression, death, lost to follow-up or 
withdrawal of consent. Imaging assessments should be scheduled using the first dose date as 
the reference date (not the date of the previous tumor assessment), and should be respected 
regardless of whether treatment with study treatment is temporarily withheld or unscheduled 
assessments performed.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by visual inspection and measurement and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Appendix 14.3).
Confirmation of Clinical Benefit
During the Extension Phase, at every 3 months visit the investigator is required to confirm that 
the patient continues to receive clinical benefit and may continue receiving study treatment.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical exam, vital signs, hematological and chemistry 
labs as well as collecting of the adverse events at every visit during Core Phase (Table 7-1). For 
patients who continue study participation during Extension Phase, (S)AEs and related 

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assessments and, pregnancy test will be performed (Table 7-2). For details on AE collection 
and reporting, refer to Section 8.
Premenopausal women must complete the following pregnancy tests:

Screening – Serum pregnancy test done locally

Every 4 weeks during treatment – urine pregnancy test. Can be administered at patient’s 
home

End of Treatment visit – serum pregnancy test done locally
Premenopausal women who administer urine pregnancy testing at home should complete a 
simple diary with the dates and the outcome of the urine pregnancy tests while on study 
treatment. In case of a positive pregnancy test, the instructions in Section 8.4 should be followed.
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. Information about the 
physical examination must be present in the source documentation at the study site. Physical 
examination is to be performed according to the visit schedule as outlined in
Table 7-1.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF.
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1.
7.2.2.4
Performance status
ECOG Performance status scale will be used as described in the Table 7-4.
Table 7-4
ECOG performance status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work

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Grade
ECOG status
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
Local site laboratories will be used for the analysis of scheduled hematology, biochemistry, and 
other blood specimens collected as part of safety monitoring. All unscheduled blood testing will 
also be performed locally. The time windows granted for laboratory evaluations are identical to 
the corresponding visit time windows for each visit (refer to Section 7.1).
Laboratory abnormalities that are considered clinically significant, induce clinical signs or 
symptoms, require concomitant therapy or require dose adjustments in ribociclib treatment (see 
Section 8.1) constitute an adverse event (AE) and must be reported as an AE on the AE eCRF 
page.
Laboratory values obtained at the screening visit will be used to assess eligibility to meet 
Inclusion criteria. If patient meets all inclusion and no exclusion criteria, the screening labs can 
be used for baseline if patient is dosed within 14 days of the screening visit. If patient cannot 
be dosed within 14 days of screening, then the labs should be repeated the day before patient 
starts dosing (see baseline visit in Table 7-1).
Only selected laboratory parameters (see Table 7-5) will be collected on the eCRF.
Table 7-5
Local Clinical laboratory parameters collection plan
Test 
Category
Test Name
Hematology
WBC, ANC, absolute lymphocyte count, hemoglobin, platelets
Chemistry
Screening
ALT (SGPT), AST (SGOT), calcium corrected for serum albumin, creatinine or 
creatinine clearance, potassium, sodium, magnesium, total bilirubin (or direct 
bilirubin if Gilbert’s syndrome)
Scheduled 
visits
Alkaline phosphatase, ALT (SGPT), AST (SGOT), total bilirubin, direct bilirubin
(if clinically indicated)
Note: potassium, sodium, calcium corrected for serum albumin, and magnesium 
are to be monitored but are not captured in the eCRF. Abnormal electrolyte lab 
results should be reported as AEs at the investigator’s discretion.
Coagulation
International normalized ratio [INR]
Pregnancy 
Serum and Urine 
7.2.2.5.1 Hematology
Hematology tests are to be performed according to the Visit Evaluation Schedules outlined in 
Table 7-1. For details of the Hematology panel refer to Table 7-5.
7.2.2.5.2 Clinical chemistry
Chemistry tests are to be performed according to the Visit Evaluation Schedules outlined in 
Table 7-1. For details of the Chemistry panel refer to Table 7-5.

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7.2.2.5.3 Coagulation
INR is to be performed according to the Visit Evaluation Schedules outlined in Table 7-1.
7.2.2.5.4 Pregnancy and Hormonal Levels
Pregnancy tests are to be performed according to the Visit Evaluation Schedules outlined in 
Table 7-1 and Table 7-2
A positive urine test is required to be confirmed by an immediate serum pregnancy test.A 
positive pregnancy test requires immediate interruption of study treatment until the assessment 
is confirmed. If positive, the patient must be discontinued from the study.
FSH and estradiol will be collected locally and used for screening and confirmation of 
menopausal status and clinically monitored as indicated. FSH and estradiol results are not 
recorded in the eCRF.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
Standard 12 lead ECG assessments will be performed locally at screening, C1D15, C2D1, and 
thereafter as clinically indicated, and EOT visit (see Table 7-1). There will be no central review 
of ECGs. QT interval corrected by Fridericia’s formula (QTcF) will be used in this trial for trial 
eligibility and safety assessments.
If an abnormal ECG or QTcF value of ≥ 481 ms is obtained at any time after C1D1, study 
treatment must be interrupted, repeat ECG and follow management guidelines detailed in Table 
6-5.
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Local cardiologist ECG assessment may be performed at 
any time during the study at the discretion of the investigator.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page.
7.2.3
Patient reported outcomes
The FACT-B will be used to explore patient-reported outcome measures of health-related 
quality-of-life, functioning, disease symptoms and treatment-related side effects in selected 
countries including United States, Canada, United Kingdom, France, Italy and Spain. The 
FACT-B (Brady MJ 1997) is a recognized, reliable and valid instrument frequently used in 
clinical trials of patients with advanced or metastatic breast cancer.

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Due to the nature of the questionnaire and validation, only females will be asked to complete 
this questionnaire.
The FACT-B quality of life questionnaire (see Appendix 14.2) will be administered at study 
site before any study drug administrations at the visits indicated in Table 7-1 and Table 7-6
utilizing electronic device for data collection. Collection of the FACT-B PRO has up to -3 day 
window unless otherwise indicated.
All questionnaires should be administered in the patient’s local language at the beginning of the 
study visit prior to any interaction with the study investigator to avoid biasing the patient’s 
perspective. This is to avoid potentially biasing patients or their responses to study 
questionnaires. Patients should be given sufficient space and time to complete the study 
questionnaire and the administered questionnaire 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 the questionnaire for all patients, including 
from those who discontinue prior to the study evaluation completion visit, however, if patients 
refuse to complete the questionnaire, this should be documented in study source records. A 
patient’s refusal to complete the study questionnaire is not considered a protocol deviation.
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.
Table 7-6
Patient reported outcomes collection plan
Patient 
Questionnaires
Cycle
Day
Time
FACT-B
Cycles 1 to 6
Every cycle during the first 6 cycles
At the beginning of the 
study visit prior to any 
interaction with the 
study investigation.
Cycle 7 and 
subsequent 
cycles
Every 2 cycles: Cycle 8,10,12
Every 3 cycles after that: 15, 18, etc.
End of treatment
Day of end of treatment assessment
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, 

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require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. Grade 1 to 5 will be used to characterize the severity 
of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding to Grades 1 - 5, will be used. 
Information about any deaths (related to an Adverse Event or not) will also 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 1-5)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
      Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met.
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown).
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.

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Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities that do not meet the definition of an adverse event should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
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:

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
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (i.e. to perform study related assessments)

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety every SAE, regardless of suspected causality, occurring after the patient 
has provided informed consent and until at least 30 days after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. A SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Chief Medical Office and Patient Safety (CMO&PS) department associate may 
urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries.

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8.3
Emergency unblinding of treatment assignment
Not Applicable.
8.4
Pregnancies
This trial is planned for men, post-menopausal women or premenopausal women with ovarian 
suppression, so no pregnancies are expected for study patients. However, in the rare cases when 
this occurs, to ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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’s 
Brochure] (IB). Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be included in 
the patient informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
Not Applicable.
8.7
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, and Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a Steering Committee charter.

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9
Data collection and management
9.1
Data confidentiality
Information about study patients 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 patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.

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9.3
Data collection
This study will use Electronic Data Capture (EDC) and the designated investigator staff will 
enter the data required by the protocol into the Electronic Case Report Forms (eCRF). The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.3.1
IRT data collection
Patient eligibility and enrollment will be tracked using an Interactive Response Technology. 
The data will be entered by the designated investigator staff. The system will be supplied by a 
vendor, who will also manage the database for that system.
9.3.2
FACT-B questionnaire data collection
FACT-B questionnaire data will be entered using ePRO. The data will be entered by the patients
at the clinic. The system will be supplied by a vendor, who will also manage the database for 
that system.
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 
COA measure in a single study is not endorsed. However, paper PRO may be utilized as a 
backup should there be a failure with the electronic version/system.
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.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
PRO data will be collected electronically and processed centrally and the results will be sent 
electronically to Novartis.

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Data about all study treatments dispensed to the patient will be tracked using an Interactive 
Response Technology. The IRT system will be supplied by a vendor(s), who will also manage 
the database. The data will be sent electronically to Novartis personnel (or designated CRO).
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked made available for data analysis. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site.
10
Statistical methods and data analysis
Novartis and/or a designated CRO will perform all analyses. Any data analysis carried out 
independently by the investigator should not be presented or published before the final analysis 
is completed. The data from all centers that participate in this trial will be combined in the 
analyses.
Final analyses will be performed when all patients have been followed for 30 days after they 
have either prematurely discontinued ribociclib or been discontinued from the study after 
completing treatment as per protocol (see Section 4.1). Data collected during the Extension 
Phase may be summarized in a separate report or publication. However, analysis may be 
performed to support regulatory submission or safety update if deemed necessary before the 
final analysis.
Following subgroup analyses may be performed if deemed necessary at interim and/or final 
analysis:

Region (Latin American, Region Europe, Asia)

Country (countries with at least 100 patients such as US, Canada, Italy, Spain, France, 
Belgium, Czech Republic)

Menopausal status (pre/post)

Prior treatments for (neo)adjuvant (no treatments, endocrine only, chemotherapy only, 
both (chemotherapy and endocrine treatment))

ECOG PS (PS 0, 1, and 2)

Location of metastasis disease (bone, liver, lung, lymphonodes, and etc.)

Number of metastatic sites (0, 1, 2, ≥3)

Age (<65, 65-70, 70-75, >75 years)

Gender (male and female)

Race (Asian vs. Non-Asian)
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.

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10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of study 
medication defined as either ribociclib or letrozole or goserelin/leuprolide (if applicable) in the 
Core Phase.
10.1.2
Safety set in Core Phase
The Safety Set includes all patients who received at least one dose of study medications defined 
as either ribociclib or letrozole or goserelin/leuprolide (if applicable). For this study, the 
definition of FAS is the same as that of Safety set in Core Phase.
10.1.3
Safety Set in Extension Phase
The Safety set in the Extension Phase includes all patients who received at least one dose of 
study medications defined as ribociclib or letrozole or goserelin/leuprolide (if applicable) in the 
Extension Phase.
10.1.4
Per-Protocol set
Not applicable.
10.1.5
Dose-determining analysis set
Not applicable.
10.1.6
Pharmacokinetic analysis set
Not applicable.
10.1.7
Other analysis sets
The patient-reported outcomes (PRO) will be collected in subgroup of patients in selected 
countries. The PRO Analysis Set (PAS) consists of all patients in the FAS population for whom 
baseline and at least one post baseline PRO measurements are available.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set in Core Phase will be used for all analysis of relevant data (dosing information, 
use of concomitant therapies, etc.) in the Core Phase, and the safety set in Extension Phase will 
be used for analysis of all data in the Extension Phase. Categorical data will be summarized as 

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frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. In addition, the duration of exposure to study 
treatment will be categorized into time intervals; frequency counts and percentages will be 
presented for the number of patients in each interval.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
10.4
Primary objective
The primary objective of this study is to further evaluate the safety and tolerability of ribociclib 
in combination with letrozole in men and postmenopausal women with HR+, HER2- aBC who 
received no prior hormonal therapy for advanced disease. For details see Section 10.5.3.
10.4.1
Variable
To evaluate the primary objective: the number (%) of patients who experienced adverse events 
(AEs) will be calculated for the following AE categories:

Any AEs

Grade 3/4 AEs

Serious Adverse Events (SAEs)

AEs of Special Interest (Neutropenia (including febrile neutropenia), QT prolongation, 
hepatobiliary AEs)

AEs leading discontinuation and deaths

AEs leading dose reduction or dose interruption

Deaths
10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypotheses will be tested in this study. The primary safety variable (AEs, Grade 
3/4 AEs and SAEs, events of special interest, and AEs leading discontinuation and deaths) will 
be summarized by count and percentage in safety set.
10.4.3
Handling of missing values/censoring/discontinuations
All attempts will be made to ensure that the database contains full information for all safety 
data. No imputation will be applied for missing data.
10.4.4
Supportive and Sensitivity analyses
Not applicable.

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10.5
Secondary objectives
10.5.1
Secondary objective(s)
The secondary objective of this study is to assess the clinical efficacy of ribociclib + letrozole
(+ goserelin or leuprolide) in Full Analysis Set.
The following endpoints as defined by RECIST1.1 will be use key secondary objectives:

Time-to-Progression (TTP) based on investigators’ assessment

Overall response rate (ORR) for patients with measurable disease

Clinical Benefit Rate (CBR) (including patients with CR, PR, SD/NCRNPD>24 weeks)
Time to progression (TTP) is defined as time from date of start of treatment to the date of event 
defined as the first documented progression or death due to underlying cancer (Appendix 14.3: 
Novartis RECIST Guideline v 3.2). Patients with symptoms of rapidly progressing disease 
without radiologic evidence will be classified as progression only when clear evidence of 
clinical deterioration is documented and/or patient discontinued due to ‘Disease progression’ 
or death due to study indication. When there is no documentation of radiologic evidence of 
progression, and the patient discontinued for ‘Disease progression’ due to documented clinical 
deterioration of disease, the date of discontinuation is used as date of progression.
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.1.
Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response 
of complete response (CR), or partial response (PR) or an overall lesion response of stable 
disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are 
defined according to RECIST 1.1 (see Appendix 14.3 for details)
The distribution of TTP will be estimated using the Kaplan-Meier method. The median TTP 
along with 95% confidence intervals will be presented. Proportions of patients with ORR and 
CBR as assessed by investigator will be calculated and presented along with the approximate 
95% confidence intervals using Clopper and Pearson (1934) exact method.
In addition, PRO will be assessed using FACT-B instrument (See Section 10.5.4).
During Extension Phase, frequency of AEs & SAEs will be summarized.
The proportion of patients with clinical benefit as assessed by investigator will be reported at 
each scheduled visit during Extension Phase.
10.5.2
Other secondary efficacy objectives
Not applicable.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For safety analyses in the Core Phase, the Safety Set in Core Phase will be used. For safety 
analyses in the Extension Phase, the Safety Set in Extension Phase will be used. All listings and 
tables will be presented.

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The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period:
Core Phase: from day of patient’s informed consent to the day before first administration of 
study treatment.
Extension Phase: Not applicable.
2. on-treatment period:
Core Phase: For patients who discontinue after the Core Phase treatment, on-treatment period 
is defined as the time from the date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date). For 
patients who transition to the Extension Phase, on-treatment period is defined as the time from 
the date of first administration of study treatment to date of last actual administration of any 
study treatment in the Core Phase.
Extension Phase: from date of the first administration of study treatment in the Extension Phase 
to 30 days after date of last actual administration of any study treatment
3. post-treatment period:
Core Phase: starting at day 31after last administration of study treatment for patients who 
discontinue after the Core Phase treatment without transitioning to the Extension Phase. Post-
treatment period is not applicable for patients who transition to Extension Phase.
Extension Phase: starting at day 31 after last administration of study treatment in the Extension 
Phase.
The safety summary tables will include assessments from the on-treatment period, unless 
otherwise specified. Further details will be included in the Statistical Analysis Plan (SAP).
All safety data collected in the study will be listed regardless of the study period with data 
collected during the pre-treatment and post-treatment period flagged.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The 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
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI)
during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.

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10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
The following summaries will be generated separately for hematology, and biochemistry tests:

Number and percentage of patients with worst post-baseline CTCAE grade (regardless of 
the baseline status). Each patient will be counted only for the worst grade observed post-
baseline.

Shift tables using CTCAE grades to compare baseline to the worst post-baseline value 
(on-treatment).
The following listings will be produced for the laboratory data:

Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges.

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades if applicable and the classifications relative to the laboratory normal ranges
10.5.3.4 Other safety data
Vital signs
Other safety data (including ECGs, vital signs and weight) will be summarized and listed, 
notable values will be flagged, and any other information collected will be listed as appropriate. 
Further details will be included in the Statistical Analysis Plan (SAP).
10.5.3.5 Supportive analyses for secondary objectives
Not Applicable.
10.5.3.6 Tolerability
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE.
10.5.4
Patient-reported outcomes
FACT-B questionnaire will be used to collect patient reported outcome data in this trial. Scores 
will be added to create subscale and overall scores. A Trial Outcome Index is generated via the 
addition of the physical well-being, functional well-being, and breast cancer subscales.
No formal statistical tests will be performed for patient-reported outcomes (PRO) data and 
hence no multiplicity adjustment will be applied. The PRO analysis set will be used for 
analyzing PRO data.

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Descriptive statistics will be used to summarize the subscale and overall scores at each 
scheduled assessment time point. Additionally, change from baseline at the time of each 
assessment will be summarized. PRO data may be summarized by country/region.
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.
10.6
Exploratory objectives
Not applicable.
10.7
Interim analysis
Interim analyses (IA) may be performed periodically. The first IA is planned to be performed 
about 12 months after FPFV, and periodically thereafter, if needed, to fulfill regulatory requests, 
safety updates, or for publication purposes. Subgroup analyses may be performed at interim if 
deem necessary (based on the number of patients enrolled in each subgroup). Details of the IA 
will be provided in the SAP.
10.8
Sample size calculation
A sample size of 3,000 patients is planned to be enrolled in this study to detect rare AEs 
(frequency ~0.1%) with high probability. This will allow for a greater precision when reporting 
rare, but clinically meaningful AEs (e.g. febrile neutropenia, QT prolongation, renal 
insufficiency, thromboembolic events, etc.). For example, if the rate of an AE is 0.1%, then the 
probability of observing at least 1 AEs out of 3000 patients is 95.0%. A sample size of 3,000 
patients will allow for a meaningful safety analysis of specific patient subgroup of particular 
interest. For example, the expected size of male patients may be 30 (~ 0.1% of total population), 
patients with ECOG PS=2 may be 150 (~5% of total population), and patients with one prior 
line of chemotherapy may be 300 (~10% of total population). Table 10-1 below provides a 95% 
confidence interval (CI) and the corresponding width of the 95% CI, with different rates of rare 
AEs observed in [LEE011A2301] study) for overall population as well as for subgroups of 
various sizes.
Table 10-1
Confidence Intervals associated with AEs of interest for subgroups
Number of 
Patients
Number of AE
Rate
Lower 
95% CI
Upper 
95% CI
Width*
QT prolongation (observed rate = 3.5%)
30
1
0.0333
0.0008
0.1722
0.1713
150
5
0.0333
0.0109
0.0761
0.0652
300
10
0.0333
0.0161
0.0604
0.0443
3000
99
0.0330
0.0269
0.0400
0.0131
Febrile neutropenia (observed rate = 1.5%)
30
0
0
0
0.1157
0.1157
150
3
0.020
0.0041
0.0573
0.0532
300
5
0.0167
0.0054
0.0385
0.0330
3000
45
0.0150
0.0110
0.0200
0.0091

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10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or if applicable, 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 his/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. 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 
eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
Renal insufficiency / creatinine increase (observed rate = 0.5%)
30
0
0
0
0.1157
0.1157
150
1
0.0067
0.0002
0.0366
0.0364
300
2
0.0067
0.0008
0.0239
0.0231
3000
15
0.0050
0.0028
0.0082
0.0054

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must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Male participants will be requested to provide an information form to female partners.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted in a on the publicly accessible database, e.g. such as www.clinicaltrials.gov, 
before study start. In addition, results of interventional clinical trials in adult patients are posted 
on www.novartisclinicaltrials.com, a publicly accessible database of clinical study results 
within 1 year of upon study completion (i.e., LPLV), and finalization of the study report the 
results of this study will be either submitted for publication and/or posted in those for 
interventional clinical trials involving pediatric patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (//.icmje.org) and other specific guidelines 
of the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to //.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 

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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, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.

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

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13
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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 ribociclib.
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based onNovartis PK Science Memorandum, Drug-Drug Interaction and Co-Medication 
Considerations for Novartis Clinical Trials (release date: Jan 2018), which was compiled from 
the 
Indiana 
University 
School 
of 
Medicine’s 
P450 
Drug 
Interaction
Table 
(medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.p
df), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation and/or torsades de pointes 
(TdP), refer to the CredibleMeds® website crediblemeds.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, eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole, indinavir, idelalisib, Ombitasvir,/ Paritaprevir, 
Ritonavir/ Dasabuvir (VIEKIRA PAK)
Strong CYP3A4/5 inducers
Apalutamide, Carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)2,3
CYP3A4/5 substrates with 
NTI1
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine, 
dihydroergotamine, ergotamine, fentanyl, lomitapide5, lovastatin, nicardipine, 
nisoldipine, pimozide, quinidine, simvastatin, sirolimus, tacrolimus
Medications with a known 
risk for QT prolongation4
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin,bepridil 
chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, levomethadyl, mesoridazine methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, probucol, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, 
terlipressin, terodiline, terfenadine, thioridazine, vandetanib

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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 herbal include, but are 
not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 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 crediblemeds.org/healthcare-providers/drug-list for the most 
updated list. 
5 Drug has warning for risk of hepatotoxicity
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of 
ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, 
or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org.
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers.

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Table 14-2
List of medications to be used with caution during study drug 
treatment
Category
Drug Name
Moderate CYP3A4/5 
inhibitors
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, 
crizotinib, diltiazem, faldaprevir, imatinib, isavuconazole, netupitant, nilotinib,
tofisopam, Schisandra sphenanthera (nan wu wei zi), verapamil
Moderate CYP3A4/5 
inducers
Bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin,
telotristat, lopinavir5
Sensitive CYP3A4/5 
substrates1
Alpha-dihydroergocryptine, apixaban, aprepitant,  atorvastatin, avanafil, 
bosutinib,brotizolam, budesonide, buspirone, cannabinoids6, cannabidiol6, 
cobimetinib,   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, granisetron, hydrocodone-ER, iloperidone, 
imipramine (melipramine), isradipine, ketanserin, lapatinib, lenvatinib, 
leuprolide, loperamide, lithium, melperone, midostaurin, mifepristone, 
mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, , nilotinib, norfloxacin, 
nortriptyline, nusinersen, ofloxacin, olanzapineosimertinib,  oxytocin, 
paliperidone, palonosetron, panabinostat, pasireotide, pazopanib, perflutren 
lipid microspheres, perphenazine, pilsicainide, pimavanserin, pipamperone,
promethazine, prothipendyl, quetiapine, ranolazine rilpivirine, risperidone, 
romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, telavancin,tetrabenazine,
tipiracil/trifluridine, tizanidine, tolterodine, toremifene,trimipramine, tropisetron, 
vardenafil, vemurafenib, venlafaxine, 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.

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Category
Drug Name
1 Sensitive substrates: 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 www crediblemeds.org/healthcare-providers/drug-list for 
the most updated list.
3 MATE1 and MATE2 share considerable substrate specificity. 
4 OCT1 and OCT2 share considerable substrate specificity.
5 Lopinavir and atazanvir 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.

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14.2
Appendix 2 – Patient Reported Outcomes FACT-B

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

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14.3.1
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 14.3.2 and the definition of best response in 
Section 14.3.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.3.18 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 14.3.29 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
14.3.2
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.
14.3.3
Definitions
14.3.4
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 14.3.26
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.

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
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.
14.3.5
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 
14.3.26.
14.3.6
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.

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
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.

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
Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.3.7
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 eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.3.4.

Nodal target: See Section 14.3.4.
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.

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
Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.3.8
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.
14.3.9
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.
14.3.10
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.

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14.3.11
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 
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.
14.3.12
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 mm 2.
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 14.3.6).
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

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
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 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 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.

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
Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.

A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria.
14.3.13
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.

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
The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.3.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.3.14
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 eCRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.3.15).

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 14.3.6.
14.3.15
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.

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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
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 14.3.8.
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.
14.3.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.3.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.3.17
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.

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Longer intervals may also be appropriate. However, this must be clearly stated in the protocol.
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

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 

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PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
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 

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8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
14.3.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.3.19
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.
14.3.20
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.
14.3.21
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.

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14.3.22
PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen.
14.3.23
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.3.24
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)

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It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis, et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
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.
14.3.25
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 14.3.23. 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.

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
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.
14.3.26
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.

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
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 14.3.26).
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 
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.
14.3.27
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 non-
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 14.3.8.

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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.
14.3.28
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 14.3.25, 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

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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
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 14.3.25.
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in
Section 14.3.25.
3. =The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
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.

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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 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.
14.3.29
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).

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14.3.30
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).
14.3.31
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

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial.
14.3.32
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

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
Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
14.3.33
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 
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.
14.3.34
Programming rules
The following should be used for programming of efficacy results:

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14.3.35
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.
14.3.36
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 14.3.25). 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.
14.3.37
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.
14.3.38
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)’.
14.3.39
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.3.40
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

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
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 14.3.25. 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.
14.3.41
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
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16

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14.4
Appendix 4 - Bone Marrow Reserve in Adults
Table 14-8
Bone Marrow Reserve in Adults
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
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol. 5, 255-258, 1961