Conditions: Breast Cancer
Keywords: Hormone receptor-positive Estrogen and/or progesterone receptor-positive HER2-negative High risk early breast cancer Adjuvant Ribociclib LEE011 CDK4/6 inhibitor Endocrine therapy Phase II Breast carcinoma Breast cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
This was an open label, multi-center protocol for U.S. patients enrolled in the study of ribociclib with endocrine therapy as an adjuvant treatment in patients with hormone receptor-positive, HER2-negative, high risk early breast cancer

Detailed description:
The purpose of this study was to evaluate the preliminary safety and tolerability of ribociclib to standard adjuvant endocrine therapy (ET) in patients with hormone receptor (HR) positive, Human Epidermal Growth Factor Receptor2 (HER2) negative high risk early breast cancer (EBC).

Originally, this was a randomized, Phase III, double-blind, placebo-controlled, multi-center, international study to evaluate efficacy and safety of ribociclib with ET as an adjuvant treatment in patients with HR-positive, HER2-negative, high risk EBC.

Patients were randomized at a ratio of 1:1 to receive either ribociclib or placebo for approximately 24 months in combination with a standard adjuvant ET with ET continued for at least 60 months.

However, following a review of the ribociclib development program strategy, a decision was taken to explore a different approach by initiating a single Phase III study for simplicity of trial logistics and for the purpose of analyzing the overall population through a single clinical trial. Therefore, this study was closed to enrollment early and was amended to be an open label, multi-center Phase II study conducted in the US only. All randomized patients were unblinded; patients randomized to placebo were permanently discontinued from the study and patients randomized to ribociclib were offered the option to continue treatment with ribociclib + ET.

The study included a screening phase (28 days), a treatment phase composed of maximum of 26 cycles of ribociclib in combination with ET (approximately 24 months) or until disease recurrence, intolerable toxicity, withdrawal of consent, or discontinuation from the study treatment for any other reason, whichever was earlier, and a 30 days safety follow up from last dose of ribociclib. Ribociclib was given orally once a day on days 1 to 21 in each 28 days cycle.

Safety was assessed for each patient until 30 days after the last dose of ribociclib and included routine safety monitoring except in case of death, loss to follow up or withdrawal of consent.

Arms:
arm 1: Patients in this arm took Ribociclib in combination with standard adjuvant endocrine therapy.

ET was one of these 4: Letrozole, Anastrozole, Exemestane, Tamoxifen (Tamoxifen no longer permitted after protocol amendment 2) arm 2: Patients in this arm took Placebo in combination with standard adjuvant endocrine therapy. ET was one of these 4: Letrozole, Anastrozole, Exemestane, Tamoxifen

Interventions: intervention 1: Ribociclib intervention 2: Adjuvant endocrine therapy intervention 3: Placebo
Intervention descriptions: intervention 1: Ribociclib 600 mg daily on days 1 to 21 of a 28-day cycle for 26 cycles (approximately 24 months).

Ribociclib was supplied in the form of 200 mg film-coated tablets taken by mouth. intervention 2: Letrozole 2.5 mg by mouth daily, or anastrozole 1 mg by mouth daily, exemestane 25 mg by mouth daily, tamoxifen 20 mg by mouth daily, for a total duration of at least 60 months. In premenopausal women, a GnRH agonist administered every 28 days. intervention 3: Placebo 600 mg daily on days 1 to 21 of a 28-day cycle for 26 cycles (approximately 24 months).

Placebo was supplied in the form of 200 mg film-coated tablets taken by mouth.

Protocol document:
Prot_001.pdf: 
Clinical Development 
Ribociclib (LEE011) 
Oncology Clinical Protocol CLEE011G2301 (EarLEE-1) / NCT03078751
An open label, multi-center protocol for U.S. patients enrolled in 
a study of ribociclib with endocrine therapy as an adjuvant 
treatment in patients with hormone receptor-positive, HER2-
negative, high risk early breast cancer 
Authors 
 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2014-001795-53 
Version number 
02 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
17-Apr-2018
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 22-Jul-2016 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 10 
Amendment 2 (17-Apr-2018) ............................................................................................ 14 
Amendment 1 (21-Jun-2017) ............................................................................................ 17 
1 
Background ........................................................................................................................ 19 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 19 
1.1.1 
Epidemiology ........................................................................................ 19 
1.1.2 
Treatment of EBC ................................................................................. 19 
1.1.3 
Role of the CDK4/6 pathway in BC ..................................................... 21 
1.2 
Introduction to investigational treatments and other study treatments .................. 22 
1.2.1 
Overview of ribociclib .......................................................................... 22 
1.2.2 
Overview of adjuvant endocrine therapy .............................................. 25 
2 
Rationale ............................................................................................................................ 27 
2.1 
Study rationale and purpose ................................................................................... 27 
2.2 
Rationale for the study design ............................................................................... 28 
2.3 
Rationale for dose and regimen selection .............................................................. 30 
2.4 
Rationale for choice of combination drugs ............................................................ 30 
2.5 
Rationale for choice of comparators drugs ............................................................ 30 
2.6 
Risks and benefits .................................................................................................. 30 
3 
Objectives and endpoints ................................................................................................... 31 
4 
Study design ...................................................................................................................... 31 
4.1 
Description of study design ................................................................................... 31 
4.1.1 
Screening phase ..................................................................................... 32 
4.1.2 
Treatment phase .................................................................................... 32 
4.1.3 
Follow up phase .................................................................................... 33 
4.2 
Definition of end of study ...................................................................................... 33 
4.3 
Early study termination .......................................................................................... 34 
5 
Population .......................................................................................................................... 34 
5.1 
Patient population .................................................................................................. 34 
5.2 
Inclusion criteria .................................................................................................... 34 
5.3 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 39 


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6.1 
Study treatment ...................................................................................................... 39 
6.1.1 
Dosing regimen ..................................................................................... 40 
6.1.2 
Guidelines for continuation of treatment .............................................. 42 
6.1.3 
Study treatment duration ....................................................................... 42 
6.2 
Dose modifications ................................................................................................ 42 
6.2.1 
Dose modification and dose delay ........................................................ 42 
6.2.2 
Follow-up for toxicities ......................................................................... 46 
6.3 
Concomitant medications ...................................................................................... 48 
6.3.1 
Permitted concomitant therapy ............................................................. 48 
6.3.2 
Permitted concomitant therapy requiring caution ................................. 49 
6.3.3 
Prohibited concomitant therapy ............................................................ 50 
6.3.4 
Other procedures ................................................................................... 51 
6.4 
Patient numbering, treatment assignment or randomization ................................. 51 
6.4.1 
Patient numbering ................................................................................. 51 
6.4.2 
Treatment assignment or randomization ............................................... 51 
6.4.3 
Treatment blinding ................................................................................ 52 
6.5 
Study drug preparation and dispensation ............................................................... 52 
6.5.1 
Study treatment packaging and labeling ............................................... 52 
6.5.2 
Drug supply and storage ........................................................................ 53 
6.5.3 
Study drug compliance and accountability ........................................... 53 
6.5.4 
Disposal and destruction ....................................................................... 54 
7 
Visit schedule and assessments ......................................................................................... 54 
7.1 
Study flow and visit schedule ................................................................................ 54 
7.1.1 
Screening ............................................................................................... 59 
7.1.2 
Treatment period ................................................................................... 61 
7.1.3 
Discontinuation of study treatment ....................................................... 61 
7.1.4 
Follow up for safety evaluations ........................................................... 63 
7.1.5 
Follow-up phase .................................................................................... 63 
7.1.6 
Lost to follow-up ................................................................................... 63 
7.2 
Assessment types ................................................................................................... 63 
7.2.1 
Recurrence assessments ........................................................................ 63 
7.2.2 
Safety and tolerability assessments ....................................................... 64 
7.2.3 
Biomarkers ............................................................................................ 68 
7.2.4 
Resource utilization ............................................................................... 68 
7.2.5 
Patient reported outcomes ..................................................................... 68 
8 
Safety monitoring and reporting ........................................................................................ 68 


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8.1 
Adverse events ....................................................................................................... 68 
8.1.1 
Definitions and reporting ...................................................................... 68 
8.1.2 
Laboratory test abnormalities ................................................................ 70 
8.1.3 
Adverse events of special interest ......................................................... 70 
8.2 
Serious adverse events ........................................................................................... 70 
8.2.1 
Definitions ............................................................................................. 70 
8.2.2 
Reporting ............................................................................................... 71 
8.3 
Emergency unblinding of treatment assignment ................................................... 71 
8.4 
Pregnancies ............................................................................................................ 72 
8.5 
Warnings and precautions ...................................................................................... 72 
8.6 
Data Monitoring Committee .................................................................................. 72 
8.7 
Steering Committee ............................................................................................... 72 
9 
Data collection and management ....................................................................................... 72 
9.1 
Data confidentiality ............................................................................................... 72 
9.2 
Site monitoring ...................................................................................................... 73 
9.3 
Data collection ....................................................................................................... 73 
9.4 
Database management and quality control ............................................................ 74 
10 Statistical methods and data analysis ................................................................................ 75 
10.1 
Interim analysis ...................................................................................................... 75 
10.2 
Sample size calculation .......................................................................................... 75 
11 Ethical considerations and administrative procedures ...................................................... 75 
11.1 
Regulatory and ethical compliance ........................................................................ 75 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 75 
11.3 
Informed consent procedures ................................................................................. 76 
11.4 
Discontinuation of the study .................................................................................. 76 
11.5 
Publication of study protocol and results............................................................... 76 
11.6 
Study documentation, record keeping and retention of documents ....................... 77 
11.7 
Confidentiality of study documents and patient records ....................................... 78 
11.8 
Audits and inspections ........................................................................................... 78 
11.9 
Financial disclosures .............................................................................................. 78 
12 Protocol adherence ............................................................................................................ 78 
12.1 
Amendments to the protocol .................................................................................. 78 
13 References (available upon request) .................................................................................. 80 
14 Appendices ........................................................................................................................ 84 
14.1 
Appendix 1: Guidelines for Anatomic and Prognostic Stage Group III of HR-
positive, HER2-negative Breast Cancer for breast cancer staging (based on 
AJCC Ed. 8th) ......................................................................................................... 84 


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14.2 
Appendix 2: Concomitant medications ................................................................. 86 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 31 
Table 6-1 
Dose and treatment schedule ................................................................. 40 
Table 6-2 
Dose modification guidelines ................................................................ 42 
Table 6-3 
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions ........................................................... 43 
Table 6-4 
Ribociclib dose adjustment and management recommendation for 
hepatic toxicities .................................................................................... 44 
Table 6-5 
Ribociclib dose adjustment and management recommendation for 
QTcF prolongation ................................................................................ 45 
Table 6-6 
Ribociclib dose adjustment and management recommendation for 
all other adverse reactions ..................................................................... 46 
Table 6-7 
Packaging and labeling ......................................................................... 53 
Table 6-8 
Supply and storage of study treatments ................................................ 53 
Table 7-1 
Visit evaluation schedule ...................................................................... 55 
Table 7-2 
Clinical laboratory parameters collection plan (all are done locally 
with the protocol amendment 02) ......................................................... 65 
Table 7-3 
Local clinical laboratory parameters assessment plan .......................... 67 
Table 7-4 
ECG collection plan (all ECGs are performed and assessed locally 
with the protocol amendment 02) ......................................................... 67 
Table 14-1 
AJCC 8th edition Anatomic Stage Groups (not including Group IV 
- all M-category M0) ............................................................................. 84 
Table 14-2 
AJCC 8th edition Prognostic Stage Group III of HR-positive, 
HER2-negative Breast Cancer (all M-category M0) ............................ 84 
Table 14-3 
List of prohibited medications during study drug treatment ................. 86 
Table 14-4 
List of medications to be used with caution during study drug 
treatment ................................................................................................ 87 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
AI 
Aromatase inhibitor 
AJCC 
American Joint Committee on Cancer 
ALND 
Axillary lymph node dissection 
ALP 
Alkaline Phosphatases 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolutely Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
Area Under the Curve 
BC 
Breast cancer 
BCRP 
Breast cancer resistance protein 
BSEP 
Bile salt export pump 
BUN 
Blood Urea Nitrogen 
CABG 
coronary artery bypass graft 
CAP 
College of American Pathologists 
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DDFS 
Distant disease free survival 
DDI 
Drug-Drug Interaction 
DHEA 
dehydroepiandrosterone 
DILI 
Drug-Induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DS&E 
Drug Safety and Epidemiology 
DSS 
Disease-specific survival 
EBC 
Early Breast Cancer 
EBCTCG 
EBC Trialists’ Collaborative Group 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/Record Form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of Treatment 
ER 
Estrogen receptor 
ET 
Endocrine Therapy 
FISH 
Fluorescence in situ hybridization 
FMO3 
flavin-containing monooxygenase 3 
FSH 
Follicle-stimulating hormone 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GnRH 
Gonadotropin-releasing hormone 
HADS 
Hospital Anxiety and Depression Scale 
HBV 
Hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HER2 - 
Human epidermal growth factor receptor 2 negative 
HR 
Hormone Receptor 
HR positive 
Hormone Receptor positive 
HSV 
Herpes Simplex Virus 
i.v. 
intravenous(ly) 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
iDFS 
Invasive disease-free survival 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LRRFS 
Loco-regional recurrence-free survival 
LVEF 
Left Ventricular Ejection Fraction 
MATE1 
multidrug and toxin extrusion protein-1 
MI 
Myocardial infection 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple Gated acquisition 
NaF-PET 
Sodium fluoride positron emission tomography 
NASH 
Non-alcoholic fatty liver disease 
NCI 
National Cancer Institute 
OCT2 
Organic cation transporter 2 
OS 
Overall survival 
p.o. 
per os/by mouth/orally 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 


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PgR 
Progesterone Receptor 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PT 
Prothrombin time 
PVCs 
Premature ventricular contractions 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
Rb 
Retinoblastoma protein 
RBC 
Red Blood Cells 
REB 
Research Ethics Board 
RFS 
Recurrence free survival 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SEER 
Surveillance, Epidemiology, and End Results Program 
SISH 
Silver in situ Hybridization 
SLN 
Sentinel lymph node 
SOP 
Standard Operating Procedure 
TBIL 
Total Bilirubin 
TdP 
Torsades de Pointe 
Tmax 
The time at which the maximum observed concentration (Cmax) occurs 
ULN 
Upper Limit of Normal 
WBC 
White blood cell count 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or study patient 
Control drug 
A study treatment used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate comparative 
effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: 28 days) 
Dose level 
The dose of drug given to the patient (e.g. total daily)  
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 USA Code of Federal Regulations (CFR) 21 Section 312.3 and is 
synonymous with “investigational new drug” 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated placebo 
and active treatment controls (when applicable). This also includes approved drugs 
used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by the 
protocol when used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that was 
not included in the investigational treatment 
Subject Number 
(Subject No.) 
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study 
Phase 
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, treatment, follow up 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm/group assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug 
run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any reason 
Treatment group 
A treatment group defines the dose and regimen or the combination. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points 
Withdrawal of consent 
Withdrawal of consent 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, multi-center protocol for U.S. patients enrolled in a study of ribociclib 
with endocrine therapy as an adjuvant treatment in patients with hormone receptor-
positive, HER2-negative, high risk early breast cancer 
Brief title 
A protocol for U.S. patients enrolled in a study of ribociclib with endocrine therapy 
in patients with hormone receptor-positive, HER2-negative, high risk early breast 
cancer. 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
While adjuvant endocrine therapy (ET) is effective in reducing risk of recurrence in 
patients with hormone receptor (HR)-positive early breast cancer (EBC), 
recurrences are still common, especially in patients with unfavorable clinical, 
pathological and/or molecular features. Ribociclib, a CDK4/6 inhibitor, 
demonstrated clinical efficacy with tolerable toxicity when added to ET in patients 
with HR-positive, HER2-negative advanced breast cancer. 
The purpose of this study is to collect the safety data on the combination of 
ribociclib + ET in HR+, HER2-negative high–risk EBC patients who enrolled in this 
study prior to the early closure of enrollment on 12 Feb 2018.Patients were 
randomized in the US only. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients 
randomized to ribociclib were offered the option to continue treatment with 
ribociclib + ET (excluding tamoxifen) for 26 cycles of ribociclib.  
Primary Objective(s) and 
Key Secondary Objective 
Primary:  
The main objective of the study is to evaluate the preliminary safety and tolerability 
of the ribociclib + ET in patients that were randomized to ribociclib + ET prior to the 
early closure of enrollment. 
Key secondary: none 
Secondary Objectives 
None 
Study design 
This was a randomized, phase III, double-blind, placebo-controlled, multi-center, 
international study to evaluate efficacy and safety of ribociclib with ET as an 
adjuvant treatment in patients with HR-positive, HER2-negative high risk EBC.  
Following the early  closure of enrollment and the protocol amendment 02, the 
study will change to a phase II study conducted in the US only.  
It will include:  
● Screening phase where written informed consent will be collected and all 
eligibility criteria verified (28 days) – this phase has been completed for all patients 
as of 12 February 2018; 
● Treatment phase: Ribociclib patients were randomizedreceive ribociclib 600 mg 
once daily on days 1 to 21 of a 28 day cycle or placebo in combination with 
standard adjuvant ET.  With the early closure of enrollment, all patients were 
unblinded. Patients randomized to placebo + ET permanently discontinued study 
treatment after unblinding. 
After unblinding, patients randomized to ribociclib will receive ribociclib + ET 
treatment for a maximum of 26 cycles (approximately 24 months) or until first 
disease recurrence, intolerable toxicity, withdrawal of consent, death or 
discontinuation from the study treatment for any other reason, whichever is earlier 
ET may start up to 12 weeks before the date of randomization. ET includes orally 
administered, letrozole, anastrozole, or exemestane. In premenopausal women the 
ET will include GnRH agonists (such as goserelin, triptorelin or leuprolide.) 
(Tamoxifen is not permitted as an ET combination partner as of 17 Feb 2018). ET 
should not be changed during treatment with ribociclib unless intolerable toxicity, 
patient’s request, or any other medically-important event that requires change of 
ET.  
Patients will have safety and recurrence assessments while on ribociclib therapy 


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as per protocol. 
All patients, regardless of the reason for treatment discontinuation (except death) 
will be followed for safety for 30 days after the last dose of ribociclib 
● Follow up phase 
With the protocol amendment 02, follow-up phase assessments are no longer 
performed.  
● For each patient randomized to placebo + ET, study participation will end 
following the safety follow-up after the last dose of placebo.  
● For each patient randomized to ribociclib + ET, study participation will end 
following the safety follow up after the last dose of ribociclib.   
● Patients who are during their follow-up phase assessments at the time of the 
protocol amendment 02 will end study participation. 
The study will end when all patients have discontinued ribociclib treatment and 
have undergone the safety follow-up 30 days after the end of treatment (EOT). The 
study is expected to continue for approximately 25 months after the last patient 
randomized to ribociclib completed an end of treatment safety follow-up.   
Population 
The study will include pre- and postmenopausal women with HR-positive, HER2-
negative high risk EBC after adequate surgical resection, radiotherapy (if 
indicated), adjuvant or neo-adjuvant chemotherapy, and who are deemed to be 
eligible for adjuvant ET for at least 60 months of duration. The investigator or 
designee must ensure that only patients who meet all of the following inclusion and 
none of the exclusion criteria are offered treatment in the study. 
Key Inclusion criteria 
No changes were made to the eligibility criteria since all patients were randomized 
prior to the closure of enrollment and the release of the protocol amendment 02. 
● Patient is a female with known menopausal status at the time of initiation of 
adjuvant ET or male adult ≥18 years-old at the time of informed consent 
● Patient with histologically confirmed unilateral primary invasive 
adenocarcinoma of the breast 
● Patient has breast cancer that is positive for estrogen-receptor and/or 
progesterone-receptor (determined on the most recently analyzed tissue sample 
and tested by a local laboratory based on the ASCO-CAP Guidelines (Hammond et 
al 2010)) 
● Patient has HER2-negative breast cancer by local laboratory testing 
● Patient has available archival tumor tissue from the surgical specimen 
● Patient after surgical resection where tumor was removed completely, with the 
final surgical specimen microscopic margins free from tumor, and: 
● 
Patients who received adjuvant chemotherapy and have tumor 
characteristics as defined in the AJCC 8th edition Prognostic Stage Group III 
Note: Categorization into AJCC 8th edition Prognostic Stage Group III requires 
determination of the T- and N-categories, grade of the tumor and ER and PR 
status. Axillary lymph node dissection (ALND) is a preferred method for axillary 
lymph node staging, however sentinel lymph node (SLN) dissection can be 
used to determine the N-category as follows: 
● 
no metastasis in SLN - patient is considered as having N-
category N0, 
● 
at least one tumor metastasis larger than 2.0 mm in 1-2 SLNs in 
a patient with no clinically-detectable lymph nodes, T1-2 tumors, and no 
gross extra-nodal tumor extension - patient is considered as having N-
category N1 (This category of selected patients with metastatic SLN and 
no ALND will be limited to no more than 20% of the accrual total), 
● 
ALND is required to determine the N-category and Prognostic 
Stage Group in all other patients, 
or 
● 
Patients who received neoadjuvant chemotherapy and have 1 or 
more ipsilateral axillary lymph nodes with residual tumor metastases 
greater than 2.0 mm in lymph node(-s) and residual tumor greater than 
10.0 mm in breast tissue surgical specimen 


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● Patient has completed multi-agent adjuvant or neoadjuvant chemotherapy of ≥ 
4 cycles or ≥ 12 weeks in duration which included taxanes in the regimen 
● Patient has completed adjuvant radiotherapy (if indicated) according to the 
institutional guidelines prior to screening 
● Patient has no contraindication for the adjuvant ET and is planned to be treated 
by ET for 5 years or more 
● Patient may already have initiated ET at the time of randomization, but 
randomization must take place within 52 weeks of date of initial histological 
diagnosis of breast cancer and within 12 weeks of initiating standard adjuvant ET. 
Ovarian suppression for fertility preservation is not considered adjuvant ET 
● Patient has an Eastern Cooperative Oncology Group (ECOG) Performance 
Status 0 or 1 
● Patient has adequate bone marrow and organ function per pre-defined criteria 
as assessed by the central lab 
● Patient has, sodium, potassium, phosphorus, magnesium and total calcium 
laboratory values within normal limits 
● QTcF interval (using Fridericia’s correction) < 450 msec and mean resting heart 
rate 50-90 bpm 
Please refer to Section 5.2 for the complete list and all specific details on Inclusion 
Criteria. 
Key Exclusion criteria 
● Patient has received any CDK4/6 inhibitor 
● Patient has received prior treatment with tamoxifen, raloxifene or aromatase 
inhibitors for reduction in risk (chemoprevention) of breast cancer and/or treatment 
for osteoporosis within last 2 years prior to screening 
● Patient has received prior treatment with anthracyclines at cumulative doses of 
450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin 
● Patient with distant metastases of breast cancer beyond regional lymph nodes 
● Patient has not recovered from clinical and laboratory acute toxicities of 
chemotherapy, radiotherapy and surgery (i.e., patient has adverse events 
attributed to prior anti-neoplastic therapy NCI CTCAE version 4.03 grade ≥1 at day 
of enrollment, excluding alopecia and amenorrhea) 
● Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality ( per defined criteria) 
● Clinically significant cardiac arrhythmias 
● Uncontrolled hypertension with systolic Blood Pressure >160 mmHg 
● Patient is currently receiving any of the following prohibited substances and 
cannot be discontinued 7 days prior to Cycle 1 Day 1: concomitant medications, 
herbal supplements, and/or fruits and their juices that are known as strong 
inhibitors or inducers of CYP3A4/5; medications that have a narrow therapeutic 
window and are predominantly metabolized through CYP3A4/5; systemic 
corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully 
recovered from side effects of such treatment; concomitant medications with a 
known risk to prolong the QT interval and/or known to cause Torsades de Pointes 
that cannot be discontinued or replaced by safe alternative medication. 
● Patient has any concurrent severe and/or uncontrolled medical condition that 
would, in the investigators judgment cause unacceptable safety risks, 
contraindicate patient participation in the clinical study or compromise compliance 
with the protocol, or limit life expectancy to ≤5 years 
● Pregnant or breast-feeding (lactating) women or women who plan to become 
pregnant or breast-feed during the study 
● Women of child-bearing potential defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of 
contraception during the study treatment and for 21 days after stopping the study 
treatment. 
Please refer to Section 5.3 for the complete list and all specific details on Exclusion 
Criteria. 
Investigational and 
reference therapy 
During Treatment phase ribociclib will be given orally once a day on days 1-21 of 
each 28 day cycle. Days 22-28 of each cycle will be a “rest” period from ribociclib. 


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Endocrine therapy (ET) will be given orally once a day on a continuous daily 
schedule (e.g., days 1-28 of each 28-day cycle). GnRH agonist (examples include 
but not limited to goserelin, triptorelin or leuprolide) will be given every 4 weeks for 
pre-menopausal women only. There will be no “rest” period in the ET schedule. 
The study drugs will be administered as a flat-fixed dose, and not by body weight 
or body surface area. All oral study treatment drugs must be administered together 
at approximately the same time each day and can be given with or without food. 
Evening or night doses are strongly not recommended. 
Recurrence assessments 
Recurrence (including local, regional, or distant, or contralateral invasive breast 
cancer, or second primary non-breast invasive cancer) will be assessed by 
investigator according to local or institutional standards of care, as clinically 
indicated, or at any time when recurrence is suspected.  
Suspicion of recurrence during clinical evaluation may be evaluated by CT or MRI, 
bone scan, ultrasound, PET, plain X-ray films, or mammography, and maybe 
confirmed by histological (or cytological, when applicable) examination.  
Safety assessments 
● Physical examinations 
● Height, weight, and vital signs 
● 12 lead ECGs 
● Laboratory assessments including hematology, biochemistry, coagulation, 
pregnancy tests (for women of childbearing potential) and urinalysis 
● All adverse events (AEs) will be reported until end of the 30-days safety follow 
up 
Other assessments 
Starting with the protocol amendment 02, tissue and blood samples collection, 
collection of patient questionnaires, and reporting of data regarding hospitalizations 
will no longer be collected. 
Data analysis 
The final data summaries will be reported after all patients discontinue ribociclib 
and complete the safety follow-up assessment 30 days after the last dose of 
ribociclib. 
All key baseline and safety data will be summarized. Additional listings may be 
provided to summarize efficacy data collected. 
Key words 
hormone receptor-positive, HER2-negative, high risk early breast cancer, adjuvant, 
ribociclib, endocrine therapy, CDK4/6, Phase II, estrogen receptor-positive, 
progesterone receptor-positive 


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Amendment 2 (17-Apr-2018) 
Study CLEE011G2301 was initiated on June 20, 2017. On 19 January 2018, a planned safety 
review by the independent Data Monitoring Committee was performed and no safety concerns 
were identified.  
The study had an early enrollment closure on 12 February, 2018; the decision to close 
enrollment was not based on safety concerns. As of 12 February 2018, 54 female patients 
were randomized at sites in the United States (U.S.) only. All randomized patients were 
unblinded; patients randomized to the placebo arm permanently discontinued the study after 
the safety follow-up assessment and patients randomized to the ribociclib arm were offered 
the opportunity to continue investigational treatment with ribociclib + ET for a maximum of 
26 cycles. The decision to continue ribociclib was left to investigator and patient discretion.  
Amendment Rationale 
1. The study was closed to enrollment early. The main purpose of this amendment is to 
evaluate the preliminary safety and tolerability of the ribociclib + ET in patients that were 
randomized to ribociclib + ET prior to the early closure of enrollment, and to allow 
patients randomized to ribociclib + ET to continue treatment for a maximum of 26 cycles 
if desired, based upon investigator and patient decision. Patients were randomized in the 
U.S. only. 
2. In another Novartis study CLEE011E2301 (MONALEESA-7) an imbalance in the QT 
prolongation was observed in the subgroup of patients receiving tamoxifen versus non-
steroidal aromatase inhibitors in combination with ribociclib while the overall safety 
profile was comparable. Specifically, a greater than expected QT prolongation was 
observed in the tamoxifen with placebo group (Tripathy et al 2017). Novartis is continuing 
to analyze the MONALEESA-7 study results to better understand the efficacy and safety 
data of combination of tamoxifen and ribociclib. However, due to availability of 
alternative therapies to tamoxifen in the EarLEE-1 protocol (i.e. letrozole, anastrozole, or 
exemestane), tamoxifen is not permitted to be used in combination with ribociclib in this 
study.  
As of 12 February 2018, there were no patients in the study on treatment by combination 
of tamoxifen and ribociclib.  
3. Changes were introduced to the ribociclib dose adjustment and management 
recommendations in Table 6-5 to mitigate the risk of subsequent QTcF prolongation in 
patients who experienced QTcF prolongation > 480 msec. 
4. Recurrence is assessed periodically by investigator as clinically indicated, or at any time 
when recurrence is suspected according to local or institutional standard of care.  
5. The lists of prohibited medications and medications to be used with caution during study 
drug treatment were updated, along with other updates. 
Changes to the protocol 
Section 1.2, Section 1.2.2.1, Section 2.4, Section 2.5, Section 4.1.2, Section 6.1.1, Table 6.1, 
Section 6.3.4, Section 6.5, Table 6.7 and Table 6.8 are revised to remove tamoxifen. 


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Section 1.2.2 Update with a new clinical data from [CLEE011E2301] (MONALEESA-7) 
study related to tamoxifen. 
Section 2.1, Section 2.2, Section 5.1, Section 6.4.1, Section 6.4.2 and Section 7.1 are revised 
as the enrolment is early terminated. 
Section 2.6, Table 3.1, Section 4.2, Section 6.4.3 and Section 8.3, are revised as the enrolment 
is early terminated and the patients have been unblinded. 
Section 2.2, Section 2.4, Section 2.5, Section 4.1, Section 6.1.1 and section 6.4.2 are revised 
to remove the men as no man has been enrolled at the time of the enrolment termination. 
Section 4.1, Section 4.1.2, Section 4.1.3, Section 4.3, Section 6.1.1, Section 6.1.2, Table 7.1, 
Section 7.1.2 and Section 7.1.5 are revised as the unblinded patients will continue on 
ribociclib + ET arm till end of treatment (26 cycles maximum) and the patient under placebo 
discontinued the study. The follow up phase is removed. 
Table 3-1, Section 4, Section 6, Section 7 and Section 9 are revised as placebo is removed. 
Figure 4-1 has been removed as only patients randomized to ribocilib are in the treatment 
phase and the follow up phase is not applicable anymore. 
Section 4.1.2, Section 6.4.1 and Table 7-1 are revised to remove the use of IRT system at 
randomization as no longer applicable. 
Section 4.1.2, Section 6.1.1, Table 7-1, Section 7.1.3, Section 7.2.1, Table 7-2, Table 7-3, 
Appendix 2 and Appendix 3 are revised as the recurrence is assessed periodically by 
investigator as clinically indicated and no longer be assessed according to the STEEP System. 
Section 4.1.3.1 is revised as the follow up phase is no longer applicable. 
Section 4.3 is revised as the patients have been unblinded and will continue in the study, and 
may have an option to be enrolled in a separate protocol, if applicable, by end of treatment of 
the current study. In addition, the maximal duration of the study has been updated. 
Section 6.1 and Table 6.8 are revised as ET will be supplied locally. 
Table 6.5 is revised for updating Ribociclib/placebo dose adjustment and management 
recommendation for QTcF prolongation. 
Section 7.1.1, Table 7-1, Section 7.2.2 and Section 7.2.2.4 are revised to remove the 
performance status (ECOG). 
Table 7-4 is removed as the performance status (ECOG) is no longer applicable in the study. 
Section 7.2.1 is revised to specify that the recurrence will be assessed by investigator 
according to local or institutional standards of care, as clinically indicated, or at any time 
when recurrence is suspected. 
Section 7.2.2, Section 7.2.5 and Table 7.1 are revised to remove Patient Reported Outcomes 
that are no longer applicable in the study. 
Table 7.9 is removed as PRO assessments are no longer applicable in the study. 
Section 7.2.2.5 and Table 7.5 are revised as all the laboratory assessments will be performed 
locally, and not centrally anymore. 


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Section 7.2.2.6 and Table 7.7 are revised as all the ECGs assessments will be performed 
locally, and not centrally anymore. 
Section 6.2.1.2, Table 7-1, Section 7.2.2.6.1 and Table 7-7 are revised to change triplicate to 
single ECGs. 
Section 7.2.3, Table 7.1 and Section 11.3 are revised to remove Biomarkers that are no longer 
applicable in the study. 
Table 7-8 is removed as Biomarkers are no longer applicable in the study. 
Section 7.2.4 and Table 7.1 are revised as collection of data for healthcare resource utilization 
is no longer performed. 
Section 8.6 and Section 8.7 are revised to remove Data monitoring Committee and Steering 
Committee that are no longer applicable in the study. 
Section 9.3 and Section 9.4 are updated as PRO and Biomarkers data will not be collected 
anymore in the eCRF. 
Section 10 is revised as the data analysis for this study will be limited to key summaries of 
safety and baseline characteristics. The final analysis will be performed after all patients have 
discontinued the study treatment and the safety follow-up. 
Appendix 4, Table 14-4 is revised to remove the strong CYP2D6 inhibitors or inducers (for 
patients receiving tamoxifen) and to update the Medications List with a known risk for QT 
prolongation. 
Appendix 4, Table 14-5 is revised to remove the strong CYP2C9 substrates with NTI (for 
patients receiving tamoxifen) and to update the Medications List with possible risk for QT 
prolongation. 
Appendix 5 is removed as PRO assessments are no longer applicable in the study. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, as required. 
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 1 (21-Jun-2017) 
Study CLEE011G2301 was initiated on June 20, 2017. 
Amendment Rationale 
The main purpose of this amendment is to address the recommendation from the Health 
Authorities to exclude patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency, glucose-galactose malabsorption or soy allergy due to excipients of 
placebo tablets. In addition, minor clarifications to inclusion criterion, study assessments and 
procedures were provided as described below. 
Changes to the protocol 
 Section 4.1.2 and 6.1.1: Clarification was added that when investigators change ET in the 
event of intolerable toxicity, patient’s request, or any other medically important event that 
required change of ET, there is no need to notify Novartis medical monitor. 
 Section 5.2 and Protocol Summary: Inclusion criteria 7 was updated to clarify that patients 
are eligible after surgical resection where tumor was removed completely with the final 
surgical specimen microscopic tumor margins free from tumor. 
 Section 5.3: Exclusion criteria 4 was updated to clarify that patients with a known 
hypersensitivity to any of the excipients of placebo (e.g. rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or soy 
allergy) will not be eligible for the study. 
 Section 6.1 and 6.5.2 (Table 6-8): It was clarified that ET will be sourced locally or will 
be supplied by Novartis or its designee according to local practices and regulations in each 
participating country. 
 Table 7.1: To address inconsistency between Table 7-1 and Table 7-7, clarification was 
provided to Table 7-1 that the ECG assessment is performed at Cycle 7 Day 1 in all 
patients. 
 Section 7.2.2.6: Clarification was added that the ECG assessment should be performed at 
least 3 business days prior to the scheduled randomization date to ensure ECG evaluation 
is received from central laboratory in time for eligibility assessment. Also, patient initials 
will not be collected on ECG tracings. 
 Section 7.2.3.3.1 and Protocol Summary: Clarification was provided to the 
Pharmacogenetics Assessments section that genome-wide association studies (GWAS) 
will include exploration of inherited genetic factors such as CYP3A4 (e.g. CYP3A4 
polymorphism) that may affect the response (both adverse [e.g. neutropenia] and 
therapeutic effects) to treatment. 
 Section 7.2.4: Clarification was added to address the inconsistency between Table 7-1 and 
Section 7.2.4 that healthcare resource utilization data regarding hospitalizations should be 
captured throughout the study treatment phase and post treatment follow up phase. 


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 Section 10.6.2.3.2: Clarification was added that any additional exploratory analysis on 
biomarkers (e.g. CYP3A4 polymorphism) will be detailed in SAP. 
 Section 14.4: List of prohibited medications during study treatment was updated as 
follows; venlafaxine was moved from medications with a known risk for QT prolongation 
category to medications that carry a possible risk for QT prolongation. Loperamide was 
added to the medications that carry a possible risk for QT prolongation. 
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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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Epidemiology 
Breast cancer (BC) is the most frequently diagnosed cancer worldwide. Approximately 1.7 
million new cases of BC and 522,000 deaths attributed to BC were estimated to occur in 2012 
worldwide (Torre et al 2012). BC incidence varies between individuals of different ethnicities 
and in different geographic locations around the world with rates ranging from 27 per 100,000 
in Middle Africa and Eastern Asia to 92 in Northern America (GLOBOCAN 2012). In the 
United States, BC was projected to be the most common cancer diagnosed in 2016 with an 
estimated incidence of 249,260 new cases and 40,890 deaths attributed to BC (Siegel et al 
2016). Estimated incidence of BC in European countries in 2012 was 458,337 (Ferlay et al 
2013). BC in men is not common with a reported frequency of approximately 1% of all BC, 
but the incidence of this disease in men is continuously rising (Eggeman et al 2013). 
The vast majority of newly diagnosed BC cases are early breast cancers (EBC) localized to 
the breast tissue and regional lymphatics and which are potentially curable with locoregional 
treatment modalities, such as surgery and radiation therapy. Based on Surveillance, 
Epidemiology, and End Results Program (SEER) data collected between years 1975 and 2012, 
93% of cases of BC diagnosed were EBC, with 61% limited to the breast tissue and 32% 
localized within the breast tissue and regional lymph nodes (Howlander et al 2015). 
1.1.2 
Treatment of EBC 
Besides primary surgery, management of EBC usually includes additional anti-neoplastic 
treatment modalities such as radiation therapy and adjuvant or neoadjuvant systemic therapy. 
Although many patients with EBC may be rendered disease-free with surgical resection and 
radiotherapy, distant recurrence due to not clinically evident at presentation (“micro-
metastatic”) disease is common and is the primary cause of death in patients with EBC 
(Anampa et al 2015). According to the EBC Trialists’ Collaborative Group (EBCTCG) meta-
analysis of almost 150,000 women in 200 randomized clinical trials, approximately 36% and 
20% of patients with EBC without any adjuvant systemic therapy will experience recurrence 
and death due to BC, respectively, during 5 years of follow up (EBCTCG 2005). Moreover, 
recurrences and BC-related deaths in patients with hormone receptor (HR)-positive EBC 
continue to occur after 5 years from surgery, with only 45% of patients reported to be 
recurrence-free at 15 years of follow-up. 
Adjuvant systemic treatments that comprise cytotoxic, biological and endocrine therapies in 
patients with EBC decrease locoregional and distant recurrences, decrease BC-specific 
mortality and improve overall survival (EBCTCG 2005). The need and selection of systemic 
adjuvant therapies is based on individual risk of recurrence and is guided by several clinical, 
pathological and genomic predictive and prognostic factors of tumor and patient such as 
tumor stage, histopathological grade, tumor HR content, human epidermal growth factor 
receptor-2 (HER2) amplification status, multi-gene testing recurrence scores, menopausal 


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status, patient’s comorbidities, age, and others. Using these factors, EBC can be classified as 
having low, intermediate/moderate or high risk for recurrence after surgery (Anampa et al 
2015). While there is no consensus on definition of these risk groups, generally, patients with 
smaller tumors, no metastasis in regional lymph nodes, low tumor grade, HR-positive and 
HER2-negative status, and low recurrence genomic score have also low risk of recurrence (i.e., 
5-10% recurrences at 5-years). These patients are usually considered for adjuvant endocrine 
treatment, without chemotherapy, due to a lower clinical benefit of latter versus the former. 
On the other hand, patients with metastases in multiple regional lymph nodes, high tumor 
grade, HER2-positive status or high recurrence genomic score have a higher risk of recurrence 
if not treated. These patients are usually considered for adjuvant chemotherapy (HER2 
targeting agents are offered to patients with HER2-positive BC), and if the tumor expressed 
HR, endocrine adjuvant therapy is considered too (usually delivered after the completion of 
chemotherapy). Complexity and importance of risk definition in EBC reflected in the recent 
8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging System for 
patients with breast cancer (Hortobagyi et al 2017). This Staging System included 
pathological features (i.e. histopathological grade) and biomarkers status (hormone receptors 
and HER2) in addition to anatomic spread of the tumor (i.e. specific T-, N- and M-categories) 
to define prognostic stage groups that have similar treatment approaches and prognosis 
(survival) of patients treated with current standard multimodality treatment (Amin 2016). 
Chemotherapy to reduce recurrence risk can be administered preoperatively too. While no 
significant difference in long-term outcomes between adjuvant and neoadjuvant 
chemotherapy was found, neoadjuvant chemotherapy increases rates of breast conservation by 
downsizing large tumors and may provide important prognostic information based on 
response to the therapy (Mauri et al 2005). For example, extent of residual disease after 
neoadjuvant chemotherapy correlates with disease-specific survival (DSS) when patients with 
less than complete pathological response tend to have a higher disease-specific mortality and 
patients with residual disease in lymph nodes had poorer outcomes than patients with residual 
disease in the breast tissue only (Jeruss et al 2008). 
It is estimated that 75% of BC express receptors for steroid hormones (estrogen and/or 
progesterone) (Hammond et al 2010), and therefore may benefit from endocrine therapy with 
tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole or exemestane). Endocrine 
therapy (ET), independent of chemotherapy, reduces the risk of recurrence and BC deaths in 
HR-positive EBC (EBCTCG 2005). Current clinical guidelines for adjuvant ET in the HR-
positive EBC recommend for premenopausal women use of (1) 5-10 years of tamoxifen with 
or without ovarian suppression (ovarian suppression is recommended for women with high 
risk for recurrence after adjuvant chemotherapy), or (2) 5 years of AI with ovarian 
suppression. Clinical guidelines and expert opinions recommend for postmenopausal women, 
either (1) initial AI for 5 years (or up to 10 years, based on recently reported results of 
MA.17R, a randomized clinical trial of extending adjuvant letrozole for 5 years after 
completing initial 5 years (Goss et al 2016)), or (2) initial tamoxifen for 2-3 years followed by 
AI either to up to total 5 years, or up to 5 years of treatment with AI, or (3) tamoxifen for ~5 
years followed by 5 years of AI, or (4) tamoxifen up to 10 years (Gradishar et al 2016; Senkus 
et al 2016). Limited data on EBC in men suggest that tamoxifen without gonadotropin-
releasing hormone (GnRH) agonist should be the ET of choice for HR-positive, HER2-
negative EBC (Fentiman et al 2006; Eggeman et al 2013; Sousa et al 2013). 


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In spite of extensive research and recent advances in a multimodality management of EBC, 
recurrences are still common, especially in patients with adverse clinical, pathological and 
genomic features. Approximately 25%-30% of patients with HR-positive, HER2-negative 
EBC with multiple (≥4) metastatic regional lymph nodes will recur within 5 years with the 
therapy that includes AIs (EBCTCG 2015). In addition, worse clinical outcomes are observed 
in patients with EBC that had residual disease in lymph nodes after neoadjuvant 
chemotherapy (Mittendorf et al 2011). Therefore, new therapeutic strategies are required to 
improve clinical outcomes in patients with high risk EBC. 
1.1.3 
Role of the CDK4/6 pathway in BC 
While 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. 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 


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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 14.5 months 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-naive 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, 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. 
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, and it should be explored in the adjuvant setting too. 
1.2 
Introduction to investigational treatments and other study 
treatments 
This study includes treatments with ribociclib (LEE011), tamoxifen, anastrozole, letrozole, 
exemestane, and GnRH agonist (such as goserelin, triptorelin or leuprolide). 
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. 
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 


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mucosa (atrophy), the kidney (concurrent degeneration and regeneration of tubular epithelial 
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 being investigated in patients with BC 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 being evaluated in several phase I and III combination trials. The 
recommended dose of ribociclib in combination with these agents was declared as 600 mg 
once daily on days 1-21 of a 28 day cycle schedule. 
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. Four patients (1.2%) met the 
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returning to normal values after treatment discontinuation. Eleven patients (3.3%) presented 
on treatment QTcF prolongation >480 msec. Serious AEs were reported in 21.3% of patients 
in the ribociclib arm with 7.5% of serious AEs deemed by investigators as treatment-related. 
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). 
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 (CV%). 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. 
Ribociclib undergoes extensive hepatic metabolism via CYP3A in humans based on in vitro 
and in vivo studies. Ribociclib is mainly eliminated via hepatic clearance, with renal clearance 
playing a lesser role in humans. The majority of the administered dose was excreted in feces 
(69.1%), with a minor amount excreted in urine (22.6%). Ribociclib accounted for 
approximately 23% of the total radioactivity in plasma ([CLEE011A2102]). The most 
prominent metabolites in plasma are CCI284 (N-hydroxylation), LEQ803 (N-demethylation), 
and M1 (secondary glucuronide), each representing <10% of total radioactivity. The clinical 
activity (pharmacological and safety) of ribociclib is primarily due to parent drug, with a 
negligible contribution from circulating metabolites. 
Concomitant use of ribociclib with strong CYP3A4 inhibitors or strong CYP3A4 inducers 
should be avoided as ribociclib exposure may be markedly affected. Co-administration of a 


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strong CYP3A4 inhibitor (ritonavir) increased ribociclib AUC by 3.2-fold following a single 
oral dose of 400 mg ribociclib ([CLEE011A2101]). Co-administration of a strong CYP3A4 
inducer (rifampicin) decreased ribociclib AUCinf by 89% following a single oral dose of 600 
mg ribociclib ([CLEE011A2101]). 
Ribociclib is a moderate to strong inhibitor of CYP3A4, but did not have a substantial effect 
on CYP1A2 substrates in humans ([CLEE011A2106]). Co-administration of midazolam 
(CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased midazolam 
exposure by 3.8-fold. Co-administration of caffeine (CYP1A2 substrate) with multiple doses 
of ribociclib (400 mg) increased caffeine exposure by 20% (1.2-fold). Concurrent use of 
sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. Concurrent 
use of CYP1A2 substrates is not expected to lead to clinically important DDIs. 
Food does not affect the PK of ribociclib administered as a capsule or tablet formulation; 
therefore ribociclib capsules or tablets can be taken without regard to meals 
([CLEE011A2111], [CLEE011A2103]). 
Refer to the most recent [Ribociclib Investigator’s Brochure] for additional details. 
1.2.2 
Overview of adjuvant endocrine therapy 
Tamoxifen and AIs letrozole, anastrozole and exemestane are used for adjuvant use in women 
with HR-positive early breast cancer. AIs can be used either as an upfront therapy or after 2-3 
or 5 years of prior tamoxifen (see Section 1.1.2). The long-term efficacy of both approaches 
of AIs administration is similar (EBCTCG 2015). Clinical treatment guidelines suggest that 
there is no compelling evidence showing meaningful clinical efficacy or toxicity differences 
between the letrozole, anastrozole and exemestane (Gradishar et al 2016), therefore similar 
precautions and monitoring activities should apply irrespective of type of AI administered. 
GnRH agonists are used to achieve ovarian suppression in premenopausal women. Tamoxifen 
(without GnRH agonist) is the adjuvant therapy of choice for men with HR-positive EBC (see 
Section 1.1.2).  
In another Novartis study CLEE011E2301 (MONALEESA-7) an imbalance in the QT 
prolongation was observed in the subgroup of patients receiving tamoxifen versus non-
steroidal aromatase inhibitors in combination with ribociclib while the overall safety profile 
was comparable. Specifically, a greater than expected QT prolongation was observed in the 
tamoxifen with placebo group (Tripathy et al 2017). Novartis is continuing to analyze the 
MONALEESA-7 study results to better understand the efficacy and safety data of 
combination of tamoxifen and ribociclib. However, due to availability of alternative therapies 
to tamoxifen in the EarLEE-1 protocol (i.e. letrozole, anastrozole, or exemestane), tamoxifen 
is not permitted to be used in combination with ribociclib in this study. 
1.2.2.1 
Overview of letrozole 
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole 
acts by highly selective inhibition of conversion of androgens (mainly from adrenal glands, 
the primary source of estrogens in postmenopausal women) to estrogens. Letrozole induces a 
75% to 95% decrease of estrogen levels after two weeks of treatment with daily doses of 0.1 


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to 5 mg, with no significant clinical and laboratory toxicities or changes in levels of other 
hormones of the endocrine system (Lipton et al 1995; Trunet et al 1996). 
Letrozole is administered orally once daily at a dose of 2.5 mg. It is rapidly and completely 
absorbed from the gastrointestinal tract. Concomitant intake of food has no effect on the 
extent of letrozole absorption. Letrozole is metabolized via CYP3A4 to a pharmacologically-
inactive metabolite and renal excretion of the glucuronide conjugate of this metabolite is the 
major pathway of letrozole clearance. 
Letrozole (2.5 mg daily) and ribociclib (600 mg, qd, 3 weeks on/1 week off) did not affect 
metabolism of each other in a phase Ib/II dose escalation/expansion study ([CLEE011X2107]). 
Additionally, in a phase III study ([CLEE011A2301]), ribociclib had no effect on letrozole 
PK based on a comparison of letrozole PK data between treatment groups. 
The most frequently reported AEs for letrozole in the adjuvant and extended adjuvant clinical 
trials were hot flashes, arthralgia/arthritis and myalgia. In general, the observed adverse 
reactions were mild to moderate in intensity. Adjuvant use of letrozole is associated with a 
decrease in bone mass density which may lead to osteoporosis and associated bone fractures. 
Consideration should be given to monitoring bone mass density. 
Due to its mechanisms of action, letrozole, as well as other AIs, should not be used for above-
mentioned indications in women with an intact ovarian function or in non-castrated men. 
Refer to the most recent regional prescribing information for more information on letrozole. 
1.2.2.2 
Overview of anastrozole 
Anastrozole, like letrozole, is a selective non-steroidal AI. It significantly lowers serum 
estradiol concentrations with no detectable effect on formation of adrenal corticosteroids or 
aldosterone. 
Anastrozole is administered orally once daily at a dose of 1 mg, taken with or without food. 
Anastrozole is metabolized by N-dealkylation, hydroxylation and glucuronidation. Hepatic 
metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination 
accounts for approximately 10% of total clearance. The major circulating metabolite of 
anastrozole lacks pharmacologic activity. Anastrozole metabolism occurs mainly via CYP3A4 
and UGT1A4 based on in vitro data (Edevana et al 2013). Therefore, anastrozole metabolism 
may potentially be affected by co-administration with ribociclib. However, anastrozole has 
been studied up to doses of 10 mg/day (10-times daily dose) and all doses evaluated were well 
tolerated with no serious acute toxicities attributed to anastrozole (Plourde et al 1995). 
Refer to the most recent regional prescribing information for more information on anastrozole. 
1.2.2.3 
Overview of exemestane 
Exemestane is a steroidal irreversible AI that is initially recognized by the aromatase enzyme 
as a false substrate and is then transformed through an NADPH-dependent mechanism to an 
intermediate that binds irreversibly to the enzyme, causing inactivation. Exemestane 
significantly lowers circulating estrogen concentrations (estradiol, estrone and estrone sulfate), 
but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone (Goetz et 
al 2015). 


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The recommended daily dose of exemestane is 25 mg via oral administration after a meal. 
Exemestane is rapidly absorbed from the gastrointestinal tract. Its bioavailability is limited by 
first-pass metabolism, but is increased when taken with food. Exemestane is metabolized by 
CYP3A4 and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, 
including CYP1A2, 2C9, 2D6, 2E1 and 3A4 (Buzdar 2003). 
Although no formal drug-drug interaction studies have been conducted, significant effects on 
exemestane clearance by CYP isoenzyme inhibitors appear unlikely. The most frequently 
reported adverse effects for exemestane are gastrointestinal disturbances, hot flushes, 
arthralgia, myalgia, sweating, fatigue, and dizziness. Reductions in bone mineral density can 
occur with long-term use of exemestane. Exemestane is generally well tolerated, and AEs are 
usually mild to moderate. Androgenic effects were reported in a limited number of patients 
(Buzdar 2003). 
Refer to the most recent regional prescribing information for more information on exemestane. 
1.2.2.4 
Overview of GnRH agonists 
GnRH agonists are synthetic analogues of gonadotropin-releasing hormone that by continuous 
stimulation of the GnRH receptor achieve desensitization of the pituitary gland to GnRH. 
GnRH agonists differ from the naturally-occurring GnRH by modification(-s) in the 
decapeptide structure (usually by amino acid substitution in position 6, but also in positions 9 
and 10) to decrease degradation of the molecule. Examples for GnRH agonists for use in this 
study include but not limited to goserelin, triptorelin or leuprolide. One-month depot 
formulation of GnRH agonists must be used to 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 goserelin (one of the GnRH agonists) 
included hot flushes, headache, sweating, acne, emotional lability, depression, decreased 
libido, vaginitis, breast atrophy, seborrhea and peripheral edema. 
Refer to the most recent regional prescribing information and/or clinical guidelines for more 
information on GnRH agonists. 
2 
Rationale 
2.1 
Study rationale and purpose 
While adjuvant ET for HR-positive EBC is effective in reducing risk of recurrence and 
improving survival, recurrences are still common, especially in patients with unfavorable 
clinical, pathological and/or molecular features. These recurrences, mostly in the form of 
distant metastases, are usually incurable and will eventually translate into BC deaths. 
Since addition of CDK4/6 inhibitor ribociclib to ET has proven clinical efficacy with tolerable 
toxicity profile in HR-positive, HER2-negative advanced BC, its use in the adjuvant setting 
may decrease risk of recurrences in patients with HR-positive, HER2-negative EBC with high 
risk for presence of micro-metastatic disease after surgical resection of the primary tumor by 


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enhancing primary endocrine responsiveness and preventing, or delaying the development of 
acquired resistance for ET. 
Therefore, the purpose of this study was to evaluate the effect of addition of ribociclib to 
standard adjuvant ET on invasive disease-free survival (iDFS) in patients with HR-positive, 
HER2-negative EBC with adverse clinical and/or pathological features that predispose 
patients for an increased risk of recurrence. 
The study enrollment was early closed on 12 February 2018. All randomized patients were 
unblinded; patients randomized to placebo permanently discontinued study treatment and 
patients randomized to ribociclib were offered the option to continue treatment with ribociclib 
+ ET (excluding tamoxifen). The purpose of this amended protocol is to evaluate the 
preliminary safety data on the combination of ribociclib + ET in HR+, HER2-negative high-
risk EBC patients who enrolled in this study prior to the early closure of the enrollment and to 
allow patients randomized to ribociclib + ET to continue treatment with ribociclib + ET for a 
maximum of 26 cycles as long as they stay on study. 
2.2 
Rationale for the study design 
This was a phase III, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the addition of ribociclib to standard adjuvant ET in patients with HR-positive, 
HER2-negative high risk EBC. 
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen). 
The study included pre- and postmenopausal women with HR-positive, HER2-negative EBC 
that have high risk of recurrence (“high risk EBC”) after standard multimodality therapy. 
Pre-menopausal women were included in addition to post-menopausal women since major 
differences in efficacy and safety of ribociclib are not expected in these populations of 
patients. In planned subgroup analysis of the palbociclib phase III clinical trial of fulvestrant 
with ribociclib vs fulvestrant with placebo in patients with advanced HR-positive, HER2-
negative BC (ovarian suppression was achieved with goserelin in pre-/perimenopausal 
patients in both arms), no differences in efficacy and safety profile were observed in pre-
/perimenopausal vs postmenopausal patients (Turner et al 2015; Loibl et al 2016). In addition, 
palbociclib did not alter ovarian function suppression and PFS in pre-/perimenopausal patients 
was not significantly associated with plasma estrogen (E2) levels (Loibl et al 2016). To 
mitigate potential differences between pre- and postmenopausal women in this study, 
randomization by a menopausal status will be employed. 
Patients with high risk for recurrence included in this study are the following two groups (the 
rationale for including each group is provided below): 
1. Patients who received adjuvant chemotherapy and have tumor characteristics as defined in 
the AJCC 8th edition Prognostic Stage Group III (see Table 14-1 in Appendix 1) 
Note: Categorization into AJCC 8th edition Prognostic Stage Group III requires 
determination of the T- and N-categories, grade of the tumor, and ER and PR status. 
Axillary lymph node dissection (ALND) is a preferred method for axillary lymph node 


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staging, however sentinel lymph node (SLN) dissection can be used to determine the N-
category as follows: 
 no metastasis in SLN - patient is considered having N-category N0, 
 at least one tumor metastasis larger than 2.0 mm in 1-2 SLNs in a patient with no 
clinically-detectable lymph nodes, T1-2 tumors, and no gross extra-nodal tumor 
extension - patient is considered having N-category N1, 
 ALND is required to determine the N-category and Prognostic Stage Group in all 
other patients. 
2. Patients who received neoadjuvant chemotherapy and have 1 or more ipsilateral axillary 
lymph nodes with residual tumor metastases greater than 2.0 mm in lymph node(-s) and 
residual tumor greater than 10.0 mm in breast tissue surgical specimen. 
The rationale for including patients with the AJCC 8th edition Prognostic Stage Group III in 
the adjuvant trial of high-risk EBC is based on the fact that Prognostic Stage Groups that 
incorporate anatomical staging (i.e. T-, N- and M-categories) with histopathological grade and 
biomarker status (i.e. HR and HER2 status) predict prognosis after standard multimodality 
treatment (including adjuvant chemotherapy and ET) better than classification based solely on 
the anatomic extent of the disease (Hortobagyi et al 2017). 
Recently, SLN dissection without subsequent ALND in case of metastatic SLN became 
acceptable practice in selected patients following the results of the ACOSOG Z0011 clinical 
trial where patients with metastatic SLN were randomized to either ALND or no additional 
surgery. The trial demonstrated comparable 5-y disease-free survival (83.9% vs 82.2% in 
SLN dissection only and SLN dissection followed by ALND, respectively) and OS (92.5% vs 
91.8%, respectively) between the two arms and less surgical co-morbidity with SLN 
dissection only (Giuliano et al 2011). This approach has been recommended by several 
clinical guidelines and consensuses (Coates et al 2015; Senkus et al 2015; Gradishar et al 
2016; Lyman et al 2016). Since in the ALND arm of Z0011 ~85% of patients had N1 disease 
(Giuliano et al 2011), patients who conform with the trial eligibility criteria (T1-2, <3 
metastatic SLNs, no clinically-evident nodal disease before the surgery, no gross extranodal 
tumor extension, no neoadjuvant systemic therapy, and were treated with lumpectomy with 
adjuvant radiotherapy) can be considered as having N-category N1 for the purpose of 
assignment these patients to the AJCC 8th edition Prognostic Stage Group. 
The rationale for including patients treated with neoadjuvant chemotherapy is that 
neoadjuvant chemotherapy is one of the recommended treatment options for patients with 
EBC (see Section 1.1.2). To be eligible for this trial, patients treated by neoadjuvant 
chemotherapy has to have residual tumors in lymph nodes and breast tissue, since these 
characteristics were shown to be associated and/or predictive for high risk for recurrence (von 
Minckwitz et al 2012) and worse DSS (Jeruss et al 2008). 
Randomization will be stratified by a menopausal status, stage group and geographical region 
(see Section 4.1). Menopausal status was selected as a stratification factor since it may reflect 
different treatment choices and prognosis. Premenopausal women will be combined with men 
in the same stratum since both men and premenopausal women may have higher recurrence 
rate compared to postmenopausal women and number of men is expected to be small to make 


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it as a separate stratum. During the randomization, patients with metastatic SLN(-s) and no 
ALND will be limited to no more than 20% of the accrual total. 
The primary efficacy of the investigational intervention will be evaluated by its effect on the 
iDFS as it is defined in the STEEP System for Standardized Definitions for Efficacy End 
Points in Adjuvant Breast Cancer Trials (Hudis et al 2007). The definition of iDFS in the 
STEEP System is broad, clinically-relevant and includes the most commonly accepted DFS 
events used in published trials for EBC. 
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 1.1.2). In this trial, ET that is combined with ribociclib or 
placebo will be administered according to local clinical guidelines and regional prescribing 
information. 
Due to a protracted pattern of recurrences of HR-positive, HER2-negative EBC, with the 
majority of events observed starting from a year after the surgery (EBCTCG 2015), a short 
duration (i.e. ≤12 months) of ribociclib treatment might not be sufficient for a meaningful 
impact on recurrence rate of EBC. In order to provide sufficient ribociclib exposure while 
balancing potential toxicity of prolonged treatment with the medication, ribociclib (or placebo; 
both in combination with the ET) will be administered for 26 cycles (approximately 24 
months) in this study. 
2.4 
Rationale for choice of combination drugs 
Preclinical and clinical data of co-administration of ET with ribociclib showed that 
combinations with ET are efficacious in HR-positive, HER2-negative advanced BC, and have 
reversible and manageable toxicities (see Section 1.2). 
Ribociclib will be combined with the standard ET that has been approved for adjuvant 
treatment of EBC and will include either letrozole, anastrozole, or exemestane, with GnRH 
agonist (in premenopausal women only) administered according to the local clinical 
guidelines and regional prescribing information (see Section 1.1.2). In premenopausal women 
with high risk EBC, ET will include ovarian suppression by GnRH agonist. GnRH agonist 
will be administered every 4 weeks subcutaneously. 
2.5 
Rationale for choice of comparators drugs 
Since, all patients randomized to placebo discontinued study participation at the end of safety 
follow up, this section is longer applicable.  
2.6 
Risks and benefits 
Based on preclinical and clinical data, treatment of ribociclib in combination with ET is 
expected to be tolerable and toxicities of the treatment are expected to be manageable and 
reversible upon dose reduction, treatment interruption or discontinuation. 


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Patients in this study will be carefully monitored for key toxicities that have been observed 
with ribociclib (see Section 1.2.1) or endocrine treatments (see Section 1.2.2). Risk will be 
further minimized by adherence to inclusion/exclusion selection criteria (see Section 5), 
avoidance of prohibited medication (see Section 6.3.3), close safety monitoring (see Section 8) 
and dose adjustment guidelines (see Section 6.2). 
Since the study was closed to enrollment and all patients were unblinded, the Novartis study 
team will monitor safety in conjunction with the Novartis Safety Management Team.  
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10 
To evaluate the preliminary safety and 
tolerability of the ribociclib + ET in patients 
that were randomized to ribociclib + ET 
prior to the early closure of enrollment. 
Tolerability and Safety of the 
treatment regimen based on 
frequency and severity of AEs, 
laboratory and ECG abnormalities 
 
The study has an early enrollment closure. All randomized patients were unblinded. Health related quality of life, 
hospital resource utilization, blood and tissue samples for biomarkers will no longer be collected and analyzed.  
4 
Study design 
4.1 
Description of study design 
This was a randomized, phase III, double-blind, placebo-controlled, multi-center, international 
study to evaluate efficacy and safety of ribociclib with ET as an adjuvant treatment in patients 
with HR-positive, HER2-negative, high risk EBC. 
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen). Patients randomized to placebo have to complete 30-day safety follow up after the 
last dose of placebo. 
Following the protocol amendment 02, this study is an open label, multi-center phase II 
conducted in the US only. 
The study will include 
 Screening phase (28 days); this phase has been completed for all patients as of 12 
February 2018 
 Treatment phase composed of 26 cycles of ribociclib treatment (approximately 24 months) 
in combination with ET (where treatment with ET may start up to 12 weeks before the 
date of randomization) and 30 days safety follow up from last dose of ribociclib; 


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 During treatment phase, patients will be treated with combination of ribociclib + ET for a 
maximum of 26 cycles or until disease recurrence, intolerable toxicity, withdrawal of consent, 
or discontinuation from the study treatment for any other reason, whichever is earlier. 
Starting with the protocol amendment 02, post-treatment follow-up phase assessments are not 
performed. For each patient randomized to placebo + ET, study participation will end 
following the safety follow-up after the end of treatment (EOT) within 30 days from the last 
dose of placebo. For each patient randomized to ribociclib + ET, study participation will end 
following the safety follow-up after the EOT after the last dose of ribociclib. Patients in 
follow-up phase will end study participation following the protocol amendment 02. 
4.1.1 
Screening phase 
Pre- or post-menopausal women with high risk HR-positive, HER2-negative EBC who 
provided written informed consent will be screened for eligibility during the period up to 28 
days immediately prior to starting ribociclib or placebo in combination with the standard 
adjuvant endocrine therapy (ET) prescribed by the investigator (tamoxifen, letrozole, 
anastrozole, or exemestane, with GnRH agonist for premenopausal women; only tamoxifen 
will be allowed to be used in men). ET may start ≤ 12 weeks prior to randomization. 
During the screening phase the investigator must: 
 Obtain signed informed consent from the patient prior to any study procedures 
 Assess the inclusion and exclusion criteria as detailed in Section 5 
 Perform all screening procedures as detailed in Table 7-1 
Results of all screening/baseline evaluations must be reviewed by the investigator or his/her 
designee prior to enrollment of each patient into the study to assure that all inclusion and 
exclusion criteria have been satisfied. 
4.1.2 
Treatment phase 
Ribociclib will be given orally once a day on days 1 to 21 in each 28 day cycle. Standard 
adjuvant ET will be administered according to the local clinical guidelines and regional 
prescribing information. Acceptable ET in women includes letrozole 2.5 mg by mouth daily, 
or anastrozole 1 mg by mouth daily, or exemestane 25 mg by mouth daily. In premenopausal 
women, ET, besides AI, should include a GnRH agonist administered every 4 weeks 
(examples include but not limited to goserelin, triptorelin or leuprolide). Patients receiving 
GnRH agonist should be regularly monitored per local institutional clinical guidelines to 
confirm a postmenopausal value of gonadotropin and sex hormones according to local 
laboratory ranges. 
Study treatment will continue until completion of a maximum of 26 cycles of ribociclib 
treatment (approximately 24 months), first recurrence (any of the following or combination of 
local, regional or distant recurrences, or contralateral invasive breast cancer, or second 
primary non-breast invasive cancer), intolerable toxicity, withdrawal of consent by the patient, 
patient is lost to follow up, death, or discontinuation from the study treatment due to any other 
reason or the sponsor terminates the study, whichever is earlier. 


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During treatment with ribociclib, investigators will not be allowed to change ET unless 
intolerable toxicity, patient’s request, or any other medically-important event that requires 
change of ET (Investigator should clearly document in the eCRF the reason for changing of 
ET during the treatment with ribociclib. After end of treatment with ribociclib no further 
information will be collected after the safety follow-up assessment 30 days after the last dose 
of ribociclib. Patients who permanently discontinue adjuvant ET for any reason and do not re-
initiate any adjuvant ET, must discontinue ribociclib and complete the safety follow-up 30 
days from the last dose of ribociclib. Patients who permanently discontinue ribociclib, will 
undergo the safety follow-up assessment for 30 days after the last dose of ribociclib 
assessments. 
Recurrence will be assessed by the investigator periodically as clinically indicated, or at any 
time when recurrence is suspected. The end of the study for a given patient is defined when 
the patient permanently discontinues ribociclib and all the end of trial procedures for that 
individual patient are completed at the end of the safety follow-up assessment. 
Safety will be assessed for each patient until 30 days after the last dose of ribociclib and will 
include routine safety monitoring except in case of death, loss to follow up or withdrawal of 
consent. 
4.1.3 
Follow up phase 
4.1.3.1 
Post treatment follow-up 
Starting with the protocol amendment 02, follow-up phase assessments are not performed.  
4.1.3.2 
Survival follow up 
Starting with the protocol amendment 02, survival follow up will not be performed. 
The end of the study for a given patient is defined when the patient permanently discontinues 
study specified treatments  and all the end of trial procedures for that individual patient are 
completed. For a patient randomized to placebo + ET, study participation will end following 
the safety follow-up after the end of treatment (EOT) after the last dose of placebo. For 
patient randomized to ribociclib + ET, study participation will end following the safety 
follow-up within 30 days from the last dose of ribociclib.   
4.1.3.3 
Timing of interim analyses and design adaptations 
Following early enrolment closure and unblinding of the patients’ randomization arm, the 
interim analyses are no longer planned. The final data analysis is planned to be performed 
after all patients discontinue the ribociclib treatment and complete the safety follow-up 
assessment 30 days after the last patient’s last dose of ribociclib. 
4.2 
Definition of end of study 
The end of study will be declared after all patients have discontinued ribociclib treatment  and 
completed the safety follow-up period (until 30 days after last dose of ribociclib. The end of 
study may be declared also when the last patient on treatment has been enrolled in another 


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Novartis-sponsored protocol that will allow treatment continuation for patients who benefited 
from the study treatment with ribociclib. 
The study is expected to continue for maximum approximately 25 months (24 months + 30 
day follow-up) and will end once the last patient randomized to ribociclib has completed 
safety their follow-up safety assessment within 30 days after the last dose of ribociclib.  
4.3 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
5 
Population 
5.1 
Patient population 
The study includes men and pre- and postmenopausal women with HR-positive, HER2-
negative high risk EBC after adequate surgical resection, radiotherapy (if indicated), adjuvant 
or neo-adjuvant chemotherapy, and who are deemed to be eligible for adjuvant ET for at least 
60 months of duration. 
The patients are not permitted to participate in any additional parallel investigational drug or 
device studies. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.  
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen). 
5.2 
Inclusion criteria 
The protocol includes patients that were eligible under following eligibility criteria. 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Patient is a female with known menopausal status at the time of initiation of (neo-) 
adjuvant therapy/GnRH agonist or male adult ≥18 years-old at the time of informed 
consent 
Note: Postmenopausal status is defined when: 
 patient underwent bilateral oophorectomy, or 
 age ≥ 60 years, or 


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 age < 60 years and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, or ovarian suppression) and FSH and plasma estradiol are 
in the postmenopausal ranges per local normal range, or 
 For women with therapy-induced amenorrhea, serial measurements of FSH and/or 
estradiol per local clinical guidelines are required for determination of 
postmenopausal status 
All non postmenopausal women are considered premenopausal 
3. Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the 
breast 
4. Patient has breast cancer that is positive for estrogen-receptor and/or progesterone-
receptor (determined on the most recently analyzed tissue sample and tested by a local 
laboratory based on the ASCO-CAP Guidelines (Hammond et al 2010)) 
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 (based on the most recently analyzed tissue sample and all tested by 
a local laboratory) 
6. Patient has available archival tumor tissue from the surgical specimen 
7. Patient after surgical resection where tumor was removed completely, with the final 
surgical specimen microscopic margins free from tumor, and: 
 Patients who received adjuvant chemotherapy and have tumor characteristics as 
defined in the AJCC 8th edition Prognostic Stage Group III (see Table 14-2 in 
Appendix 1) 
Note: Categorization into AJCC 8th edition Prognostic Stage Group III requires 
determination of the T- and N-categories, histopathological grade of the tumor and 
ER and PR status. ALND is a preferred method for axillary lymph node staging, 
however SLN dissection can be used to determine the N-category as follows: 
 no metastasis in SLN - patient is considered as having N-category N0, 
 at least one tumor metastasis larger than 2.0 mm in 1-2 SLNs in a patient with no 
clinically-detectable lymph nodes, T1-2 tumors, and no gross extra-nodal tumor 
extension - patient is considered as having N-category N1. (This category of 
patients with metastatic SLN and no ALND will be limited to no more than 20% 
of the total accrual), 
 ALND is required to determine the N-category and Prognostic Stage Group in all 
other patients, 
or 
 Patients who received neoadjuvant chemotherapy and have 1 or more ipsilateral 
axillary lymph nodes with residual tumor metastases greater than 2.0 mm in lymph 
node(-s) and residual tumor greater than 10.0 mm in breast tissue surgical specimen 
8. Patient has completed multi-agent adjuvant or neoadjuvant chemotherapy of ≥ 4 cycles or 
≥ 12 weeks in duration which included taxanes in the regimen 
9. Patient has completed adjuvant radiotherapy (if indicated) according to the institutional 
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10. Patient has no contraindication for the adjuvant ET and is planned to be treated by ET for 
5 years or more 
11. Patient may already have initiated ET at the time of randomization, but randomization 
must take place within 52 weeks of date of initial histological diagnosis of breast cancer 
and within 12 weeks of initiating standard adjuvant ET. Ovarian suppression for fertility 
preservation is not considered adjuvant ET 
12. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
13. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory for eligibility): 
 Absolute neutrophil count ≥ 1.5 × 109/L 
 Platelets ≥ 100 × 109/L 
 Hemoglobin ≥ 9.0 g/dL 
 Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault 
formula. 
 Alanine transaminase (ALT) ≤ 1.5 × ULN 
 Aspartate transaminase (AST) ≤ 1.5 × ULN 
 Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin ≤ 
1.5 × ULN of the central laboratory in patients with well documented Gilbert’s 
Syndrome 
 International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving 
anticoagulants and the INR is within the therapeutic range of intended use for that 
anticoagulant within 7 days prior to the first dose of study drug) 
 Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements (the central laboratory value should be 
documented within normal limits after the correction) before the first dose of study 
drug: 
 Sodium 
 Potassium 
 Phosphorus 
 Magnesium 
 Total Calcium 
14. Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by 
the central laboratory: 
 QTcF interval (using Fridericia’s correction) at screening < 450 msec 
 Mean resting heart rate 50-90 bpm (determined from the ECG) 
15. Subjects must be able to communicate with the investigator and comply with the 
requirements of the study procedures 
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17. Premenopausal women must have confirmed negative pregnancy test (for β-hCG) during 
the screening period and before starting study treatment unless this patient had a 
hysterectomy 
18. All sexually active male patients are required to use a condom during intercourse while 
taking drug and for 21 days after stopping medication and should not father a child in this 
period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the ribociclib via seminal 
fluid. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient has received any CDK4/6 inhibitor 
2. Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk 
(“chemoprevention”) of breast cancer and/or treatment for osteoporosis within last 2 years 
prior to screening 
3. Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² 
or more for doxorubicin or 900 mg/m² or more for epirubicin 
4. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET and 
placebo (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency, glucose-galactose malabsorption, and soy allergy) 
5. Patient with distant metastases of breast cancer beyond regional lymph nodes 
6. Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant 
ET (for duration of no more than 12 weeks) from the date of randomization 
7. Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to 
starting treatment with ribociclib or placebo 
8. Patient has not recovered from clinical and laboratory acute toxicities of chemotherapy, 
radiotherapy and surgery (i.e., patient has AEs attributed to prior anti-neoplastic therapy 
NCI CTCAE version 4.03 grade ≥1 at day of enrollment, excluding alopecia and 
amenorrhea) 
9. Patient has a concurrent malignancy or malignancy within 5 years prior to screening, with 
the exception of adequately treated, basal or squamous cell carcinoma of the skin or 
curatively resected cervical carcinoma in situ 
10. Patient has a history of HIV infection (testing is not mandatory) 
11. Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is 
not mandatory) 
12. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, 
including any of the following: 
 History of documented myocardial infarction (MI), angina pectoris, symptomatic 
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study 
entry 
 Documented cardiomyopathy 
 Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory) 


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 Long QT syndrome or family history of idiopathic sudden death or congenital long 
QT syndrome, or any of the following: 
 Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
 Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause TdP that cannot be discontinued or replaced by safe alternative 
medication (e.g. within 5 half-lives or 7 days prior to starting study drug) 
 Inability to determine the QTcF interval 
 Clinically significant cardiac arrhythmias (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) 
 Uncontrolled hypertension with systolic blood pressure (SBP) >160 mmHg 
13. Patient is currently receiving any of the following substances and these cannot be 
discontinued 7 days before the first dose of study drug: 
 Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, 
pumeloes, star fruit, Seville oranges) and their juices that are known as strong 
inhibitors or inducers of CYP3A4/5 
 Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5 
14. 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) 
15. 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) 
16.  Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol (e.g. 
chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver 
disease, active untreated or uncontrolled fungal, bacterial or viral infections, active 
infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ≤5 
years 
17. Participation in a prior investigational study within 30 days prior to enrollment or within 5 
half-lives of the investigational product, whichever is longer 
18. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or 
breast-feed during the study. 
19. Women of child-bearing potential defined as all women physiologically capable of 
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during the study treatment and for 21 days after stopping the study treatment. 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 patient on 
the study the vasectomized male partner should be the sole partner for that patient. 
 Placement of an intrauterine device (IUD) 
Note: Use of oral (estrogen and progesterone), transdermal, injected or implanted 
hormonal methods of contraception as well as hormonal replacement therapy is not 
allowed in this study 
Note: Women are considered not of child bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment she 
is considered not of child bearing potential 
Note: After the end of study treatment and while on standard endocrine treatment, 
women of child-bearing potential and men should use effective contraception 
according to the local prescribing information 
6 
Treatment 
6.1 
Study treatment 
For this study, the term “investigational or study drug” refers to Novartis study drug ribociclib. 
The other drugs to be used in this study are endocrine therapy (ET), which will be 
administered according to the local clinical guidelines and regional prescribing information 
depending on patient’s needs and according to the investigator’s clinical judgement. 
“Study treatment” in this study refers to the combination of the ET with ribociclib. ET alone 
after discontinuation of the ribociclib is not considered a “study treatment”. 
Ribociclib will be supplied by Novartis or its designee in the form of 200 mg tablets as 
individual patient supply packaged bottles. ET will be sourced locally according to local 
practices and regulations in each participating country. 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 ribociclib and ET dosages prescribed and dispensed to the patient and all dose changes 
during the study must be recorded in the eCRF. 


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6.1.1 
Dosing regimen 
All eligible patients will receive starting from Cycle 1 Day 1   
 Ribociclib 600 mg tablets once daily on days 1 to 21 of a 28 day cycle + ET 
Ribociclib will be given orally once a day on days 1 to 21 in each 28 day cycle. Days 22 to 28 
will be a “rest” from ribociclib (Table 6-1). Treatment of ribociclib + ET will continue for 26 
cycles (approximately 24 months). 
ET will be administered according to the local clinical guidelines and regional prescribing 
information (Table 6-1). Acceptable ET that will be combined with ribociclib in female 
patients includes one of the following medications: 
 Letrozole 2.5 mg by mouth daily, 
 Anastrozole 1 mg by mouth daily, 
 Exemestane 25 mg by mouth daily. 
In pre-menopausal women, ET will include also a GnRH agonist (examples include, but not 
limited to, goserelin, triptorelin or leuprolide) administered every 4 weeks. Patients receiving 
GnRH agonist will be monitored regularly per local institutional clinical guidelines to confirm 
a post-menopausal value of gonadotropin and sex hormones according to local laboratory 
ranges (see Table 7-3). 
Patients will be allowed to start ET up to 12 weeks before the day of randomization. During 
treatment with ribociclib, investigators will not be allowed to change ET unless intolerable 
toxicity, patient’s request, or any other medically important event that requires change of ET 
(Investigator must clearly document in the eCRF the reason for changing of ET during the 
treatment with ribociclib). 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or Regimen 
Ribociclib 
Tablets for oral use 
600 mg 
Once daily on days 1 to 21 in each 28 day cycle 
Letrozole 
Tablets for oral use 
2.5 mg 
Days 1 to 28 of a 28 day cycle 
Anastrozole 
Tablets for oral use 
1 mg 
Days 1 to 28 of a 28 day cycle 
Exemestane 
Tablets for oral use 
25 mg 
Days 1 to 28 of a 28 day cycle 
GnRH agonists 
Per local prescribing information 
Day 1 of a 28 day cycle 
Ribociclib will be administered as a flat-fixed dose, and not by body weight or body surface 
area. There will be no breaks between dosing cycles. A complete cycle of treatment is defined 
as 28 days. All study treatment drugs should be administered as described below in Section 
6.1.1.1 and Section 6.1.1.2.  
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen). Patients randomized to placebo permanently discontinued treatment and 
completed the safety follow-up assessment. Patients randomized to ribociclib are allowed to 
continue treatment with ribociclib + ET for a maximum of 26 cycles (approximately 24 


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months) or until first disease recurrence, intolerable toxicity, withdrawal of consent, death or 
discontinuation from the study treatment for any other reason, whichever is earlier. 
The investigator or responsible site personnel should instruct the patient to take the study 
drugs as per protocol (to promote compliance). Drug accountability must be performed on a 
regular basis. Patients will be instructed to return unused study drugs to the site at the end of 
each cycle. The site personnel will ensure that the appropriate dose of each study drug is 
provided at each cycle. 
6.1.1.1 
General dosing guidelines 
Study treatments should be taken as follows: 
 Ribociclib is dosed for the first 21 days of the 28-day cycle. 
 On scheduled visit days, patients must take study treatments in the clinic under the 
supervision of the Investigator or designee. On all other days patients may take ribociclib 
at home. 
 Patients should be instructed to take ribociclib and ET with a large glass of water (~250 
mL or ~8 oz) at the same time each day. Patients can determine if they prefer morning or 
early afternoon dosing, but they should maintain a consistent time. Evening doses are 
strongly not recommended. 
 Ribociclib can be administered with or without food. 
 Patients should be instructed to swallow the tablets whole and not to chew, crush or open 
them. 
 If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the eCRF. Refer to Section 
6.3.1.4 for use of anti-emetic medications. 
 Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day. 
 Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, 
Seville oranges, pomegranates or products containing the juice of each during the entire 
study treatment and preferably 7 days before the first dose of study drug. These foods are 
known as CYP3A4 inhibitors and have a potential to increase exposure to ribociclib. 
Note: Oranges and orange juice are allowed. Herbal or dietary supplements known as 
strong inhibitors or inducers of CYP3A4 are prohibited. 
 Multivitamins, glucosamine, probiotics, fish oil are permitted. 
 GnRH agonist must be administered by injection every 28 days in accordance with the 
regional prescribing information. 
6.1.1.2 
Additional dosing guidelines for ECG panel collection 
On days with ECG panel, the following additional guidelines should be followed: 
 If a pre-dose ECG measurement is to be collected, then the ECG measurement should 
occur before dosing the study treatment. 


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6.1.2 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment with ribociclib, see Section 6.2 “Dosing 
modification”. 
Patients who permanently discontinue ribociclib for any reason are considered to have 
completed the treatment phase and will proceed to End of Treatment (EOT) visit.  
After End of Treatment, patents may continue on the same ET regimen or another ET regimen 
as determined by the Investigator according to local clinical guidelines and regional 
prescribing information depending on patient’s needs and according to the investigator’s 
clinical judgement. Patients who permanently discontinue ET during the treatment phase will 
also discontinue ribociclib and will move to End of Treatment.   
6.1.3 
Study treatment duration 
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen).  
Patients will be treated with ribociclib + ET for 26 cycles (approximately 24 months) until 
first recurrence, intolerable toxicity, withdrawal of consent by the patient, patient is lost to 
follow up, death, discontinuation from the study treatment due to any other reason or the 
sponsor terminates the study, whichever is earlier. 
6.2 
Dose modifications 
6.2.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow patients to continue the study treatment (Table 6-2). These dose 
changes must be recorded on the Dosage Administration Record CRF. 
Table 6-2 
Dose modification guidelines 
 
Ribociclib 
Dose 
Number of tablets & 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 tablet 
6.2.1.1 
Ribociclib  
Recommendations for dose interruption, reduction 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 and Table 6-6. 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 and Table 6-6 or listed in Section 7.1, treatment with 


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ribociclib must be discontinued. If dosing was interrupted for >28 days due to ribociclib-
related toxicity, ribociclib must be discontinued and study participation will end with the 
safety assessment 30 days after the last dose of ribociclib. 
Unscheduled local laboratory assessments may be performed and recorded in the eCRF if 
required according to the visit evaluation schedule, for documentation of adverse event, for 
treatment decision and any clinically significant laboratory values per investigator’s discretion. 
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used, with exception of FSH and plasma estradiol levels to determine 
menopausal status. 
Table 6-3 
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions 
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. 
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. 


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Toxicity/Grade 
Dose Adjustment and Management Recommendations 
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 adjustment and management recommendation for 
hepatic toxicities 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48-72h later) 
Maintain dose level with LFTs monitored bi-weekly 
Grade 2 (> 1.5 – 3.0 x ULN)  
Dose interruption of ribociclib  
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 ducts disease, hyperbilirubinemia due to the indirect 
component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert Syndrome, pharmacologic 
treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only. 
Bilirubin will be fractionated if elevated. 
AST or ALT 
AST or ALT without bilirubin elevation > 2 x ULN 
Same grade as baseline or increase from baseline 
grade 0 to grade 1 
(confirmed 48 – 72 h later) 
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or bi-weekly in case 
of increase from baseline grade 0 to 1 
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    


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HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
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 
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, liver metastases, and alcohol intake.  
Refer to Section 6.2.2.1 for additional follow-up on potential drug-induced liver injury (DILI) 
cases. 
6.2.1.2 
Dose adjustments for QTcF prolongation 
To determine QTcF duration to use in the following table, measurements of QT interval 
should be conducted on ECG and corrected (QTcF). 
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 (sodium, potassium, calcium, phosphorus, 
magnesium). 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 msec 
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment required. 
2 
QTcF 481-500 msec 
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 msec.  
Repeat ECG as clinically indicated until the QTcF returns to < 481 msec.  
Restart ribociclib with dose reduced by 1 dose level. Refer to Table 6-2 for dosing 
schedule. 
If QTcF ≥ 481 msec recurs, ribociclib should be reduced again by 1 dose level. Refer 
to Table 6-2 for dosing schedule. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) 
for any patients who had therapy interrupted due to QTcF ≥ 481 msec 


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3 
QTcF ≥ 501 msec 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 msec. 
● If QTcF remains ≥ 501 msec, consult with a cardiologist (or qualified specialist) 
and repeat cardiac monitoring as indicated until the QTcF returns to < 481 msec. 
● If QTcF returns to < 481 msec, ribociclib will be reduced by 1 dose level. Refer to 
Table 6-2 for dosing schedule. 
● If QTcF remains ≥ 481 msec after performing steps 1-4 as directed in “For All 
Grades, discontinue ribociclib. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) 
for any patients who had therapy interrupted due to QTcF ≥ 501 msec 
If QTcF of ≥ 501 msec recurs, discontinue ribociclib  
4 
[QT/QTcF ≥ 501 or > 60 msec 
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 msec 
6.2.1.3 
Guidance for all other adverse reactions 
Consider performing an analysis of serum potassium, sodium, calcium, phosphorus, and 
magnesium for all adverse reactions, if indicated. 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. 
Patients who experience renal impairment (not due to other contributing factors) of grade 2 or 
higher during the treatment phase should discontinue treatment and should be followed for 
safety assessments. 
For all other AEs please follow recommendations in Table 6-6. 
Table 6-6 
Ribociclib dose adjustment and management recommendation for all 
other adverse reactions 
Grade 
Dose Adjustment and Management Recommendations 
1 
No dose adjustment recommended. Initiate appropriate medical therapy and monitor. 
2 
Dose interruption until recovery to grade 1. Initiate appropriate medical therapy and monitor. 
Re-initiate ribociclib 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. 
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. 
6.2.2 
Follow-up for toxicities 
Patients who complete treatment or whose treatment is interrupted or permanently 
discontinued due to an AE or abnormal laboratory value must be followed at least weekly for 
4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event. 


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All patients will be followed for safety (routine safety monitoring) for approximately 30 days 
following the last dose of ribociclib. Once an AE is detected, investigators are required to 
follow this AE until its resolution or stabilization. Refer to Section 8.1.1 for definitions and 
reporting of AEs. After 30 days, SAEs that are deemed by the investigator to be related to the 
study treatment (i.e., combination of ribociclib and ET) or ET alone will continue to be 
reported, until withdrawal of consent, death, loss to follow up, or the end of study, whichever 
is earlier. 
6.2.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered as clinically-important event. 
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 (i.e. ≤ ULN) 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 (i.e. > ULN) AST or ALT or TBIL value at baseline: [AST or 
ALT > 2 x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is 
lower, combined with [TBIL > 2 x baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis. 
(Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic or hepatocellular liver injury or mixed type injury). 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is 
grade 2 or higher), creatine kinase, prothrombin time (PT)/INR and GGT. For patients with 
Gilbert syndrome: total and direct bilirubin must be monitored, intensified monitoring applies 
to changes in direct bilirubin only. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
 Repeating liver enzyme and serum bilirubin tests two or three times weekly. 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. 


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 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 liver metastases 
 Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
 Obtaining a history of exposure to environmental chemical agents. 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
 Considering gastroenterology or hepatology consultations. 
 Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction. 
 Considering 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 met 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 
Concomitant medications 
6.3.1 
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-diarrheal are allowed. 
Potential drug interaction between ribociclib and concomitant medications should always be 
taken into consideration. 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications (other than study treatment) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Concomitant 
Medications / Relevant Non-Drug Therapies CRF. 
If patients take concomitant medications chronically, any change in dose or schedule of 
concomitant medication throughout the study period should be clearly documented. 
6.3.1.1 
Use of bisphosphonates and denosumab 
Bisphosphonates and denosumab are generally allowed per local/regional prescribing 
information and clinical guidelines. Administration and reason for bisphosphonate/denosumab 
use must be clearly documented in the eCRF. Refer to regional prescribing information and 


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clinical guidelines for comprehensive safety and efficacy information and guidance for each 
medication. 
6.3.1.2 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing ribociclib 
drug exposure to sub-therapeutic levels. Systemic corticosteroid treatment should not be given 
during the study, except for: 
 Topical applications (e.g., rash), inhaled sprays (e.g., 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). 
6.3.1.3 
Hematopoietic growth factors 
Prophylactic use of WBC growth factors with ribociclib is not recommended. 
6.3.1.4 
Use of antiemetic medications 
Ribociclib has minimal to low emetogenic potential according to a definition of anti-
neoplastic agent emetogenicity (Grunberg et al 2010). Antiemetic therapy can be used 
according to clinical guidelines for anti-neoplastic medications with low to minimal 
emetogenic potential for treatment and/or prevention of nausea and vomiting as a result of 
study treatment (NCCN 2016; Roila et al 2016). 
Potential drug interaction between ribociclib and antiemetic medications should always be 
taken into consideration. Example of prohibited antiemetic medication is intravenously 
administered ondansetron that in combination with ribociclib may precipitate TdP. Refer to 
Section 6.3.2 and Section 6.3.3 for list of medications that are allowed or prohibited to be 
used with ribociclib. 
6.3.2 
Permitted concomitant therapy requiring caution 
Medications to be used with caution during combined ribociclib and ET in this study (see 
Table 14-4 in Appendix 2) are listed below. These medications should be avoided 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. 
Following medications should be used with caution and with proper clinical and laboratory 
monitoring: 
 Medications that carry a possible risk for QT prolongation and/or Torsades de Pointes 
(TdP) (may precipitate QT prolongation and TdP; see Section 6.3.3.2 for additional 
details). 
 Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib 
exposure, respectively - see Section 1.2.1.2.3 for additional details). 
 Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib 
may increase exposure to these medications - see Section 1.2.1.2.3 for additional details). 


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 Based on in vitro data (see Section 1.2.1.1 for additional details), co-administration of 
ribociclib with strong inhibitors of BSEP (see Table 14-4 in Appendix 2) may lead to 
intrahepatic cholestasis, and co-administration of ribociclib with sensitive substrates of 
MATE1, OCT2, and BCRP has a potential to increase exposure to substrates of these 
transporters, although no animal or clinical data are available to support these statements. 
6.3.3 
Prohibited concomitant therapy 
The following medications are prohibited during combined ribociclib and ET treatment in this 
study (Table 14-4 in Appendix 2): 
 Strong inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease 
ribociclib exposure, respectively) 
 Herbal medications/preparations that are strong inhibitors or inducers of CYP3A4/5. 
These include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, DHEA, yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop 
using all herbal medications at least 7 days prior to first dose of study treatment. 
 Substrates of CYP3A4/5 with a narrow therapeutic index (ribociclib may increase 
exposure to these medications resulting in toxicity to these medications) 
 Medications with a known risk for QT prolongation and/or TdP (may precipitate QT 
prolongation and TdP in combination with ribociclib) 
 Hormonal contraception, or hormonal medications used as a hormonal replacement 
therapy for symptoms of menopause (as these have potential to reduce efficacy of ET) 
 Other investigational and anti-neoplastic therapies 
6.3.3.1 
Concomitant medications associated with menopausal status 
It is important to consider potential drug-drug interactions when using concomitant 
medications associated with hot flushes and other anticipated symptoms associated with this 
indication/use of ET. Use of systemically administered medications containing estrogens is 
not allowed (see Section 6.3.3). Please see Table 14-3 in Appendix 2 for further information 
on prohibited concomitant medications. 
6.3.3.2 
Drugs with QT prolongation 
As far as possible avoid co-administering medications with a “Known”, “Possible” or 
“Conditional” risk of TdP (www.qtdrugs.org) or any other medication with the potential to 
increase the risk of drug-related QT prolongation (e.g. via a potential DDI increasing the 
exposure of ribociclib or the exposure of the QT prolonging drug). If concomitant 
administration of drugs with a known risk of TdP is required and cannot be avoided, ribociclib 
must be interrupted (see Table 6-5). If during the course of the study, concomitant 
administration of a drug with “Possible risk” or “Conditional risk” of TdP is required, based 
on the investigator assessment and clinical need, study treatment may be resumed under close 
clinical and ECG monitoring to ensure patient safety. A list of drugs associated with QT 
prolongation and/or TdP is available online (www.qtdrugs.org). Medications with a known 
risk for QT prolongation are prohibited during study treatment. 


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6.3.4 
Other procedures 
Use of AIs may cause decrease in bone mineral density. Consider bone mineral density 
monitoring in patients receiving AIs, and appropriate preventive or therapeutic measures for 
osteopenia and osteoporosis in these patients per local clinical guidelines. 
Use of letrozole or anastrozole may cause increase in total blood cholesterol. Consider 
monitoring cholesterol, and taking appropriate preventive or therapeutic measures in patients 
receiving AIs per local clinical guidelines. 
Please refer to regional prescribing information of specific endocrine agent for additional 
procedures and supportive measures required during administration of ET. 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen).  
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 remote data capture (RDC) 
interface. 
The investigator or designated staff will contact the interactive response technology (IRT) and 
provide the requested identifying information for the patient to register them into the IRT. 
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. 
for that individual must not be changed, even if the patient is re-screened. If the patient fails to 
be randomized or start treatment for any reason, the reason will be entered into the Screening 
Disposition page. 
6.4.2 
Treatment assignment or randomization 
Since the study has been closed to enrollment and no new patients will be randomized, this 
section is no longer applicable.  
Patients will be assigned to one of the two treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1. 
Randomization will be stratified by 
 Menopausal status: (premenopausal women/men) vs (postmenopausal women), 
 Stage group (AJCC 8th edition Prognostic Stage Group IIIA) vs (AJCC 8th edition 
Prognostic Stage Groups IIIB/C) vs (residual disease after neoadjuvant chemotherapy), 


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 Geographical region: (North America/Europe/Australia) vs (rest of the world). 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication randomization list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to medication packs containing 
each of the study treatments. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will contact the IRT and 
confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of ribociclib/placebo to be 
dispensed to the patient in combination with ET at Cycle 1 Day 1 no later 3 days after the 
randomization of the patient. The randomization number will not be communicated to the 
caller. 
6.4.3 
Treatment blinding 
Since all randomized patients were unblinded, this section is no longer applicable.  
6.5 
Study drug preparation and dispensation 
Patients will be provided with an adequate supply of study drug (ribociclib) 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 
will provide the patient with instructions for ribociclib administration according to the 
protocol. 
Letrozole, anastrozole, exemestane and GnRH agonist should be dispensed and administered 
according to local prescribing information and practice. 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Ribociclib and other study treatments 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 in the eCRF. 
6.5.1 
Study treatment packaging and labeling 
Ribociclib/placebo will be provided as global clinical blinded supply and will be packed and 
labeled under the responsibility of Novartis Drug Supply Management (see Table 6-7 and 
Table 6-8). 
Following the protocol amendment 02, only ribociclib will be dispensed to patients. 
Ribociclib/placebo packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms. Responsible site 


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personnel will identify the package(s) to dispense to the patient by using the IRT and 
obtaining the medication number(s). Site personnel will add the Patient Number on the label. 
Immediately before dispensing the package to the patient, site personnel will detach the outer 
part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
Table 6-7 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Ribociclib/placebo 
Tablets in bottles 
Study drug packaging has a 2-part label. 
A unique medication number is printed on each part of 
this label which corresponds to one of the two treatment 
arms. 
Anastrozole 
Refer to local product information 
Refer to local product information 
Letrozole 
Refer to local product information 
Refer to local product information 
Exemestane 
Refer to local product information 
Refer to local product information 
GnRH agonist 
Refer to local product information 
Refer to local product information 
6.5.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Ribociclib Investigator’s 
Brochure]. 
Table 6-8 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
Ribociclib 
Centrally supplied by Novartis 
Refer to study treatment label 
Anastrozole 
Locally according to local practices 
and regulations in each participating 
country 
Refer to local product information 
Letrozole 
Locally according to local practices 
and regulations in each participating 
country 
Refer to local product information 
Exemestane 
Locally according to local practices 
and regulations in each participating 
country 
Refer to local product information 
GnRH agonist 
Locally according to local practices 
and regulations in each participating 
country 
Refer to local product information 
6.5.3 
Study drug compliance and accountability 
6.5.3.1 
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 


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Accountability Form. This information must be captured in the source document at each 
patient visit. 
6.5.3.2 
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. 
6.5.4 
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). No CRF will be used as a 
source document. 
Allowed visit windows are specified as follows: 
 Screening assessments, apart from those listed below, must occur within 28 days prior to 
the randomization as per Table 7-1. 
 Randomization and Cycle 1 Day 1 should preferably occur on the same day. A maximum 
of a 3 days window between randomization and Cycle 1 Day 1 visit is permitted. 
 For all visits a general ±3 days visit window is permitted on assessments to take into 
account scheduling over public holidays, if not explicitly specified otherwise. 
 Radiological and histological assessments must be performed as outlined in Table 7-1. A 
visit window of ± 2 weeks is allowed unless otherwise specified.  
 Every effort should be made to follow the schedule outlined in Table 7-1. 
At the time of the protocol amendment 02, all patients have been randomized. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
Ribociclib + endocrine therapy (26 cycles / approx. 24 months) 
Visit Name 
 
 
Screening 
Cycle 
1 
Cycle 2 
Cycles 
3 to 6 
Cycles 7 to 26 (every 
3 cycles from C7D1) 
End of treatment 
Safety follow up 
Study/treatment 
cycle day 
 
 
-28 to -1 
1 
15 
1 
15 
1 
1 
Within 15 days from 
last dose of ribociclib  
Last dose of 
ribociclib + 30 days 
Screening 
Obtain Study Informed 
Consent 
D 
7.1.1  
X 
 
 
 
 
 
 
 
 
IRT Screening (after 
ICF) 
D 
7.1.1  
X 
 
 
 
 
 
 
 
 
Disposition assessment 
End of phase 
disposition 
D 
7  
X 
 
 
 
 
 
 
X 
 
Patient history 
Demography 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
Medical history 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
Diagnosis, stage and 
grade of cancer 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
ER status 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
PgR status 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
HER2 status 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
Prior anti-neoplastic 
therapies 
D 
7.1.1.3  
X 
 
 
 
 
 
 
 
 
Prior/concomitant 
D 
7.1.1.3  
Continuous, up to 30 days after last dose of ribociclib 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
Ribociclib + endocrine therapy (26 cycles / approx. 24 months) 
Visit Name 
 
 
Screening 
Cycle 
1 
Cycle 2 
Cycles 
3 to 6 
Cycles 7 to 26 (every 
3 cycles from C7D1) 
End of treatment 
Safety follow up 
Study/treatment 
cycle day 
 
 
-28 to -1 
1 
15 
1 
15 
1 
1 
Within 15 days from 
last dose of ribociclib  
Last dose of 
ribociclib + 30 days 
medications 
IRT Dispensation 
IRT ribociclib 
dispensation 
S 
7.1.1.1  
 
X 
 
X 
 
X 
X (every cycle) 
 
 
Physical examination 
Physical examination 
S 
7.2.2.1  
X 
 
 
X 
 
X 
X 
X 
 
Vital signs 
D 
7.2.2.2  
X 
X 
X 
X 
 
X 
X 
X 
 
Weight 
D 
7.2.2.3  
X 
X 
X 
X 
 
X 
X 
X 
 
Height 
D 
7.2.2.3  
X 
 
 
 
 
 
 
 
 
Menopausal status assessment 
Menopausal status 
D 
7.2.2.5.5  
X 
Every 12 months or as clinically indicated 
Laboratory assessments 
Hematology 
D 
7.2.2.5.1  
X 
 
X 
X 
X 
X 
X 
X 
 
Biochemistry 
D 
7.2.2.5.2  
X 
 
X 
X 
X 
X 
X 
X 
 
Coagulation 
D 
7.2.2.5.3  
X 
As clinically indicated  
 
Urinalysis 
D 
7.2.2.5.4  
X 
As clinically indicated 
 
Serum pregnancy test 
(for women of child 
bearing potential only) 
D 
7.2.2.5.5  
X 
 
 
 
 
 
X 
 
Urine pregnancy test 
(for women of child 
bearing potential only) 
D 
7.2.2.5.5  
 
X 
 
X 
 
X 
X (every cycle) 
 
 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
Ribociclib + endocrine therapy (26 cycles / approx. 24 months) 
Visit Name 
 
 
Screening 
Cycle 
1 
Cycle 2 
Cycles 
3 to 6 
Cycles 7 to 26 (every 
3 cycles from C7D1) 
End of treatment 
Safety follow up 
Study/treatment 
cycle day 
 
 
-28 to -1 
1 
15 
1 
15 
1 
1 
Within 15 days from 
last dose of ribociclib  
Last dose of 
ribociclib + 30 days 
Recurrence assessment 
Clinical evaluation for 
recurrence 
D 
 
X 
After randomization as clinically indicated, or at any time when recurrence is suspected 
Mammography 
(unless bilateral 
mastectomy) 
D 
7.2.1  
X (unless 
done 
within 
previous 
12 months) 
As clinically indicated, or at any time when recurrence is suspected 
Radiological 
evaluation (CT, MRI, 
US, PET, bone scan, 
X-ray or 
mammography) 
D 
7.2.1  
If clinically 
indicated 
As clinically indicated, or at any time when recurrence is suspected 
Histological (or 
cytological, when 
applicable)  
D 
7.2.1  
If clinically 
indicated 
As clinically indicated, or at any time when recurrence is suspected 
Cardiac assessments 
  Single ECG 
(standard 12-lead) 
D 
7.2.2.6  
X 
 
X 
X 
 
X 
X (at C7D1 for all 
patients, then assessed 
only if QTcF > 481 
msec during previous 
cycles) 
X 
 
Safety 
Adverse events 
D 
8  
Continuous, up to 30 days after last dose of ribociclib  
 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
Ribociclib + endocrine therapy (26 cycles / approx. 24 months) 
Visit Name 
 
 
Screening 
Cycle 
1 
Cycle 2 
Cycles 
3 to 6 
Cycles 7 to 26 (every 
3 cycles from C7D1) 
End of treatment 
Safety follow up 
Study/treatment 
cycle day 
 
 
-28 to -1 
1 
15 
1 
15 
1 
1 
Within 15 days from 
last dose of ribociclib  
Last dose of 
ribociclib + 30 days 
Study Drug administration 
Ribociclib 
D 
6  
 
Day 1-21 daily, Day 22-28 off 
 
 
Adjuvant endocrine 
therapy (ET) 
D 
6  
letrozole / anastrozole / exemestane daily, GnRH agonist (if indicated) every 4 weeks 
Discontinuation 
IRT Discontinuation 
ribociclib 
S 
7.1.3  
 
 
 
 
 
 
 
X 
 
Subsequent anti-
neoplastic therapies 
(medication, surgery, 
radiotherapy) 
D 
7.1.5  
 
 
 
 
 
 
 
X 


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7.1.1 
Screening 
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to randomization (see Table 7-1 for list of assessments to be performed). 
Re-screening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (i.e. IRT randomization). In this case the Subject Number 
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. If patient has been randomized, re-
screening of patient is not allowed. 
In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria. A 
new informed consent form must be signed only if there is an interruption in the patient’s 
eligibility evaluation and the investigator chooses to re-screen the patient following screen 
failure; the 28 day screen period does not apply to the informed consent process. If a new 
informed consent form is signed, AEs and medical history will be assessed relative to the new 
informed consent date. 
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range before screen 
failing the patient. If the repeated laboratory result meets the criteria, that result may be used 
to determine eligibility. If the repeated laboratory result does not meet the criteria, the patient 
will be considered a screening failure. For details of assessments, see Table 7-1. 
A mandatory archival paraffin tumor tissue (tumor blocks or slides with tumor tissue) from 
surgical specimen should be shipped to the designated laboratory before the planned 
randomization date (see Section 7.2.3.1.1). 
Assessments of patient reported outcomes during the Screening should be collected prior to 
any clinical assessments, drug dosing or diagnostic testing. 
Any imaging assessments, if clinically indicated, are to be done during Screening period (i.e. 
within 28 days prior to randomization). 
An additional biomarkers informed consent will be available to the patient for optional 
participation.  
7.1.1.1 
Eligibility screening 
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Please refer and comply with detailed guidelines in the IRT manual. 
7.1.1.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be randomized for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Phase Disposition Page. The demographic information, informed consent, 
Inclusion/Exclusion pages and, if applicable, withdrawal of informed consent must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 


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for patients who are screen failures, unless the patient experienced an SAE during the 
Screening Phase (see Section 8 for SAE reporting details). 
If a screen failure patient experiences an AE which does not meet the SAE criteria, details 
about the AE will be recorded only in the investigator’s source documents. In case of an SAE 
after signing of main study informed consent, data must be recorded on both the AE and SAE 
forms. 
If the patient fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the patient was not randomized. 
7.1.1.3 
Patient demographics and other baseline characteristics 
The data that will be collected on patient characteristics at screening includes: 
 Demography (Date of birth or partial date of birth and initials (where permitted by local 
regulations), sex, race, ethnicity). 
 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 per 
CTCAE v 4.03. 
 ER, PgR, HER2, histopathological grade (the Nottingham combined histologic grade 
(Elston and Ellis 2002)) and, if available, Ki-67, genomic subtype and results of any of the 
genomic predictive and prognostic tests. 
 Diagnosis and extent of cancer (including histology and AJCC 8th edition Anatomic 
(“TNM staging”) and Prognostic Stage Groups (see Table 14-1 and Table 14-2 in 
Appendix 1): 
 Anatomic Stage Group at time of diagnosis, i.e. before the curative surgery, if 
available 
 Anatomic and Prognostic Stage Groups at the study entry, i.e. after the curative 
surgery: 
 for patients who received adjuvant chemotherapy reporting of both Anatomical 
Stage Group and Prognostic Stage Group is required 
 for patients who received neoadjuvant chemotherapy reporting of Prognostic 
Stage Group is not required. 
 All prior anti-neoplastic therapies including surgical interventions, and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for the current early breast 
cancer as well as any adjuvant ET started prior to the randomization (ovarian suppression 
for fertility preservation by GnRH agonists is not considered anti-neoplastic therapy). 
 All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded on the Prior and Concomitant medication or 
Surgical and medical procedures eCRF page and updated on a continual basis if there are 
any new changes to the medications. 


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 Patient-reported outcome questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23 (for 
women only), EQ-5D-5L, and HADS (See Section 7.2.5). 
Furthermore the following assessments will be performed: 
 Vital signs 
 Height, weight 
 Physical examination 
 ECOG Performance Status 
 Menopausal status (for women) 
 Laboratory evaluations (hematology, coagulation, chemistry, urinalysis, pregnancy test for 
women of child bearing potential) 
 Triplicate ECG 
 Clinical evaluation for recurrence and if clinically indicated, radiological and/or 
histological/cytological assessments.  
 A mandatory archival paraffin tumor tissue (tumor block or tumor slides with tumor tissue) 
from surgical specimen. 
7.1.2 
Treatment period 
Patients will be randomized using menopausal status, stage group (i.e., Prognostic Stage 
Groups (see Table 14-2 in Appendix 1) for patients who were treated with adjuvant 
chemotherapy, or patients with residual disease in lymph nodes and breast tissue after 
neoadjuvant chemotherapy) and geographical region for stratification. Study treatment should 
be started as soon as possible and no later than 3 days after the randomization of the patient. 
The study has been closed to enrollment. All randomized patients were unblinded; patients 
randomized to placebo permanently discontinued study treatment and patients randomized to 
ribociclib were offered the option to continue treatment with ribociclib + ET (excluding 
tamoxifen) for a maximum of 26 cycles (approximately 24 months) of ribociclib or until first 
recurrence, intolerable toxicity, withdrawal of consent by the patient, patient is lost to follow 
up, death, discontinuation from the study treatment due to any other reason, or the sponsor 
terminates the study, whichever is earlier. Treatment ends with the last dose of ribociclib. 
For details of assessments, see Table 7-1.  
7.1.3 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, he/she believes 
that continuation would be detrimental to the patient’s well-being. 


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In addition to mandatory discontinuation reasons for investigational treatment (ribociclib) 
listed in Section 6.2, study treatment must also be discontinued under the following 
circumstances: 
 Pregnancy 
 Lactation 
 Death 
 Subject/Guardian decision 
 Adjustments to study treatment due to toxicity that result in treatment discontinuation (see 
Section 6.2) 
 Use of prohibited medication (see Section 6.3). 
 Any other protocol deviation that results in a significant risk to the patient’s safety. 
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently for 
any reason. 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2 for an EOT visit. If 
they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
email, letter) should be made to contact them as specified in Section 7.1.6. 
The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment within 2 days of the EOT visit. 
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. 
7.1.3.1 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 


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7.1.4 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of ribociclib. Once an 
AE is detected, investigators are required to follow this AE until its resolution or stabilization. 
Refer to Section 8.1.1 for definitions and reporting of AEs. Patients whose treatment is 
interrupted or discontinued due to an AE, including abnormal laboratory value, must be 
followed until resolution or stabilization of the event, whichever comes first. This could 
include all study assessments appropriate to monitor the event. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
If patients refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
patient should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.). 
7.1.5 
Follow-up phase 
7.1.5.1 
Post treatment follow up for recurrence 
Since the study will end after the completion of safety follow up within 30 days after the last 
dose of ribociclib, no post-treatment follow-up for recurrence will be conducted. Patients in 
post-treatment follow-up phase assessments will end study participation with the protocol 
amendment 02. 
7.1.5.2 
Survival follow-up 
Since the study will end after the completion of safety follow-up assessment within 30 days 
after the last dose of ribociclib, no survival follow up will be conducted. Patients in survival 
follow-up phase assessments will end study participation with the protocol amendment 02. 
7.1.6 
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 
CRF. 
7.2 
Assessment types 
7.2.1 
Recurrence assessments 
Recurrence will be assessed by investigator according to local or institutional standards of 
care, as clinically indicated, or at any time when recurrence is suspected.  
Any of the following radiological assessments may be used for evaluation of suspicion of 
recurrence: 


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 Chest, abdomen and pelvis computer tomography (CT) or magnetic resonance imaging 
(MRI) 
 Brain CT or MRI 
 Whole body bone scan (bone scintigraphy) 
 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 
 CT or MRI of other sites (e.g., neck, extremities) 
 Ultrasound 
 Fludeoxyglucose (18F) positron emission tomography (FDG-PET) 
 Mammography 
Biopsy or cytology maybe used to confirm recurrence histologically (or cytologically), unless 
the biopsy poses an unacceptable risk to the patient. Recurrence will be reported in eCRF. 
Treatment with ribociclib + ET will be discontinued at time of recurrence (any type of 
recurrence - either local, regional, distant, contralateral non-invasive breast cancers or second-
primary invasive non-breast cancer).   
7.2.2 
 Safety and tolerability assessments 
Safety of patients will be monitored by assessing physical examinations, height and weight, 
vital signs, ECG, laboratory assessments including hematology, chemistry, and coagulation as 
well as collecting of the AEs at every visit. For details on AE collection and reporting, see 
Section 8. 
The ECOG Performance Status and patient-reported outcomes are no longer collected 
following the protocol amendment 02. 
7.2.2.1 
Physical examination 
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site. Physical 
examination is to be performed according to the visit schedule as outlined in Table 7-1. 
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF. 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) will be monitored as per the visit 
schedule (see Table 7-1). Blood pressure (systolic and diastolic) and pulse should be 
measured after the patient has been sitting for approximately five minutes. 


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7.2.2.3 
Height and weight 
Height will be measured at screening only. 
Weight will be measured at screening and at subsequent time points as specified in Table 7-1. 
7.2.2.4 
Performance status 
Following the protocol amendment 02, the performance status assessment is no longer 
performed. 
  
7.2.2.5 
Laboratory evaluations 
Following the protocol amendment 02, all clinical laboratory analyses (Hematology, 
Chemistry, Coagulation, Urinalysis, and serum pregnancy test) will be performed by the  local 
laboratory only (see Table 7-3). The investigator is responsible for reviewing all laboratory 
reports for patients in the study and evaluating any abnormalities for clinical significance. 
For assessment of patients’ eligibility to the study, only laboratory results from the 
central laboratory will be used (except for FSH and estradiol for determination / 
confirmation of menopausal status). 
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) AE.  
At any time during the study up to safety follow-up, abnormal laboratory parameters which 
are clinically relevant and require an action to be taken with study treatment (e.g., require 
dose modification and/or interruption of study treatment, lead to clinical symptoms or signs, 
or require therapeutic intervention), whether specifically requested in the protocol or not, will 
be recorded on the AE eCRF page. The severity of laboratory data will be graded using the 
Common Terminology Criteria for Adverse events (CTCAE) version 4.03. Additional 
analyses are left to the discretion of the investigator.  
Table 7-2 
Clinical laboratory parameters collection plan (all are done locally with 
the protocol amendment 02) 
Test Category 
Test Name 
Hematology 
White blood cell count (WBC) with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils), bands, differential other, hemoglobin and platelet count 
Biochemistry 
Sodium, potassium, uric acid, urea or BUN, creatinine, glucose (fasting only if non-fasting 
is out of range), calcium, magnesium, phosphorous and albumin. 
AST (SGOT), ALT (SGPT), total bilirubin, direct bilirubin and alkaline phosphatase, 
Amylase, lipase and LDH, total cholesterol 
Coagulation 
aPTT, International normalized ratio [INR] 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
If there are any significant findings on the dipstick then a microscopic evaluation should 
be measured: Microscopic Panel (WBC and RBC sediments, Casts, Crystals, Bacteria, 
Epithelial cells) 
Other Tests 
Pregnancy test (serum) 


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7.2.2.5.1 Hematology 
Hematology tests are to be performed according to the Visit Schedule outlined in Table 7-1. 
For details of the Hematology panel see Table 7-2. 
Hematology should be assessed on the actual scheduled day, even if study drug is being 
withheld. 
7.2.2.5.2 Biochemistry 
Biochemistry tests are to be performed according to the Visit Schedules outlined in Table 7-1. 
For details of the Biochemistry panel see Table 7-2. Biochemistry should be assessed on the 
actual scheduled day, even if study drug is being withheld. Estimate of GFR (via estimated 
creatinine clearance rate) will be done centrally using Cockcroft-Gault formula 
 
7.2.2.5.3 Coagulation 
INR and aPTT are to be performed according to the Visit Schedules outlined in Table 7-1. If 
the coagulation blood sample collected at screening is clotted when received by central 
laboratory for testing or the central laboratory results of only the coagulation are delayed, the 
patient is still eligible to enter the study with a local laboratory INR test ≤ 1.5. 
Coagulation will be performed by local laboratory following the protocol amendment 02. 
7.2.2.5.4 Urinalysis 
Urinalysis is to be performed according to the Visit Schedules outlined in Table 7-1. For 
details of the urinalysis panel see Table 7-2. 
7.2.2.5.5 Pregnancy and assessments of fertility 
FSH, estradiol, serum and urine pregnancy tests (patients who have undergone a hysterectomy 
do not need pregnancy tests performed) are to be performed according to the Visit Schedules 
outlined in Table 7-1 and Table 7-3. 
At screening and at EOT, a serum pregnancy test should be performed for women of child 
bearing potential only, while at Cycle 1 day 1 and at each cycle, urinary pregnancy tests are 
sufficient. 
FSH and estradiol will be done locally at screening for eligibility and for confirmation of the 
menopausal status. Menopausal status will be recorded in eCRF. 


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Table 7-3 
Local clinical laboratory parameters assessment plan 
Test Category 
Test Name 
Other local Tests 
FSH, estradiol for confirmation of menopausal status (pre- / post-), urine pregnancy. 
Note: FSH and estradiol are not recorded in eCRF, but used to determine menopausal 
status 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
Standard single 12 lead ECG assessments will be performed (in the supine position) after the 
patient has been resting for 5-10 minutes prior to each time point indicated in Table 7-4 below. 
ECG assessments are to be done prior to blood collection sampling (if applicable). Following 
the protocol amendment 02, all ECG will be performed and assessed locally. 
Table 7-4 
ECG collection plan (all ECGs are performed and assessed locally 
with the protocol amendment 02) 
Cycle 
Patients 
Day 
Time 
ECG Type 
Screening 
All 
-28 to -1 
Anytime 
Triplicate 12 Lead 
1 
All 
Day 15 
Pre-dose1 
Single 12 Lead 
All 
2h post-dose (± 15 min) 
Single 12 Lead 
2 
All 
Day 1 
Pre-dose1 
Single12 Lead 
3 
All 
Day 1 
Pre-dose1 
Single 12 Lead 
4 
All 
Day 1 
Pre-dose1 
Single 12 Lead 
5 
All 
Day 1 
Pre-dose1 
Single 12 Lead 
6 
All 
Day 1 
Pre-dose1 
Single 12 Lead 
7 
All 
Day 1 
Pre-dose1 
Single 12 Lead 
10 and every 
3rd cycle 
For patients with QTcF ≥ 481 msec 
at any time prior to cycle 7 
Day 1 
Pre-dose1 
Single 12 Lead 
EOT 
Anytime 
Single 12 Lead 
Unscheduled ECG 
Anytime 
Single 12 Lead 
1The exact date and time of dosing must be recorded on the appropriate eCRF 
The QTcF values using Fridericia’s correction (formula is provided below) will be assessed 
locally following the protocol amendment 02. 
 
Eligibility will be based on the average of the triplicate ECGs conducted at screening.  
If any of the readings include a new clinically-relevant abnormal ECG or a QTcF value of ≥ 
481 msec is obtained at any time after randomization, 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. Interpretation of the tracing must be made by a qualified 
physician and documented on the ECG CRF page. Local cardiologist ECG assessment may be 
performed at any time during the study at the discretion of the investigator. 


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All ECGs including unscheduled ECGs with clinically relevant findings, collected during the 
study should be assessed locally. Each ECG tracing should be labeled with the study number, 
patient number, date, and kept in the source documents at the study site. Clinically significant 
ECG abnormalities present at screening when the patient signed informed consent should be 
reported on the Medical History CRF page. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events CRF page. 
7.2.3 
Biomarkers 
Following the protocol amendment 02, tumor and blood samples collection for biomarkers 
assessments are no longer performed. 
7.2.4 
Resource utilization 
Following the protocol amendment 02, collection of data for healthcare resource utilization is 
no longer performed. 
7.2.5 
Patient reported outcomes 
Following the protocol amendment 02, collection of data for patients reported outcomes is no 
longer performed. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event (AE) 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 AEs 
only if they induce clinical signs or symptoms, are considered clinically significant, require 
therapy (e.g., hematologic abnormality that requires transfusion or hematological stem cell 
support), or require changes in study treatment(s). 
AEs that begin or worsen after informed consent should be recorded in the Adverse Events 
CRF. Conditions that were already present at the time of informed consent should be recorded 
in the Medical History page of the patient’s CRF. AE monitoring should be continued for at 
least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment. 
AEs (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 AE. 
AE will be assessed and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 


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be used. Information about any deaths (related to an AE or not) will also be collected through 
a Death form. 
The occurrence of AEs 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. 
AE 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 AE should be evaluated to determine: 
 The severity grade (CTCAE v4.03 Grades 1-5) 
 Its duration (Start and end dates) 
 Its relationship to the study treatment. Reasonable possibility that AE is related: 
 No (i.e. not treatment-related); 
 Yes, investigational treatment (i.e. related to treatment with ribociclib); 
 Yes, other study treatment (i.e. related to treatment with ET); 
 Yes, both and/or indistinguishable (i.e. related to treatment with both ribociclib and 
ET, or indistinguishable) 
 Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
 Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
 Whether it is serious, where an SAE is defined as in Section 8.2.1 and which seriousness 
criteria have been met 
 Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For all AEs, if improvement to a lower grade is 
determined a new entry for this event should be reported in the CRF noting the start date 
when the event improved from previous grade. 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the Adverse Event CRF. 
Once an AE 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. 
Recurrence of malignancy (including resulting in fatal outcomes), if documented by use of 
appropriate method (for example, confirmed recurrence per STEEP Criteria is reported), 
should not be reported as an AE, including SAE. 
AEs 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. 


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8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes 
in study treatment), should be recorded on the Adverse Events CRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for AEs 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 AE, 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 AE, should not be reported as 
AEs. 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 of medication for the lab abnormality may be required by the protocol 
in which case the lab abnormality would still, by definition, be an AE and must be reported as 
such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. 
AESIs are defined on the basis of an ongoing review of the safety data. AESIs are discussed 
in detail in the [Ribociclib Investigator’s Brochure]. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
Note that hospitalizations for the following reasons should not be reported as SAEs: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent. 


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 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 an SAE. 
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. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period should be reported 
to Novartis within 24 hours of learning of its occurrence 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. 
8.3 
Emergency unblinding of treatment assignment 
This is not applicable since all patients have been unblinded. 


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8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational 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 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee 
The study enrollment was early closed. All randomized patients were unblinded. After the 
unblinding, the Novartis Clinical Trial Team will be responsible for reviewing safety data and 
conducting all analysis(-es) as defined in the protocol. 
8.7 
Steering Committee 
Following the protocol amendment 02, this section is no longer applicable. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
What protected health information (PHI) will be collected from subjects in this study 
Who will have access to that information and why 
Who will use or disclose that information 
The rights of a research subject to revoke their authorization for use of their PHI. 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
Following the protocol amendment 02, laboratory and ECG data will be collected and 
performed locally at the sites; data will be entered into the eCRF. PRO data will not be 
collected any longer. Blood and tumor samples for laboratory data and biomarker assessments 
will no longer be collected. 


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For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Blood and tumor samples for laboratory data and biomarkers assessments will be collected by 
sites and sent to the Novartis designated central laboratory for processing. The laboratory 
results and IRT data will be sent electronically to Novartis. ECG data will be collected at the 
sites and the data will be transmitted to a designated CRO for centralized analysis, as well as 
further processing. PRO data will be recorded by patients onto the electronic tablet device 
maintained at the study site. The device will be programmed to ensure that all relevant 
observations are recorded. 
9.4 
Database management and quality control 
For studies using eCRFs, 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 AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Samples and/or data (e.g. biomarkers, ECG, safety samples) will be processed centrally and 
the results will be sent electronically to Novartis (or a designated CRO). PRO data collected 
using an electronic tablet device will be documented into a separate study-specific database 
supplied and managed by a designated vendor. The PRO database will be accessible to study 
sites and Novartis personnel (or a designated CRO) for data management. All PRO data will 
be sent electronically to Novartis personnel (or a designated CRO).  
Following the protocol amendment 02, PRO data will not be recorded as this assessment is no 
longer required. Blood and tumor samples for laboratory data and biomarker assessments will 
no longer be collected. Randomization codes and data about all study treatments dispensed to 
the patient and all IRT assigned dosage changes will be tracked using an Interactive Response 
Technology. The system will be supplied by a vendor(s), who will also manage the database. 
The data will be sent electronically to Novartis personnel (or designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 


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After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
The final analysis will be performed after all patients have discontinued ribociclib and the 
safety follow-up assessment within 30 days after the last dose of ribociclib. 
No analyses for statistical inference is planned. Descriptive summaries of key safety and 
baseline characteristics will be provided. These include summaries of treatment duration 
exposure, adverse events, labs, and ECG findings. The efficacy data collected will be 
summarized via listings. The details are described in the statistical analysis plan.  
10.1 
Interim analysis 
Not applicable 
10.2 
Sample size calculation 
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. 


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11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given 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 (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
Additional consent form 
Sub-studies and studies with an optional Exploratory Biomarker component will have a 
separate consent form covering those studies (See Section 7.2.3.3.1 for pharmacogenetic 
informed consent details). This form will be adapted for each Study based on a standard 
template used globally for all Studies. These informed consent forms will be submitted for 
ethical approval together with the Study Protocol and the main informed consent form of the 
Study. If a subject opts not to participate in the optional assessments, this in no way affects 
the subject’s ability to participate in the main research study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study 


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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 study completion (i.e., last patient last visit (LPLV)), those for interventional clinical 
trials involving pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.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 www.novartis.com. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 


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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 Novartis 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. 
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 


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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 
References (available upon request) 
Amin MB (2016) AJCC Cancer Staging System, 8th Edition: UPDATE. Creating the Bridge 
from a “Population Based” to a More “Personalized” Approach. 
https://cancerstaging.org/About/news/Documents/NCRA%20AJCC%20Cancer%20Staging%
20Manual%208th%20Edition%20Update.pdf Accessed on 07-Nov-2016. 
Anampa J, Makover D, Sparano JA (2015) Progress in adjuvant chemotherapy for breast 
cancer: an overview. BMC Medicine 13:195. 
Bachelot T, Bourgier C, Cropet C, et al (2012) Randomized phase II trial of everolimus in 
combination with tamoxifen in patients with hormone receptor-positive, human epidermal 
growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase 
inhibitors: a GINECO study. J Clin Oncol 30:2718–2724. 
Beroukhim R, Mermel CH, Porter D, et al (2010) The landscape of somatic copy-number 
alteration across human cancers. Nature 463:899-905. 
Bosco EE, Wang Y, Xu H, et al (2007) The retinoblastoma tumor suppressor modifıes the 
therapeutic response of breast cancer. J Clin Invest 117:218-228. 
Buzdar AU (2003) Pharmacology and pharmacokinetics of the newer generation aromatase 
inhibitors. Clin Cancer Res. 9:468S-472S. 
Coates AS, Winer EP, Goldhirsch A, et al (2015). Tailoring therapies – improving the 
management of early breast cancer: St Gallen International Expert Consensus on the Primary 
Therapy of Early Breast Cancer 2015. Ann Oncol 26:1533-1546 
Dawson SJ, Rosenfeld N, Caldas C. (2013) Circulating tumor DNA to monitor metastatic 
breast cancer. N Engl J Med. 369(1):93-4. 
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of 
chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year 
survival: an overview of the randomised trials. Lancet 365:1687–1717. 
Early Breast Cancer Trialists’ Collaborative Group (2015) Aromatase inhibitors versus 
tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 
386:1341–1352. 
Edevana VK, Dhakal IB, Williams S, et al (2013) Potential role of UGT1A4 promoter SNPs 
in anastrozole pharmacogenomics. Drug and Metabolism Dispos 41:870-877. 
Eggeman H, Ignatov A, Smith BJ, et al (2013) Adjuvant therapy with tamoxifen compared to 
aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat 137:465–
470. 
Elston, CW, and Ellis, IO (2002) Pathologic prognostic factors in breast cancer. I. The value 
of histological grades in breast cancer. Experience from a large study with long-term follow-
up". Histopathology. 1991;19: 403–10. Republished in Histopathology 41:154–161. 
Esposito A, Bardelli A, Criscitiello C, et al (2014) Monitoring tumor-derived cell-free DNA 
in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat 
Rev; 40(5):648-55. 
Fentiman IS, Fourquet A, Hortobagyi GN (2006) Male breast cancer. Lancet 367:595–604. 


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Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al (2013). Cancer incidence and mortality 
patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 49:1374-1403 
Finn RS, Dering J, Conklin D, et al (2009) PD 0332991, a selective cyclin D kinase 4/6 
inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human 
breast cancer cell lines in vitro. Breast Can Res 11:R77. 
Finn RS, Crown JP, Lang I, et al (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib 
in combination with letrozole versus letrozole alone as first-line treatment of oestrogen 
receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A 
randomised phase 2 study Lancet Oncol 16:25–35. 
Finn RS, Martin M, Rugo HS, et al (2016) Palbociclib and letrozole in advanced breast cancer. 
NEJM 375:1925-1936. 
Francis PA, Regan MM, Fleming GF, et al (2015). Adjuvant ovarian suppression in 
premenopausal breast cancer. N Engl J Med. 372:436-446. 
Giuliano AE, Hunt KK, Ballman KV, et al (2011) Axillary dissection vs no axillary dissection 
in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. 
JAMA 305:569-575. 
GLOBOCAN (2012) Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012. 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (assessed 17-October-2016). 
Goetz MP, Erlichman C, Loprinzi CL, and Kohli M (2015) Hormonal agents. In DeVita VT, 
Lawrence TS, and Rosenberg SA “DeVita, Hellman, and Rosenberg’s Cancer: principles & 
practice of oncology”. 10th edition. Wolters Kluwer Health. 
Goss PE, Ingle JN, Pritchard KI, et al (2016) Extending aromatase-inhibitor adjuvant therapy 
to 10 years. N Engl J Med 375:209-219. 
Gradishar WJ, Anderson BO, Balassanian R, et al (2016) Invasive Breast Cancer Version 
1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 14:324-
354. 
Grunberg SM, Warr D, Gralla RJ, et al (2010) Evaluation of new antiemetic agents and 
definition of antineoplastic agent emetogenicity- state of the art. Support Care Cancer 19:S43-
S47. 
Hammond ME, Hayes DF, Dowsett M, et al (2010) American Society of Clinical 
Oncology/College Of American Pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin 
Oncol 28:2784–2795. 
Holm K, Staaf J, Jönsson G, et al (2012) Characterisation of amplification patterns and target 
genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. 
Breast Cancer Res Treat 133:583-594. 
Hortobagyi GN, Connolly JL, D’Orsi CJ, et al (2017). Breast. From AJCC Cancer Staging 
Manual 8th ed. By Amin MB, Edge S, Greene FL, et al. Springer 
Hortobagyi GN, Stemmer SM, Burris HA, et al (2016) Ribociclib as first-line therapy for HR-
positive, advanced Breast Cancer. N Engl J Med 375:1738-1748. 


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Hoskins JM, Carey LA, McLeod HL (2009) CYP2D6 and tamoxifen: DNAA matters in 
breast cancer. Nat Rev Cancer 9:576-586. 
Howlander N, Noone AM, Krapcho M, et al (2015) SEER Cancer Statistics Review, 1975-
2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based 
on November 2014 SEER data submission, posted to the SEER web site, April 2015. 
Jemal A, Center MM, DeSantis C, and Ward EM (2010) Global patterns of cancer incidence 
and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19:1893–1907. 
Jeruss JS, Mittendorf EA, Tucker SL, et al (2008) Combined use of clinical and pathologic 
staging variables to define outcomes for breast cancer patients treated with neoadjuvant 
therapy. J Clin Oncol 26:246-252. 
Lan KK, DeMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika; 
70:659-63. 
Lipton A, Demers LM, Harvey HA, et al (1995) Letrozole (CGS 20267). A phase I study of a 
new potent oral aromatase inhibitor of breast cancer. Cancer. 75:2132-2138 
Loibl S, Turner NC, Ro J, et al (2016) Palbociclib (PAL) in combination with fulvestrant (F) 
in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior 
progression on endocrine therapy – results from Paloma-3. J Clin Oncol 34 (suppl; abstr 524) 
Lyman GH, Temin S, Edge SB, et al (2016) Sentinel lymph node biopsy for patients with 
early-stage breast cancer: American Society of Clinical Oncology Clinical Practice Guideline 
update. J Clin Oncol 32:1365-1383. 
Mauri D, Pavlidis N, and Ioannidis (2005) Neoadjuvant versus adjuvant systemic treatment in 
breast cancer: a meta-analysis. JNCI J Natl Cancer Inst 97:188-194. 
Miller TW, Balko JM, Fox EM, et al (2011) ERα-dependent E2F transcription can mediate 
resistance to estrogen deprivation in human breast cancer. Cancer Discov 1:338-351. 
von Minckwitz G, Untch M, Blohmer JU et al (2012) Definition and Impact of Pathologic 
Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic 
Breast Cancer Subtypes J Clin Oncol. 30(15):1796-804. 
Mittendorf EA, Jeruss JS and Tucker SL (2011) Validation of a novel staging system for 
disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. 
J Clin Oncol 15:1858-1882. 
Murtaza M, Dawson SJ, Pogrebniak K et al (2015) Multifocal clonal evolution characterized 
using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun. 6:8760. 
Musgrove EA, Caldon CE, Barraclough J, et al (2011) Cyclin D as a therapeutic target in 
cancer. Nat Rev Cancer 11:558-572. 
NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2016 
https://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf 
Nichols M (2015) New directions for drug-resistant breast cancer: the CDK4/6 inhibitors. 
Future Med Chem 12:1473-1481. 
Plourde PV, Dyroff M, Dowsett M, et al (1995) Arimidex: A new oral, once-a-day aromatase 
inhibitor. J Steroid Biochem Molec Biol 53:175-199. 


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Rizzo JD, Brouwers M, Hurley P, et al (2010) American Society of Clinical Oncology/ 
American Society of Hematology Clinical Practice Guideline update on the use of epoetin and 
darbepoetin in adult patients with cancer J Clin Oncol 33:4996-5010 
Roila F, Molassiotis A, Herrstedt J, et al (2016) MASCC and ESMO Consensus Guidelines 
for the Prevention of Chemotherapy and Radiotherapy-Induced Nausea and Vomiting: ESMO 
Clinical Practice Guidelines. Ann Onc 27:v11-v133. 
Senkus E, Kyriakides, S, Ohno S, et al (2015) Primary breast cancer: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (suppl 5): v8-v30. 
Siegel RL, Miller KD, Jemal (2016) A Cancer statistics, 2016. CA Cancer J Clin 66:7-30. 
Smith TJ, Bohlke K, Lyman GH, et al (2015) Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin 
Oncol 33:3199-3212 
Sousa B, Moser E, and Cardoso F (2013) An update on male breast cancer and future 
directions for research and treatment. Eur J Pharmacol 71:771–783. 
Thangavel C, Dean JL, Ertel A, et al (2011) Therapeutically activating RB: reestablishing cell 
cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18:333-345. 
The Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human 
breast tumours. Nature 490:61-70. 
Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 
65:87–108. 
Tripathy D, Sohn J, Im SA, et al (2017).  First-line ribociclib vs placebo with goserelin and 
tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone 
receptor-positive, HER2-negative advanced breast cancer: results from the randomized phase 
III MONALEESA-7 trial. Presented at: the 2017 San Antonio Breast Cancer Symposium; 
Abstract GS2-05.  
Trunet PF, Bhatnagar AS, Chaudri HA, et al (1996) Letrozole (CGS20267) a new oral 
aromatase inhibitor for the treatment of advanced breast cancer in postmenopausal patients. 
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Turner NC, Ro K, Andre F (2015) Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med. 373:209-219. 
  


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14 
Appendices 
14.1 
Appendix 1: Guidelines for Anatomic and Prognostic Stage 
Group III of HR-positive, HER2-negative Breast Cancer for breast 
cancer staging (based on AJCC Ed. 8th) 
Guidelines for anatomic and prognostic stage groups according to AJCC Ed. 8th applicable to 
this study are presented in Table 14-1 and Table 14-2 below (modified from Hortobagyi et al 
2017). 
Table 14-1 
AJCC 8th edition Anatomic Stage Groups (not including Group IV - all 
M-category M0) 
Anatomic Stage Group 
T-category 
N-category 
0 
Tis 
N0 
IA 
T1 
N0 
IB 
T0-1 
N1mi 
IIA 
T0-1 
N1 
T2 
N0 
IIB 
T2 
N1 
T3 
N0 
IIIA 
T0-3 
N2 
T3 
N1 
IIIB 
T4 
N0-2 
IIIC 
Any T 
N3 
Table 14-2 
AJCC 8th edition Prognostic Stage Group III of HR-positive, HER2-
negative Breast Cancer (all M-category M0) 
T-category 
N-category 
Grade  
ER Status 
PR Status 
Prognostic Stage Group IIIA 
T0-1 
N1 
3 
Positive 
Negative 
T0-1 
N1 
3 
Negative 
Positive  
T2* 
N0 
3 
Positive 
Negative 
T2 
N0 
3 
Negative  
Positive 
T2 
N1 
1 or 2 
Positive 
Negative 
T3 
N0 
1 or 2  
Positive 
Negative 
T0-2 
N2 
1  
Positive 
Negative 
T0-2 
N2 
1  
Negative 
Positive 
T3 
N1-2 
1 
Positive 
Negative 
T3 
N1-2 
1 
Negative 
Positive 
T4 
N0-2 
1 
Positive 
Positive 
Any 
N3 
1 
Positive 
Positive 


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T-category 
N-category 
Grade  
ER Status 
PR Status 
Prognostic Stage Group IIIB 
T2 
N1 
3 
Positive 
Negative 
T3 
N0 
3 
Positive 
Negative 
T0-2 
N2 
2 
Positive 
Negative 
T0-2 
N2 
2 
Negative 
Positive 
T0-2 
N2 
3 
Positive 
Positive 
T3 
N1-2 
2 
Positive 
Negative 
T3 
N1-2 
2 
Negative 
Positive 
T3 
N1-2 
3 
Positive 
Positive 
T4 
N0-2 
2 
Positive 
Positive 
Any 
N3 
2 
Positive 
Positive 
Prognostic Stage Group IIIC 
T2 
N1 
3 
Negative 
Positive 
T3 
N0 
3 
Negative 
Positive 
T0-2 
N2 
3 
Positive 
Negative 
T0-2 
N2 
3 
Negative 
Positive 
T3 
N1-2 
3 
Positive 
Negative 
T3 
N1-2 
3 
Negative 
Positive 
T4 
N0-2 
1 or 2 or 3 
Positive 
Negative 
T4 
N0-2 
1 or 2 or 3 
Negative 
Positive 
T4 
N0-2 
3 
Positive 
Positive 
Any 
N3 
1 or 2 or 3 
Positive 
Negative 
Any 
N3 
1 or 2 or 3 
Negative 
Positive 
Any 
N3 
3 
Positive 
Positive 
*If Oncotype Dx® was performed and the recurrence score is less than 11, then T1-2, N0, grade 1-3 patients 
would be considered to be Prognostic Group IA 


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14.2 
Appendix 2: 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 based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
and Co-Medication Considerations (v06 release date: 2016), which was compiled from the 
Indiana 
University 
School 
of 
Medicine’s 
“Clinically 
Relevant” 
Table 
(medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies - Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.p
df), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation and/or Torsades de Pointes 
(TdP), refer to the CredibleMeds® website (qtdrugs.org/). 
These lists are not comprehensive and are only meant to be used as a guide. Please contact the 
medical monitor with any questions. 
Table 14-3 
List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
VIEKIRA PAK2, indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat (GS-
9350), indinavir, ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir, 
elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, 
voriconazole, mibefradil, clarithromycin, posaconazole, telithromycin, 
grapefruit juice, conivaptan, nefazodone, nelfinavir, saquinavir, idelalisib, 
boceprevir, darunavir/ritonavir 
Strong CYP3A4/5 inducers 
Avasimibe2,3, carbamazepine, enzalutamide, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum 
perforatum)3 
CYP3A substrates with NTI1 
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, astemizole, cisapride, 
cyclosporine, diergotamine (dihydroergotamine), ergotamine, fentanyl, 
lovastatin, nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, 
simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine, lomitapide 
Medications with a known risk 
for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl, mesoridazine, 
methadone, moxifloxacin, ondansetron (i.v. only), oxaliplatin, papaverine HCl 
(intra-coronary), pentamidine, pimozide, procainamide, propofol, quinidine, 
sevoflurane, sotalol,   sulpiride, terfenadine, thioridazine, vandetanib 
Herbal preparations/ 
medications 
Herbal preparations/medications known as strong inducers or inhibitors of 
CYP3A4/5 are prohibited throughout the study. These herbal medications 
include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. Patients should stop using these herbal medications 7 days prior to 
first dose of study drug. 


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Category 
Drug Name 
Other investigational and anti-
neoplastic therapies 
Other investigational therapies must not be used while the patient is on the 
study. Anti-neoplastic therapy (chemotherapy, biologic or radiation therapy, 
and surgery) other than the study treatments must not be given to patients 
while the patient is on the study treatment. If such agents are required for a 
patient then the patient must discontinue 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). 
2 Herbal product 
3 P-gp inducer 
4 Source: qtdrugs.org (as of March 2, 2018) 
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.  
Table 14-4 
List of medications to be used with caution during study drug 
treatment 
Category 
Drug Name 
Moderate CYP3A4/5 inhibitors 
Amprenavir, atazanavir, casopitant, cimetidine, darunavir, diltiazem, 
fosamprenavir netupitant, tofisopam, verapamil, crizotinib, faldaprevir, imatinib, 
nilotinib 
Moderate CYP3A4/5 inducers 
Bosentan, efavirenz, etravirine, genistein, lersivirine, modafinil, nafcillin, 
talviraline, semagacestat, lopinavir 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine, alisoporivir, almorexant, aplaviroc, apixaban (doses 
< 2.5 mg only), atazanavir, atorvastatin, avanafil, bosutinib, brecanavir, 
brotizolam, budesonide, buspirone, capravirine, casopitant, 
danoprevir,darifenacin, darunavir, dasatinib, ebastine, eletriptan, elvitegravir, 
eplerenone, everolimus, felodipine, fluticasone, ibrutinib, ivacaftor, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, naloxegol, neratinib, 
perospirone, quetiapine, ridaforolimus, sildenafil, simeprevir, ticagrelor, tilidine, 
tipranavir, tolvaptan, triazolam, ulipristal, vardenafil, vicriviroc, voclosporin 
Strong BSEP inhibitors 
Alectinib, atazanavir, bromocriptine, Bosentan, clofaziminie, cerivastatin, 
fusidate, glibenclamide, glyburide, nefazadone, paritaprevir, pioglitazone, 
reserpine, rosiglitazone, sulindac, troglitazone (TGZ-sulfate), valinomycin 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine, atazanavir, 
atomoxetine, asenapine, bedaquiline, bortezomib, buprenorphine, capecitabine, 
ceritinib, clomipramine, crizotinib, clozapine, cyamemazine (cyamepromazine), 
dabrafenib, dasatinib, degarilix, delamanid, desipramine, dexmedetomidine, 
dolasetron, eribulin, ezogabine, famotidine, felbamate, fingolimod, foscarnet, 
gatifloxacin, gemifloxacin, granisertron, hydrocodone-ER, iloperidone, 
imipramine (melipramine), isradipine, lapatinib, lenvatinib, leuprolide, 
loperamide, lithium, metolazone, mifepristone, mirabegron, mirtazapine, 
moexipril, norfloxacin, nortriptyline, ofloxacin, olanzapine, osimertinib, 
ondansetron (p.o. only at 4 mg or 8 mg), oxytocin, paliperidone, panabinostat, 
pasireotide, pazopanib, pipamperone, promethazine, propafenone, quetiapine, 
ranolazine, rilpivirine, risperidone, roxithromycin, sertindole, sorafenib, sunitinib, 
telavancin, tetrabenazine, tizanidine, tolterodine, toremifene, tramadol, 
trimipramine, vardenafil, vemurafenib, venlafaxine, vorinostat, ziprasidone 
MATE1 and OCT2 substrates3 
Acyclovir, amantadine, amiloride, apricitabine, carboplatin, cisplatin, cephalexin, 
cephradine, cimetidine, dofetilde, famotidine, fexofenadine, furamidine, 
ganciclovir, glycopyrronium, Ipratropium, lamivudine, linagliptin, memantine, 
metformin (also a substrate for OCT1, MATE1, and MATE2K), oxyplatin, 
pindolol, plisicainide, pramsorafenib, ranitidine, topotecan, tropisetron, trospium, 
umeclidinium, varencicline, zidovudine 


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Category 
Drug Name 
BCRP substrates 
Daunorubicin, doxorubicin, ethinyl estradiol methotrexate, mitoxantrone, 
pitavastatin, rosuvastatin, sulfasalazine, sofosbuvir, tenofovir 
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 Source: qtdrugs.org (as of March 02,, 2018) 
3 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
implications for Dosing and Labeling (February 2012) and Yonezawa and Inui (2011) Importance of the multidrug 
and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and 
pharmacogenomics. Br J Pharmacology 164:1817-25; www.druginteractioninfo.org (as of May, 2016) 
 

SAP_000.pdf: 
Clinical Development
Ribociclib (LEE011)
CLEE011G2301 / NCT03078751
An open label, multi-center protocol for U.S. patients 
enrolled in a study of ribociclib with endocrine therapy as 
an adjuvant treatment in patients with hormone receptor-
positive, HER2-negative, high risk early breast cancer 
Statistical Analysis Plan (SAP)
Amendment 2
Author:
, Trial Statistician
Document type:
SAP Documentation
Document status:
Final
Release date:
24-Feb-2020
Number of pages:
26
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
SAP
Document History – Changes compared to previous final version of SAP
Date
Time Point
Reasons 
for 
update
Outocme 
for 
update
Section 
and 
title impacted 
(Current)
31-May-2017 
Before DBL
First Version
01-May-2019
Before DBL
The trial had an 
early enrollment 
closure on 12 
February 2018; 
the protocol was 
amended on 
April 2018. 
The study is 
now a Phase II 
trial. All 
sections related 
to Efficacy 
analysis has 
been removed.
Efficacy data 
will be 
summarized by 
a listing only. 
All the sections 
of the earlier 
version has 
been impacted
23-Feb-2020
Before DBL
1. Add one lab 
param for the 
shift table.
2. Clarify which 
CRS version 
will be used.
3. For exposure 
data, GnRH
agonist will be 
combined with 
ET to report.
1. Blood 
Creatinine was 
added to report.
2. Added a 
sentence to use 
the most up-to-
date CRS.
3. For exposure 
data, GnRH was 
combined with 
ET to report.
1. Section 4.3
2. section 
2.7.1.1
3. section 2.4.1


Novartis
SAP
Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ..........................................................................................................10
2.2.1
Subgroup of interest ..............................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment adherence/ compliance................................................12
2.4.2
Primary endpoint...................................................................................13
2.4.3
Handling of missing values/censoring/discontinuations.......................13
2.4.4
Supportive analyses...............................................................................13
2.5
Analysis of the key secondary objective ...............................................................13
2.6
Analysis of secondary efficacy objective(s)..........................................................13
2.7
Safety analyses.......................................................................................................13
2.7.1
Adverse events (AEs)............................................................................13
2.7.2
Deaths....................................................................................................15
2.7.3
Laboratory data .....................................................................................15
2.7.4
Other safety data ...................................................................................17
2.8
Pharmacokinetic endpoints....................................................................................19
2.9
PD and PK/PD analyses.........................................................................................19
2.10
Biomarkers.............................................................................................................19
2.11
Power for analysis of key secondary variables......................................................19
3
Change to protocol specified analyses ..............................................................................19
4
Appendix ...........................................................................................................................19
4.1
Imputation rules.....................................................................................................19
4.1.1
Study drug.............................................................................................19
4.1.2
AE, ConMeds and safety assessment partial date imputation...............20
4.2
AEs coding/grading ...............................................................................................22
4.3
Laboratory parameters derivations ........................................................................23
4.4
Statistical models...................................................................................................26


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Reference...........................................................................................................................26


Novartis
SAP
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DDFS
Distant disease-free survival
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
iDFS
Invasive disease-free survival
IRT
Interactive Response Technology
LRRFS
Loco-regional recurrence-free survival
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
OS
Overall Survival
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
QoL
Quality of Life
RFS
Recurrence-free survival
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


Novartis
SAP
1
Introduction
This statistical analysis plan (SAP) describes all planned analysis for the clinical study report(s) 
(CSR) of study CLEE011G2301, an open label, multicenter, Phase II, U.S based study to 
evaluate safety of ribociclib with endocrine therapy as an adjuvant treatment in patients with 
hormone receptor-positive, HER2-negative, high risk early breast cancer.
The content of this SAP is based on protocol CLEE011G2301 version 02. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock and unblinding of the study data.
1.1
Study design
This was a randomized, phase III, double-blind, placebo-controlled, multi-center, international 
study to evaluate efficacy and safety of ribociclib with ET as an adjuvant treatment in patients 
with HR-positive, HER2-negative, high risk early breast cancer. 
Following the protocol amendment 02, this study is now an open label, multi-center phase II 
conducted in the U.S only. The study has been closed to enrollment. All randomized patients 
were unblinded; patients randomized to placebo permanently discontinued study treatment and 
patients randomized to ribociclib were offered the option to continue treatment with ribociclib 
+ ET (excluding tamoxifen). Patients randomized to placebo have to complete 30-day safety 
follow up after the last dose of placebo.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1 Objectives and related endpoint
Objective
Endpoint
Primary
To evaluate the preliminary safety and tolerability 
of the ribociclib + ET in patients that were 
randomized to ribociclib + ET prior to the early 
closure of enrollment.
Tolerability and Safety of the 
treatment regimen based on frequency 
and severity of AEs, laboratory and 
ECG abnormalities


2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis. SAS version 9.4 or later will be used to 
perform all data analyses and to generate tables, figures and listings.
Data included in the analysis
All data collected up to the last patient last visit will be used in the analysis. 
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. Protocol deviations, number of patients in analysis populations and 
discontinuations from study treatment will be summarized by center.
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the ribociclib/placebo only. Whereas, study treatment will 
refer to ribociclib + endocrine therapy (ET) and placebo + ET. In this study, ET may include 
tamoxifen, letrozole, anastrozole or  exemestane. For premenopausal women, ET also include 
GnRH agonist to suppress ovarian function. ET alone after discontinuation of the 
ribociclib/placebo is not considered a “study treatment”.
The term investigational treatment may also be referred to as study treatment which is used 
througouht this document.
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) (e)CRF. The date of first administration of investigational drug will also be 
referred as start of investigational drug.


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Date of last administration of investigational drug
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug is administered and recorded on DAR eCRF. The date of last 
administration of investigational drug will also be referred as end of investigational drug.
Date of first administration of study treatment 
The date of first administration of study treatment will be derived as the first date on/after 
randomization when a nonzero dose of any component of study treatment was administered as 
per the (e)CRF. (Example: if randomization date is 03-Jan-2015, and 1st dose of ribociclib is 
administered on 05-Jan-2015, and 1st dose of ET is administered on 03-Jan-2015, then the date 
of first administration of study treatment is on 03-Jan-2015). 
ET prior to and on/after randomization will be entered in the Adjuvant Endocrine Therapy eCRF 
page. First date on/after randomization of ET will be derived based on the start and end dates 
in the eCRF. (Example: randomization date is 03-Jan-2015, if ET with non-zero dose has a start 
date of 15-Dec-2014 and an end date on/after randomization, then first date on/after 
randomization of ET will be 03-Jan-2015; if ET start date is 15-Dec-2014 and end date is 02-
Jan-2015, then restarts non-zero dose on 04-Jan-2015, then first date on/after randomization of 
ET will be 04-Jan-2015; in special cases in which start date is before randomization and end 
date is missing, then patient is ongoing and first date on/after randomization of ET will be date 
of randomization)
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of study treatment was administered as per (e)CRF. For patients who take at least one dose 
of ribociclib/placebo, date of last administration of study treatment is the last date when a non-
zero dose of ribociclib/placebo was administered. So date of last administration of study 
treatment is the same as date of the last administration of investigational drug for these patients. 
For patients who only take ET on/after randomization but no ribociclib/placebo, date of last 
administration of study treatment is defined as the date of first administration of study treatment.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption etc.) is the start of study 
treatment.
The reference start date for all other, non-safety assessments (e.g., recurrence assessment,) is
the date of randomization.


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The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25.
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 
the context of baseline definition, the efficacy evaluations also include PRO and performance 
status.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment.
For ECGs, the study requires triplicates per time point. The average of theses measurements 
would be calculated for baseline. In case ribociclib/placebo dosing time is recorded on the date 
of first dose of study treatment along with the ECG, the last available assessment before the 
ricobiclib/placebo start date/time will be used for baseline.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory or collected for ECGs 
or vital signs, then the last value should be considered as baseline. The last value refers to the 
one with a larger repeated sequence number recorded in the eCRF.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments, based on AE start date: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  


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However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and strata, they have been assigned to during the randomization procedure.
Safety
The Safety set includes all randomized subjects who received any study treatment (i.e. at least 
one dose of ribociclib/placebo or ET). Subjects will be analyzed according to the study 
treatment actually received.
The actual treatment received corresponds to:
-
the randomized treatment if patients took at least one dose of that treatment.
-
the first treatment received if the randomized treatment was never received
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-2. 
Table 2-2 Subject classification based on protocol deviations and non-PD criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No dose of study treatment 
Withdrawal of Informed Consent
Any data collected in the clinical database with a date after a subject withdraws informed 
consent from all further participation in the trial, will not be included in the analysis.  The date 
on which a patient withdraws full consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. biomarker etc., collected in 
the clinical database without having obtained that consent will not be included in the analysis. 
These data will be excluded by the presence of the appropriate protocol deviation criterion.


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2.2.1
Subgroup of interest
Efficacy
Not applicable
Safety
Not applicable
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
patients and listings will be reported by treatment arm to assess baseline comparability.  No 
inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups, race, ethnicity, region, ECOG
Preformance Status), will be summarized by frequency counts and percentages; the number and 
percentage of patients with missing data will be provided. Continuous data (e.g. age, weight, 
height, body mass index) will be summarized by descriptive statistics (N, mean, median, 
standard deviation, Q1, Q3, minimum and maximum). BMI (kg/m2) will be calculated as 
weight[kg] / (height[m]2) using weight at Baseline.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The number (%) of randomized patients included in the FAS will 
be presented overall and by treatment group.. The number (%) of patients in the FAS who are 
still on treatment, who discontinued the study phases and the reason for discontinuation will be 
presented overall and by treatment group.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on eCRF page 
not completed for any study treatment component, ‘DAR’ eCRF page for 
ribociclib/placebo, ‘Adjuvant endocrine therapy’ eCRF page for ET and ‘GnRH 
(Gonadotropin-Releasing Hormone) Agonist Therapies’ eCRF page for GnRH; for 
ET and GnRH page, only dose administered on/after randomization will be 
considered)

Primary reason for not being treated (based on “End of Treatment Phase Completion” 
eCRF page) 


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
Number (%) of patients who were treated (based on eCRF pages of each study 
treatment component completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment 
Phase’ page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
‘End of Treatment Phase’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment Phase’ page)
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) overall and by treatment group 
for the FAS. Major protocol deviations leading to exclusion from analysis sets will be tabulated 
separately overall and by treatment group. All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment adherence/ compliance
Duration of exposure, will be summarized by treatment arm, for ribociclib/placebo. Exposure 
summaries for ET and GnRH will also be summarized by treatment arm. Duration of exposure
will be categorized into time intervals; frequency counts and percentages will be presented for 
the number (%) of subjects in each interval. 
Subject level listings of all doses administered on treatment (for ET, also after the treatment 
phase) along with dose change reasons will be produced.  
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to investigational drug, control drug and combination 
partner
The study treatment has the following components:

Investigational drug: ribociclib/placebo

Combination partner
o
ET: Any of letrozole, anastrozole and exemestane and GnRH agonist
The duration of exposure to ribociclib/placebo, ET will be summarized. 
Duration of exposure to ribociclib/placebo and ET (tamoxifen, letrozole, anastrozole, 
exemestane and GnRH agonist) during the treatment phase will be calculated as:  


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Duration of exposure (days) during the treatment phase = (last date of exposure during the 
treatment phase) – (first date of exposure on/after randomization) + 1.
The last date of exposure during the treatment phase is defined as follows for ribociclib/placebo 
and ET:

For ribociclib/placebo: the last date of exposure is defined as the date of last 
administration of ribociclib/placebo; the first date of exposure is defined as the date of 
first administration of ribociclib/placebo

For ET: the last date of exposure during the treatment phase is defined as the date of last 
administration of any ET on/before the last date of exposure of ribociclib/placebo; the first 
date of exposure is defined as the date of first administration of any ET on/after 
randomization. 

In rare cases in which patient does not have any ribociclib/placebo but have ET on/after 
randomization, the last date of exposure of ET during the treatment phase is defined as the 
date of first exposure of ET on/after randomization
2.4.2
Primary endpoint
The primary endpoints of this study are the tolerability and safety of the treatment regimen 
based on frequency and severity of AEs, laboratory and ECG abnormalities. Descriptive 
summaries of key safety and baseline characteristics will be provided. These include summaries 
of treatment duration exposure, adverse events, labs, and ECG findings.  The details can be 
found in section 2.7.
2.4.3
Handling of missing values/censoring/discontinuations
Not applicable
2.4.4
Supportive analyses
Not applicable 
2.5
Analysis of the key secondary objective
Not applicable
2.6
Analysis of secondary efficacy objective(s)
Not applicable
2.7
Safety analyses
All safety analyses will be based on the safety set. 
2.7.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 


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relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the ribociclib + ET arm.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths (number and % of subjects who died, with any AE, any SAE),  AEs 
by SOC and PT, summarized by relationship (all AEs and AEs related to study treatment), 
seriousness (SAEs and non-SAEs), leading to treatment discontinuation, and leading to fatal 
outcome. In addition, a summary of serious adverse events with number of occurrences will
also be produced (an occurrence is defined as >1 day between start and prior end date of record 
of same preferred term). 
2.7.1.1
Adverse events of special interest / grouping of AEs
In this section the Adverse Events of Special Interest (AESI), safety risks as defined in the 
Safety Profiling Plan (SPP) and Risk Management Plan (RMP) and their targeted analyses will 
be described. Each risk consist of one or more well-defined safety events which are similar in 
nature and for which there is a specific clinical or safety interest in connection with the study 
treatment.
All AE grouping will be stored in the Compound Case Retrieval Strategy sheet (CRS) with 
clear versioning and reference to the MedDRA version used. 
All AESIs will exclusively be based on adverse events only. The case retrieval sheet contains 
all MedDRA terms which need to be considered for case retrieval (NMQs, HLGTs, PTs, etc.). 
Note that certain adverse events may be reported within multiple groupings.
All AESI definitions or AE grouping need to be specified in the CRS. If a CRS update is 
necessary, the final version needs to be available in a reasonable time ahead of the DBL. The 
CRS version will be included in a footnote of the AESI tables. Table 2-5 provides AESI 
groupings per latest CRS. The most up-to-date version of the CRS will be used at the time of 
the analysis.


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Table 2-5
AESI groupings
AESI grouping
MedDRA category
Anemia
SMQ
Diarrhea
SMQ
Hepatobiliary toxicity
SMQ
Infections
SMQ and SOC
Leukopenia 
HLT
Nausea, emesis
HLT
Neutropenia
HLT and PT
Pulmonary embolism 
SMQ and HLT
QTc interval prolongation
SMQ
Renal impairment
SMQ
Reproductive toxicity
SMQ
Thrombocytopenia
SMQ
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ribociclib. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. An NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. For each specified AESI, number and percentage of patients with at least one event of 
the AESI occurring during on treatment period will be summarized.
2.7.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed, post treatment deaths will be flagged.
Note: “Study indication” as primary reason of death should be coded using MedDRA terms 
based on the diagnosis CRF field at start of study. If not coded accordingly in the database, it 
still must be included in the summary table. Coded reasons for deaths will then be summarized 
by category ‘Study indication’ and ‘Other’ (as selected by the investigator).
2.7.3
Laboratory data
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter collected 
no later than 30 days after the last study treatment administration date (see Section 2.1.1).


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Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
CTCAE version 4.03. The calculation of CTCAE grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5
will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
For hematology: Absolute neutrophils, Absolute granulocytes, Hemoglobin, WBC, Platelet 
counts, PTT.
For Biochemistry: Albumin, Alkaline phosphatase, Blood Creatinine, SGPT (ALT), Amylase, 
SGOT (AST, Total bilirubin, Calcium (hyper & hypo), GGT, Glucose (hyper & hypo), Lipase, 
Magnesium (hyper & hypo), Phosphate, Potassium (hyper & hypo), Sodium (hyper & hypo).
For both groups of laboratory tests, shift tables to compare baseline to the worst postbaseline 
value will be produced using CTCAE grade and normal range.
A single listing for all the laboratory parameters with grades, normal ranges and lab values
flagged to indicate that the values are outside the normal range will be reported.
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized:
The following summaries will be produced:

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > ULN

TBL > 2xULN

TBL > 3xULN

ALP > 1.5xULN

ALP > 2xULN

ALP > 3xULN

ALP > 5xULN

ALP > 8xULN


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
ALP > 10xULN

Combined categories of ALT/AST and total bilirubin: e.g., ALT or AST > 3xULN & 
TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (biochemistry Hy’s law)   
2.7.4
Other safety data
2.7.4.1
ECG data
Data handling
The study requires ECG triplicates at any assessment, so the average of the ECG parameters at 
that assessment will be used in the analyses. For unscheduled assessments, 15-minute windows 
will be applied to group assessments for averaging.
Data analysis
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained for each subject 
during the study. ECG data will be read and interpreted centrally.
ECG data will be summarized by presenting summary statistics of the raw data and change from 
baseline by treatment group and time point. The following parameters will be assessed: QTcF, 
QT, PR, and QRS intervals in msec, heart rate (bpm), and RR. Shift table will be presented for 
QTcF and QT by treatment arm. 
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm. 

QT, QTcF
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤  60ms
-
Increase from Baseline of > 60 ms

HR
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

PR
-
Increase from baseline >25% and  to a value > 200 ms
-
New value of PR> 200 ms

QRS
-
Increase from baseline >25% and to a value > 120 ms 
-
New value of QRS > 120 ms 


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A newly occurring notable ECG value is defined as an abnormal post-baseline ECG value that 
is not present at baseline. Baseline is defined as the average of the last ECG measurements 
(triplicate) taken on or before date of first dose of study treatment. In case ribociclib/placebo 
dosing time is recorded on the date of first dose of study treatment along with the ECG, the last 
available assessment before the ricobiclib/placebo start date/time will be used for baseline. The 
percentage of patients having notable change from baseline ECG values is based on the number 
of patients with both a baseline and post-baseline assessment.
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. A separate listing of only the subjects with notable ECG values may also be produced. 
In the listing, the assessments collected during the post-treatment period will be flagged.
The safety set will be used for all summary tables and individual listings. 
2.7.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm) (only during screening), weight (kg), body 
temperature (°C), heart rate (beats per minute), systolic and diastolic blood pressure (mmHg). 
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-6 
below.
Table 2-6
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from baseline
decrease  > 10% from baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1 
-


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The number and percentage of subjects with notable vital sign values (high only/low only/high 
and low) will be presented  by treatment arm. Summary statistic for change from baseline to the 
worst post-baseline value (in both directions, i.e. from baseline to highest post baseline and 
from baseline to lowest post baseline value) will be presented by treatment arm.
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable vital sign values may also be 
produced. In the listing, the assessments collected outside of on-treatment period will be flagged. 
2.8
Pharmacokinetic endpoints
Not applicable
2.9
PD and PK/PD analyses
Not applicable
2.10
Biomarkers
Not applicabe
2.11
Power for analysis of key secondary variables
Not applicable
3
Change to protocol specified analyses
No change from protocol specified analysis was made.
4
Appendix
4.1
Imputation rules
4.1.1
Study drug
The following rule should be used for the imputation of the dose end date for ribociclib/placebo:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available: 
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.  


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Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
The following rules will be used for the imputation of the dose end date for ET:
If the dose end date is completely missing and there is no death date or withdrawal from 
consent date, the patient is considered ongoing. The cut-off date should be used as the last 
date of dose. If there is death date or withdrawal from consent date, then the dose end date 
will be the earlier of the death date and withdrawal from consent date. After imputation, 
compare the imputed date with start date, if the imputed date is < start date of treatment:
Use the treatment start date
4.1.2
AE, ConMeds and safety assessment partial date imputation
Table 4-1
Imputation of partial start dates (AE, CM) and assessments (LB, EG, 
VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY


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Missing 
Element
Rule
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  


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Table 4-2
Imputation of partial end dates (AE, CM) 
Missing 
Element
Rule 
(*=min(last study treatment date plus 30 days, death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. For completely missing end date, it will not be considered as an event 
date for duration of AE analysis.
The above rules will be used for imputation of AE end dates if AE start date is before last dose 
of study treatment. In this study, SAEs suspected to be related with study treatment or ET alone 
after EOT will continue to be collected. The imputation of end date of SAE during the post-
treatment period will be based on the same rules by replacing end date of on-treatment period 
in above table with last contact date. 
4.1.2.1
Other imputations
Not applicable
4.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
The latest available MedDRA version at the time of the analyses will be used. The MedDRA 
version used will be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 


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4.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 4.03 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE version 4.03, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.


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Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.


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Estimated glomerular filtration rate (eGFR) will be calculated using Cockcroft-Gault formula:
 = (140 −) × ( ) × [0.85  ]
72 × $% &' ( /)*)
4.4
Statistical models
Not applicable
5
Reference
1. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
2. Hudis CA, Barlow WE, Constantino JP, et al (2007). Proposal for standardized definitions 
for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol
25:2127-2132.
3. Jeruss JS, Mittendorf EA, Tucker SL, et al (2008). Combined use of clinical and 
pathologic staging variables to define outcomes for breast cancer patients treated with 
neoadjuvant therapy. J Clin Oncol 2: 246-252.