Conditions: Breast Cancer
Keywords: HR-positive HER2-negative advanced breast cancer Ribociclib NSAI Goserelin Docetaxel / capecitabine Paclitaxel/gemcitabine Capecitabine/vinorelbine CDK4/6 inhibitors Phase II ER-positive PR-positive Premenopausal Perimenopausal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 222
Healthy volunteers: no

Brief summary:
To compare the combination of Ribociclib plus goserelin acetate with hormonal therapy versus combination chemotherapy in premenopausal or perimenopausal patients with advanced or metastatic breast cancer

Detailed description:
Patients were randomly assigned to one of the below treatment arms in 1:1 ratio:

* Ribociclib arm: non-steroidal aromatase inhibitor (NSAI) + goserelin + Ribociclib
* Combination chemotherapy arm: Either of docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine based chemotherapy treatment Randomization was stratified by (1) the presence of liver metastases (present or absent) (2) disease-free interval (DFI) \< 2 years (yes or no, de novo stage 4 was defined as DFI \> 2 years).

The study consisted of a 28-day Screening phase, treatment phase (including end of treatment (EOT) visit and safety follow-up), and survival follow-up. Patients received study treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Patients were followed for survival regardless of treatment discontinuation for any reason (except if consent was withdrawn, patient was lost to follow-up, or until death) and regardless of achieving the primary endpoint, until death, withdrawal of consent, or loss to follow-up.

Arms:
arm 1: Combination of non-steroidal aromatase inhibitor: NSAI (letrozole or anastrozole) + goserelin + ribociclib.

1. Ribociclib (600 mg) was dosed orally for the first 21 days out of a 28-day cycle.
2. Letrozole (2.5 mg) or anastrozole (1 mg) were dosed orally daily (28 days out of the 28-day cycle).
3. Goserelin (3.6 mg) was continuously released via a subcutaneous implant injected on Day 1 of each 28-day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days. arm 2: Combination chemotherapies of docetaxel/capecitabine, paclitaxel/gemcitabine or capecitabine/vinorelbine were administered to patients enrolled in the control group. The chemotherapy regimen was decided by the treating physician.

Interventions: intervention 1: Docetaxel / Capecitabine intervention 2: Capecitabine / Vinorelbine intervention 3: Paclitaxel / Gemcitabine intervention 4: Ribociclib intervention 5: Letrozole OR Anastrozole intervention 6: Goserelin
Intervention descriptions: intervention 1: Docetaxel (IV Infusion) / Capecitabine (Tablets for oral use):

Docetaxel once, on day 1 of the 3-weeks cycle. Capecitabine twice daily, on Days 1 to 14, followed by a 1-week rest period, in 3 weeks cycle.

Docetaxel (60 - 75 mg/m²)/capecitabine (1600 - 2500 mg/m²/day) intervention 2: Capecitabine (Tablets for oral use) / Vinorelbine (Capsule for Oral use/IV infusion ).

Capecitabine twice daily on day 1 to 14, followed by a 1-week rest period, in 3 weeks cycle.

Vinorelbine, once, on Day 1 and Day 8 in 3 weeks cycles.

Capecitabine (1600 - 2500 mg/m2/day)/vinorelbine (60 to 80 mg/m2/day \[oral\] or (25 to 30 mg/m2 \[IV infusion\] intervention 3: Paclitaxel (IV Infusion) / Gemcitabine (IV Infusion):

Paclitaxel via 3-hour intravenous (IV) infusion on Day 1 in 3-weeks cycles, OR Paclitaxel via 1 hour intravenous (IV) infusion on Day 1 and day 8- in 3-weeks cycles.

Gemcitabine at via 30 minute IV infusion on Day 1 and Day 8 in 3 weeks cycles.

Paclitaxel (175 mg/m2) (on Day 1 in 3-weeks cycles)/ gemcitabine (1000 - 1250 mg/m2)

OR

Paclitaxel (80 - 90 mg/m2) (on Day 1 and Day 8 in 3-weeks cycles) / gemcitabine (800 - 1250 mg/m2) intervention 4: Dose: 600 mg (200 mg \* 3) Days 1 to 21 of each 28 day cycle Tablets for oral use intervention 5: Letrozole:

Dose: 2.5 mg All days of every cycle without interruption). Tablets for oral use

Anastrozole:

dose: 1 mg All days of every cycle without interruption. Tablets for oral use

The NSAI (letrozole or anastrozole) will be decided by the treating physician. intervention 6: Dose: 3.6 mg Day 1 of each 28 day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days.

Subcutaneous implant

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
LEE011/ribociclib 
Clinical Trial Protocol CLEE011A3201C / NCT03839823
A phase II randomized study of the combination of 
Ribociclib plus goserelin acetate with Hormonal Therapy 
versus physician choice chemotherapy in premenopausal 
or perimenopausal patients with hormone receptor-
positive/HER2-negative inoperable locally advanced or 
metastatic breast cancer - RIGHT Choice Study 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017)
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
Not applicable 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
04-Mar-2021


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 30 
1.1 
Background ............................................................................................................ 30 
1.1.1 
Epidemiology ........................................................................................ 30 
1.1.2 
Treatment options for premenopausal women with hormone 
receptor positive (HR+), HER2-negative premenopausal advanced 
breast cancer .......................................................................................... 30 
1.1.3 
Role of the CDK4/6 pathway in breast cancer ...................................... 32 
1.1.4 
Introduction to investigational treatment(s) and other study 
treatment(s) ........................................................................................... 33 
1.1.5 
Potential for drug-drug interactions ...................................................... 44 
1.1.6 
Endocrine therapy versus chemotherapy: ............................................. 44 
1.2 
Purpose .................................................................................................................. 45 
2 
Objectives and endpoints ................................................................................................... 46 
3 
Study design ...................................................................................................................... 48 
3.1.1 
Screening phase ..................................................................................... 50 
3.1.2 
Treatment phase .................................................................................... 50 
3.1.3 
Survival follow-up ................................................................................ 51 
3.1.4 
Timing of interim analyses and design adaptations .............................. 51 
3.1.5 
Treatment period ................................................................................... 51 
3.1.6 
Definition of end of treatment ............................................................... 51 
3.1.7 
Definition of end of the study ............................................................... 51 
3.1.8 
Early study termination ......................................................................... 52 
4 
Rationale ............................................................................................................................ 52 
4.1 
Rationale for study design ..................................................................................... 52 
4.2 
Rationale for choice of control drugs or combination drugs ................................. 52 
4.3 
Rationale for dose/regimen and duration of treatment .......................................... 53 
4.4 
Purpose and timing of interim analyses ................................................................. 54 
4.5 
Risks and benefits .................................................................................................. 54 
4.5.1 
Potential risks to clinical trial participants ............................................ 54 
4.5.2 
Potential benefits to clinical trial participants ....................................... 55 


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5 
Population .......................................................................................................................... 55 
5.1 
Inclusion criteria .................................................................................................... 55 
5.2 
Exclusion criteria ................................................................................................... 57 
6 
Treatment ........................................................................................................................... 60 
6.1 
Study treatment ...................................................................................................... 60 
6.1.1 
Investigational and control drugs .......................................................... 61 
6.1.2 
Treatment arms/group ........................................................................... 62 
6.1.3 
Additional study treatments .................................................................. 62 
6.1.4 
General dosing guidelines ..................................................................... 62 
6.1.5 
Additional dosing guidelines for scheduled visit days .......................... 65 
6.1.6 
Guidelines for continuation of treatment .............................................. 65 
6.1.7 
Treatment duration ................................................................................ 65 
6.2 
Other treatments..................................................................................................... 66 
6.2.1 
Concomitant therapy ............................................................................. 66 
6.2.2 
Prohibited medication ........................................................................... 69 
6.2.3 
Drugs with QT prolongation ................................................................. 70 
6.2.4 
Concomitant medications associated with menopausal status .............. 70 
6.2.5 
Rescue medication ................................................................................ 70 
6.3 
Subject numbering, treatment assignment, randomization .................................... 70 
6.3.1 
Patient numbering ................................................................................. 70 
6.3.2 
Treatment assignment, randomization .................................................. 71 
6.4 
Treatment blinding ................................................................................................ 71 
6.5 
Dose escalation and dose modification.................................................................. 71 
6.5.1 
Dose modifications - Ribociclib treatment arm .................................... 71 
6.5.2 
Adjustment of starting dose in special populations - Renal 
impairment for Ribociclib treatment arm .............................................. 79 
6.5.3 
Dose modifications – combination chemotherapies arm ...................... 80 
6.5.4 
Follow-up for toxicities ......................................................................... 86 
6.6 
Additional treatment guidance ............................................................................... 86 
6.6.1 
Treatment compliance ........................................................................... 86 
6.6.2 
Disposal and destruction ....................................................................... 86 
6.7 
Preparation and dispensation ................................................................................. 86 
6.7.1 
Handling of study treatment and additional treatment .......................... 88 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 89 
7 
Informed consent procedures ............................................................................................ 89 
8 
Visit schedule and assessments ......................................................................................... 90 
8.1 
Screening ............................................................................................................... 97 


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8.1.1 
Eligibility screening .............................................................................. 97 
8.1.2 
Information to be collected on screening failures ................................. 97 
8.2 
Subject demographics/other baseline characteristics............................................. 98 
8.3 
Efficacy .................................................................................................................. 98 
8.3.1 
Efficacy Assessment ............................................................................. 98 
8.3.2 
Imaging tumor assessments................................................................... 99 
8.3.3 
Appropriateness of efficacy assessments ............................................ 102 
8.4 
Safety ................................................................................................................... 102 
8.4.1 
Performance status .............................................................................. 103 
8.4.2 
Laboratory evaluations ........................................................................ 104 
8.4.3 
Electrocardiogram (ECG) ................................................................... 106 
8.4.4 
Appropriateness of safety measurements ............................................ 107 
8.5 
Patient reported outcomes (PRO) ........................................................................ 107 
 
 108 
 
 108 
 
 109 
9 
Study discontinuation and completion ............................................................................ 111 
9.1 
Discontinuation .................................................................................................... 111 
9.1.1 
Discontinuation of study treatment ..................................................... 111 
9.1.2 
Withdrawal of informed consent ......................................................... 112 
9.1.3 
Lost to follow-up ................................................................................. 113 
9.1.4 
Early study termination by the sponsor ............................................... 113 
9.2 
Study completion ................................................................................................. 113 
10 Safety monitoring and reporting ...................................................................................... 114 
10.1 
Definition of adverse events and reporting requirements .................................... 114 
10.1.1 
Adverse events .................................................................................... 114 
10.1.2 
Adverse events of special interest ....................................................... 117 
10.1.3 
SAE reporting...................................................................................... 117 
10.1.4 
Pregnancy reporting ............................................................................ 118 
10.1.5 
Serious adverse events ........................................................................ 118 
10.1.6 
Reporting of study treatment errors including misuse/abuse .............. 119 
10.2 
Additional Safety Monitoring .............................................................................. 119 
10.2.1 
Data Monitoring Committee ............................................................... 119 
10.2.2 
Steering Committee ............................................................................. 120 
11 Data Collection and Database management .................................................................... 120 
11.1 
Data collection ..................................................................................................... 120 
11.2 
Database management and quality control .......................................................... 120 


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11.3 
Site monitoring .................................................................................................... 121 
12 Data analysis and statistical methods .............................................................................. 121 
12.1 
Analysis sets ........................................................................................................ 122 
12.1.1 
Full Analysis Set ................................................................................. 122 
12.1.2 
Safety Set ............................................................................................ 122 
12.1.3 
Per-protocol Set ................................................................................... 122 
12.2 
Subject demographics and other baseline characteristics .................................... 122 
12.3 
Treatments ........................................................................................................... 122 
12.4 
Analysis of the primary endpoint ........................................................................ 123 
12.4.1 
Definition of primary endpoint ........................................................... 123 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 123 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 123 
12.4.4 
Sensitivity and Supportive analyses .................................................... 124 
12.5 
Analysis of secondary endpoints ......................................................................... 124 
12.5.1 
Efficacy endpoints ............................................................................... 124 
12.5.2 
Safety endpoints .................................................................................. 125 
12.5.3 
Patient reported outcomes ................................................................... 127 
 
 127 
 
 127 
 
 128 
12.7 
Interim analyses ................................................................................................... 128 
12.8 
Sample size calculation........................................................................................ 128 
13 Ethical considerations and administrative procedures .................................................... 129 
13.1 
Regulatory and ethical compliance ...................................................................... 129 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 129 
13.3 
Publication of study protocol and results............................................................. 130 
13.4 
Quality Control and Quality Assurance ............................................................... 130 
14 Protocol adherence .......................................................................................................... 131 
14.1 
Protocol Amendments ......................................................................................... 131 
15 References ....................................................................................................................... 132 
16 Appendices ...................................................................................................................... 138 
16.1 
Appendix 1 – Concomitant medication ............................................................... 138 
16.2 
Appendix 2: Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1) .............. 142 
16.2.1 
Introduction ......................................................................................... 143 
16.2.2 
Efficacy assessments ........................................................................... 143 
16.2.3 
Definitions ........................................................................................... 144 


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16.2.4 
Methods of tumor measurement - general guidelines ......................... 145 
16.2.5 
Baseline documentation of target and non-target lesions ................... 146 
16.2.6 
Follow-up evaluation of target and non-target lesions ........................ 147 
16.2.7 
Evaluation of overall lesion response ................................................. 152 
16.3 
Efficacy definitions .............................................................................................. 152 
16.3.1 
Best overall response........................................................................... 152 
16.3.2 
Time to event variables ....................................................................... 155 
16.4 
Data handling and programming rules ................................................................ 163 
16.4.1 
Study/project specific decisions .......................................................... 163 
16.4.2 
End of treatment phase completion ..................................................... 163 
16.4.3 
End of post-treatment follow-up (study phase completion) ................ 164 
16.4.4 
Medical validation of programmed overall lesion response ............... 164 
16.4.5 
Programming rules .............................................................................. 165 
16.5 
References (available upon request) .................................................................... 166 
16.6 
Appendix 3 – Patient Reported Outcomes FACT-B ........................................... 168 
16.7 
Appendix 4 -Bone Marrow Reserve in Adults .................................................... 171 
 
List of tables 
Table 1-1 
Goserelin and third generation AIs in metastatic premenopausal 
BC patients ............................................................................................ 39 
Table 2-1 
Objectives and related endpoints .......................................................... 46 
Table 4-1 
Treatment information .......................................................................... 53 
Table 6-1 
Investigational and control drug ............................................................ 61 
Table 6-2 
Dose modification guideline-Ribociclib ............................................... 72 
Table 6-3 
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions ........................................................... 73 
Table 6-4 
Ribociclib dose adjustment and management recommendations for 
hepatic toxicities (CTCAE v4.03) ......................................................... 74 
Table 6-5 
Ribociclib dose adjustment and management recommendations for 
QTcF prolongation (CTCAE v4.03) ..................................................... 78 
Table 6-6 
Ribociclib dose adjustment and management recommendation for 
all other adverse reactions ..................................................................... 79 
Table 6-7 
Dose modifications for suspected toxicities related to paclitaxel ......... 81 
Table 6-8 
Criteria for cycle delay and/or dose reductions of docetaxel ................ 82 
Table 6-9 
Gemcitabine dosage reduction guidelines ............................................. 83 
Table 6-10 
Recommended dose modifications of capecitabine for both 
hematological and non-hematological toxicity ..................................... 84 


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Table 6-11 
Absolute granulocyte and platelet count parameters (Days 8) .............. 85 
Table 6-12 
Packaging and labeling ......................................................................... 88 
Table 8-1 
Assessment Schedule ............................................................................ 92 
Table 8-2 
Imaging Assessment Collection Plan .................................................. 101 
Table 8-3 
Physical Assessments .......................................................................... 103 
Table 8-4 
ECOG performance status ................................................................... 104 
Table 8-5 
Laboratory Assessments ...................................................................... 105 
Table 8-6 
Timing of study procedures ................................................................ 106 
Table 8-7 
Patient reported outcomes collection plan .......................................... 108 
 
 109 
 
 111 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 119 
Table 16-1 
List of prohibited medications during study drug treatment ............... 138 
Table 16-2 
List of medications to be used with caution during study drug 
treatment .............................................................................................. 140 
Table 16-3 
Response criteria for target lesions ..................................................... 148 
Table 16-4 
Response criteria for non-target lesions .............................................. 150 
Table 16-5 
Overall lesion response at each assessment ........................................ 152 
Table 16-6 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 159 
Table 16-7 
Options for event dates used in PFS, TTP, duration of response ........ 161 
 
List of figures 
Figure 3-1 
Schematic representation of the study design ....................................... 49 
 


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List of abbreviations 
ABC 
Advanced Breast Cancer 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
AIs 
Aromatase inhibitors 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
b.i.d. 
bis in die/twice a day 
BMI 
Body Mass Index 
BOR 
Best overall response 
BSA 
Body Surface Area 
BSEP 
Bile salt export pump 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical Benefit rate 
CDKs 
Cyclin-dependent serine-threonine protein kinases 
CDP 
Clinical Development Plan 
CK 
Creatine Kinase 
CMO&PS  
Chief Medical Office and Patient Safety 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CR 
Complete Response 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography  
CTC 
Common Terminology Criteria 
CV 
coefficient of variation 
DFS 
Disease Free Survival 
DILI 
Drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
ER 
Estrogen Receptor 
ESMO-MCBS 
The European Society for Medical Oncology - Magnitude of Clinical 
Benefit Grading Scale 
FAS 
Full Analysis Set 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte-colony stimulating factor 
H 
Hour 
HER2 
Human Epidermal Growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
HR+ 
Human Receptor Positive 
IB 
Investigator’s Brochure 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent to treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LHRH 
Luteinizing Hormone-Releasing Hormone 
MBC 
Metastatic Breast Cancer 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
ml 
milliliter(s) 
OFS 
Ovarian Function Suppression 
ORR 
Overall Response Rate 
OS 
Overall Survival 
p.o. 
oral(ly) 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PgR 
Progesterone receptor 
PK 
Pharmacokinetics 
PLD 
Pegylated liposomal doxorubicin 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
PT  
Prothrombin Time 
Q.D. 
once a day 
QoL 
Quality of Life 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RAP/SAP 
Report and Analysis Plan/ Statistical Analysis Plan 
RBC 
red blood cell(s) 
RECIST 
Response Evaluation Criteria In Solid Tumors 
 
 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
TBIL 
Total bilirubin 
TdP 
Torsades de Pointes 
TTF 
Time to treatment failure 
TTR 
Time to response 
WBC 
White blood cell(s) 
WHO 
World Health Organization  
 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject  
Cohort 
A specific group of subjects fulfilling certain criteria and generally treated 
at the same time 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must 
be obtained  
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy) 
Patient 
An individual with the condition of interest for the study 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, 
Follow-up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned 
Randomization number 
A unique identifier assigned to each randomized subject 
Screen Failure 
A subject who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size 
of the tumor, whether lymph nodes contain cancer, and whether the 
cancer has spread from the original site to other parts of the body 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject. 


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Study treatment 
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures. 
Study treatment 
discontinuation 
When the subject permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation  
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study 
Withdrawal of study 
consent  
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact 
 


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Protocol summary 
Protocol number 
CLEE011A3201C 
Full Title 
A phase II randomized study of the combination of Ribociclib plus goserelin 
acetate with Hormonal Therapy versus physician choice chemotherapy in 
premenopausal or perimenopausal patients with hormone receptor-
positive/HER2-negative inoperable locally advanced or metastatic breast 
cancer – RIGHT Choice Study 
Brief title 
Comparing the combination of Ribociclib plus goserelin acetate with 
hormonal therapy versus combination chemotherapy in premenopausal or 
perimenopausal patients with advanced or metastatic breast cancer 
Sponsor and Clinical 
Phase 
Novartis, Phase II 
Investigation type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
Recent phase III clinical trials demonstrated that CDK4/6 inhibitor plus 
endocrine therapy could generate a tumor response rate higher than 50% 
(in measurable lesions), which is higher than what has been reported by 
most of the chemotherapy regimens in phase III studies. The purpose of 
this trial is to compare the two treatment modalities in the patients with 
aggressive disease in HR+/HER2- metastatic pre/peri-menopausal breast 
cancer setting. 
Primary Objective(s)  
The primary objective of this study is to determine whether treatment with 
NSAI + goserelin+ ribociclib prolongs PFS compared to treatment with 
combination chemotherapy in premenopausal or perimenopausal women 
with HR positive, HER2 negative locally advanced or metastatic breast 
cancer. 
Secondary 
Objectives 
The secondary objectives are listed below: 
• 
To compare time to treatment failure (TTF) between the two 
treatment arms. 
• 
To compare 3-month treatment failure rate between the two 
treatment arms 
• 
To determine whether treatment with NSAI + goserelin + ribociclib 
increases overall response rate (ORR), clinical benefit rate (CBR), 
and Time to response (TTR) compared to treatment with 
combination chemotherapy. 
• 
To compare the overall survival (OS) between two treatment arms. 
• 
To evaluate the safety of ribociclib in combination with NSAI and 
goserelin, and combination chemotherapies. 
• 
To compare patient reported outcomes for health-related quality of 
life in the two treatment arms. 
Study design 
This is a randomized, phase II, open label, multi-center trial comparing the 
combination of NSAI (letrozole or anastrozole) + goserelin + ribociclib 


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versus combination chemotherapy (either of docetaxel + capecitabine, 
paclitaxel + gemcitabine or capecitabine + vinorelbine). Premenopausal or 
perimenopausal women with HR positive, HER2-negative, advanced breast 
cancer with Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 and having symptomatic visceral metastases, or rapid 
progression of disease or impending visceral compromise, or markedly 
symptomatic non visceral disease will be considered for this study. 
An end of treatment (EOT) visit will be performed either at disease 
progression (radiologically documented according to RECIST 1.1 criteria), 
unacceptable toxicity, death, or discontinuation from the study treatment for 
any other reason, including consent withdrawal, patient is lost to follow-up, 
or the sponsor terminates the study (whichever occurs first) and all the end 
of treatment procedures will be completed. End of study will be after at least 
46 months from first patient first visit (FPFV) or when required number of 
OS events have been reached (80% of 222 patients have died), whichever 
occurs first. 
Population 
The study will include approximately 222, adult premenopausal or 
perimenopausal women with ECOG status 0 - 2, HR positive, HER2-
negative, advanced breast cancer and have not received neither prior 
hormonal therapy nor chemotherapies in advanced breast cancer setting. 
To be considered for this study, the patients must have an advanced 
disease status that need combination chemotherapy according to PI’s 
judgment. 
Key Inclusion criteria 
Following are the key inclusion criteria; please refer to Section 5.1 for details 
on and full listing of inclusion criteria. 
1. 
Patient is an adult female ≥ 18 years old and < 60 years old at the 
time of informed consent. Written informed consent must be obtained 
prior to any screening procedures 
2. 
Patient has a histologically and/or cytologically confirmed diagnosis of 
estrogen-receptor positive and/or progesterone receptor positive 
breast cancer based on the most recently analyzed tissue sample 
and all tested by local laboratory. ER should be more than 10% ER 
positive or Allred ≥5 by local laboratory testing. 
3. 
Patient has HER2-negative breast cancer defined as a negative in 
situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a 
negative in situ hybridization (FISH, CISH, or SISH) test is required 
by local laboratory testing and based on the most recently analyzed 
tissue sample. 
4. Women with inoperable locally advanced or metastatic breast cancer 
not amenable to curative therapy. Patients must fulfill at least one of 
the following criteria to be considered that combination chemotherapy 
is needed according to PI’s judgment. However, for patients who are 
eligible under inoperable locally advanced breast cancer or criteria 4c, 
the recruitment is stopped to enrich patient population with visceral 
metastases.  
a 
Symptomatic visceral metastases  
b 
Rapid progression of disease or impending visceral 
compromise. 
c 
Markedly symptomatic non visceral disease if the treating 
physician opts to give chemotherapy for rapid palliation of 
patients’ symptoms. 


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5. Patient is premenopausal or perimenopausal at the time of study 
entry. 
a. 
Premenopausal status is defined as either: 
• Patient had last menstrual period within the last 12 months. 
OR 
• If on tamoxifen within the past 14 days, plasma estradiol and 
FSH are in the premenopausal range, according to local 
laboratory definition. 
• In case of therapy induced amenorrhea, plasma estradiol 
and/or FSH are in the premenopausal range according to 
local laboratory definition. 
• Patients who have undergone bilateral oophorectomy are 
not eligible. 
b. Perimenopausal status is defined as neither premenopausal 
nor postmenopausal  
6. Patients must have not received neither prior hormonal therapy nor 
chemotherapy for advanced breast cancer, except LHRH agonist. 
Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or 
anastrozole) with or without LHRH agonist for advanced breast cancer 
prior to randomization are eligible. Patient must have measurable 
disease, i.e., at least one measurable lesion as per RECIST 1.1 
criteria (a lesion at a previously irradiated site may only be counted as 
a target lesion if there is a clear sign of progression since the 
irradiation). 
Key Exclusion 
criteria 
Following are the key exclusion criteria; please refer to Section 5.2 for 
details and full listing of exclusion criteria. 
1. Patient has received prior systemic anti-cancer therapy (including 
hormonal therapy and chemotherapy, or any CDK4/6 inhibitor for 
advanced breast cancer.  
• Patients who received (neo)adjuvant therapy for breast cancer 
are eligible. If the prior (neo)adjuvant therapy included 
aromatase inhibitors, the treatment free interval must be 
greater than 12 months from the completion of aromatase 
inhibitor treatment until randomization. 
• If patients have disease recurrence during adjuvant tamoxifen 
treatment, disease free interval (defined as duration between 
the dates of patient received complete tumor resection for 
primary breast cancer lesion to the date of disease recurrence 
documented) must be greater than 12 months. 
• Patients who are receiving ≤ 14 days of tamoxifen or NSAI or 
LHRH agonists ≤ 28 days for advanced breast cancer prior to 
randomization are eligible. 
2. Patient has received extended-field radiotherapy ≤ 2 weeks prior to 
randomization or limited field radiotherapy ≤ 2 weeks prior to 
randomization, and has not recovered to grade 1 or better from 
related side effects of such therapy (with the exception of alopecia or 
other toxicities not considered a safety risk for the patient at 
investigator's discretion). Patient from whom ≥ 25% of the bone 
marrow has been previously irradiated are also excluded. 


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3. Patient has a concurrent malignancy or malignancy within 3 years of 
randomization, with the exception of adequately treated, basal or 
squamous cell skin carcinoma, or curatively resected cervical cancer 
in situ. 
Note: Central nervous system (CNS) involvement must be ruled out by 
assessments if a patient has any signs or symptoms indicating potential 
CNS metastases. 
4. Patients who have lung metastases with oxygen demand in resting 
status. 
5. Patients who have liver metastases with bilirubin > 1.5 ULN 
6. Patients with CNS involvement unless they meet ALL of the following 
criteria: 
• 
At least 4 weeks from prior therapy completion (including 
radiation and/or surgery) to starting the study treatment. 
• 
Clinically stable CNS tumor at the time of screening and not 
receiving steroids and/or enzyme inducing anti-epileptic 
medications for brain metastases. 
• 
Leptomeningeal metastases is not allowed, even with stable 
clinical condition. 
Study treatment 
For the patients enrolled in the ribociclib group, ribociclib will be given orally 
once a day on days 1 to 21 of each 28-day cycle. Days 22 to 28 will be a 
“rest” period from ribociclib. Goserelin will be administered as subcutaneous 
implant in Day 1 of each 28-day cycle (irrespective of ribociclib treatment 
cycle). NSAI will be given orally once a day on a continuous daily schedule 
(e.g., days 1-28 of each 28-day cycle). There will be no “rest” period in the 
Goserelin or NSAI schedule.  
Combination chemotherapies of docetaxel + capecitabine, paclitaxel + 
gemcitabine or capecitabine + vinorelbine will be administer to patients 
enrolled in the control group. The chemotherapy regimen will be decided by 
the treating physician. 


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Investigational/ Control 
Drug (Name and Strength) 
Pharmaceutical 
dosage form 
and route of 
administration  
Frequency and/or 
Regimen 
Ribociclib arm (endocrine treatments) 
Ribociclib 600 mg 
(200 mg × 3) 
Tablets for oral 
use 
Days 1-21 of each 
28 day cycle  
Letrozole 2.5 mg 
Tablets for oral 
use 
Daily (all days of 
every cycle without 
interruption). 
Anastrozole 1 mg 
Tablets for oral 
use 
Daily (all days of 
every cycle without 
interruption). 
Goserelin 3.6 mg 
Subcutaneous 
implant 
Day 1 of each 28 
day cycle 
(regardless of 
ribociclib treatment 
cycle) with an 
administration 
window of ± 3 days 
Control arm (combination chemotherapies) 
Docetaxel 
(60 
– 
75 mg/m²)/capecitabine 
(1600 – 2500 mg/m²/day)  
Docetaxel: 
IV Infusion 
Capecitabine: 
Tablets for oral 
use 
Docetaxel: once, on 
day 1 of the 3-weeks 
cycle, Capecitabine: 
twice daily, on Days 1 
to 14, followed by a 
1-week rest period, in 
3 weeks cycle. 
Paclitaxel (175 mg/m2)/ 
gemcitabine 
(1000 
- 
1250 mg/m2) 
 
 
OR 
 
Paclitaxel (80 - 90 mg/m2)/ 
gemcitabine 
(800 - 1250 mg/m2) 
IV infusion 
 
Paclitaxel via 3-hour 
intravenous 
(IV) 
infusion on Day 1 in 
3-weeks 
cycles. 
Gemcitabine at via 
30-minute IV infusion 
on Day 1 and Day 8 
in 3-weeks cycles 
Paclitaxel via 1-hour 
IV infusion on Day 1 
and day 8- in 3-
weeks cycles.  
Gemcitabine at via 
30-minute IV infusion 
on Day 1 and Day 8 
in 3-weeks cycles 
Capecitabine 
(1600 
- 
2500 mg/m2/day)/vinorelbine 
(60 to 80 mg/m2/day [oral] or  
(25 to 30 mg/m2 [IV infusion] 
Capecitabine: 
Tablets for oral 
use 
Vinorelbine: 
Capsule for Oral 
use/IV infusion  
Capecitabine: days 1 
to Day 14 twice daily, 
followed by a 1-week 
rest 
period, 
in 
3-weeks cycle 


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Vinorelbine, once, on 
Day 1 and Day 8 in 
3-weeks cycles  
Ribociclib, letrozole, anastrozole and goserelin will be administered as a 
flat-fixed dose, and not by body weight or body surface area. Whereas, 
combination chemotherapies (docetaxel + capecitabine, paclitaxel + 
gemcitabine, capecitabine + vinorelbine) will be administered by body 
surface area; however, less than 10% of change in body surface area will 
not warrant any change in chemotherapy treatment dose. All study 
treatment drugs must be administered together at approximately the same 
time (or within few hours for chemotherapy) each day. Except for 
ribociclib, all study treatment drugs should be used in accordance with the 
locally approved label. Ribociclib will be used in accordance to protocol 
guidelines. 
Efficacy 
assessments 
• 
Computed tomography (CT)/ Magnetic resonance imaging (MRI) 
(chest, abdomen, pelvis) at screening and then every 6 weeks 
after randomization for the first 12 weeks and every 8 weeks for 
the next 32 weeks and at every 12 weeks thereafter until disease 
progression (radiologically documented according to RECIST 1.1 
criteria), death, withdrawal of consent, loss to follow-up, or 
patient/guardian decision. 
• 
Brain CT or MRI as clinically indicated. 
• 
Whole body bone scan at screening if not performed previously 
within 42 days (6 weeks) prior to randomization; as clinically 
indicated thereafter. 
• 
Bone x-ray, CT or MRI (if bone lesion at screening) every 6 
weeks after randomization for the first 12 weeks and every 8 
weeks for the next 32 weeks and at every 12 weeks thereafter 
until disease progression (radiologically documented according to 
RECIST 1.1 criteria), death, withdrawal of consent, loss to follow-
up, or patient/guardian decision. 
• 
Skin color photography (if skin lesions at screening) every 6 
weeks after randomization for the first 12 weeks and every 8 
weeks for the next 32 weeks and at every 12 weeks thereafter 
until disease progression (according to RECIST 1.1 criteria), 
death, withdrawal of consent, loss to follow-up, or 
patient/guardian decision. 
• 
CT/ MRI for any disease outside of the chest, abdomen, pelvis (if 
lesion identified at screening) every 6 weeks after randomization 
for the first 12 weeks and every 8 weeks for the next 32 weeks 
and at every 12 weeks thereafter until disease progression 
(radiologically documented according to RECIST 1.1 criteria), 
death, withdrawal of consent, loss to follow-up, or 
patient/guardian decision. 
• 
Survival status every 16 weeks (± 4) weeks or earlier if a survival 
update is required to meet safety or regulatory needs. 
Key safety 
assessments 
• 
Physical examinations 
• 
ECOG performance status 
• 
Height, weight, and vital signs 
• 
12 lead ECG 


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• 
Laboratory assessments including hematology, biochemistry, 
pregnancy (and assessments of fertility) and coagulation 
Other assessments  
Patient-reported outcomes: FACT-B questionnaire will be used to assess 
health-related quality-of-life, functioning, disease symptoms and treatment-
related side effects. 
 
Sample size 
calculation 
Based on available data, the median PFS in the control arm is expected to 
be approximately 12 months. It is expected that treatment with ribociclib 
arm will result in a 33% reduction in the hazard rate for PFS, i.e., an 
expected hazard ratio of 0.667 (which corresponds to an increase in median 
PFS to 18 months under the exponential model assumption). 
Then in order to ensure 80% power to test the null hypothesis: PFS hazard 
ratio = 1, versus the specific alternative hypothesis: PFS hazard 
ratio = 0.667, it is calculated that a total of 110 PFS events need to be 
observed. This calculation assumes analysis by a one-sided log-rank test 
at the overall 10% level of significance, patients randomized to the two 
treatment arms in a 1:1 ratio. Considering that enrolment will continue for 
30 months, 3 patients for 0-6 months, 10 patients for 7-17 months and 6 
patients thereafter, a total of 200 patients will be needed to observe the 
targeted 110 PFS events at about 4 months after the randomization date of 
the last patient. Assuming 10% drop-out, a total of 222 patients will be 
needed. The sample size of 222 patients will be randomly assigned to each 
treatment arm in a 1:1 ratio (111 patients in the experimental arm, 
111 patients in the control arm). These calculations were made using the 
software package East 6.4. 
Data analysis 
The primary endpoint of the study is PFS. Progression-free survival will be 
summarized using Kaplan-Meier estimates. Median PFS with 95% 
confidence intervals will be provided by treatment group. Stratified Cox 
regression will be used to estimate the hazard ratio (HR) of PFS, along with 
95% confidence intervals. In the primary analysis, PFS will be censored at 
the date of the last adequate tumor assessment if no PFS event is observed 
prior to the analysis cut-off date. PFS, will be analyzed at the primary 
analysis (once 110 PFS events are observed) on the FAS. The FAS 
comprises all patients to whom study treatment has been assigned by 
randomization. According to the intent to treat (ITT) principle, patients will 
be analyzed according to the treatment they have been assigned to during 
the randomization procedure. Full analysis set will be the primary population 
for all efficacy analyses. 
As a sensitivity analysis, the distribution of PFS will be compared between 
the treatment groups using an un-stratified log-rank test and the hazard 
ratio along with the associated 95% confidence interval resulting from an 
un-stratified Cox model will be presented. 


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The secondary objectives in this study is to compare the two treatment 
groups with respect to TTF, 3-month treatment failure rate, overall survival 
(OS), ORR, CBR, and TTR. The OS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment 
group. Overall response rate and its 95% confidence interval will be 
presented by treatment group. The Cochrane-Mantel-Haenszel chi-square 
test, stratified by the randomization stratification factor, will be used to 
compare ORR between the two treatment groups. Clinical benefit rate will 
be summarized for the two treatment groups using descriptive statistics. 
The Cochran-Mantel Haenszel chi-square test (stratified by randomization 
stratification factor) will be used to compare the two treatment groups with 
respect to the CBR. Time to Response and TTF will be listed and 
summarized by treatment group. Distribution of TTR will be estimated using 
Kaplan-Meier method if sufficient number of responses are recorded. 
The assessment of safety will be based mainly on the frequency of 
adverse events and on the number of laboratory values that fall outside of 
pre-determined ranges. Other safety assessments (e.g., 
electrocardiogram, vital signs) will be summarized by treatment group. 
The safety analysis set will be used for all safety analysis. 
Key words 
HR-positive, HER2-negative, advanced breast cancer, ribociclib, NSAI, 
goserelin, docetaxel + capecitabine, paclitaxel + gemcitabine, capecitabine 
+ vinorelbine, CDK4/6 inhibitors, Phase II, ER-positive, PR-positive, 
premenopausal, and perimenopausal. 
 
 


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Amendment 2 (04-Mar-2021) 
Amendment rationale 
The study is currently open for enrollment with 182 patients enrolled to date (10-Feb-2021). 
The amendment includes updates for assumptions on the median PFS in the combination 
chemotherapy arm and ribociclib arm. In the protocol v00, the median PFS was assumed to be 
8 months in the combination chemotherapy arm and 12 months in the ribociclib arm. For IA, 
61 events was expected to be 15.477 months from the date of first patient randomized in the 
study. However, only approximately 30 events were observed 18 months from the data of first 
patient randomization. Based on the assessment and review on the available data, assumptions 
for median PFS were updated. A summary of key changes proposed in this amendment is listed 
below: 
• Inclusion criterion 4 was amended to clarify that for patients who are eligible under 
inoperable locally advanced breast cancer or criteria 4c, the recruitment is stopped to 
enrich patient population with visceral metastases. 
• The median PFS assumptions were updated as 12 months in the control arm and 18 
months in ribociclib arm, and the significance level was updated from 5% to 10% (one-
sided) to maintain the sample size. 
• Interim analysis was removed. The rationale to stop early for futility is no longer valid due 
to increased PFS.  
• Patient accrual period was extended to 30 months given slow enrollment due to COVID-
19. 
• There were tests (laboratory evaluations) mentioned in the original version of protocol, but 
not applicable to the study, were not part of visit assessment schedule, and now they are 
being removed for consistency. 
• Updated the protocol with program standard language as appropriate. 
• Pregnancy follow-up information was added and pregnancy should be followed up to one 
year after the baby was due to be born. 
• Updated the protocol with COVID-19 (Coronavirus) Guidance (Version 3.0, 19-Nov-
2020) for ongoing clinical studies. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Abbreviations: added ABC, ESMO-MCBS, GCSF, HR+ and LHRH. 
• Glossary of terms: removed mis-randomized subjects. 
 
 
• Protocol summary: made few edits in study design, key exclusion criteria and efficacy 
assessments. 
• Protocol summary: amended key inclusion criterion 4 and 4c. 
• Protocol summary: updated study treatment including an administration window for 
goserelin and dose frequency for capecitabine, gemcitabine and vinorelbine. 


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• Protocol summary: key safety assessments (added assessments of fertility and coagulation 
and deleted hepatic safety markers) to match with Section 8.4.2 (laboratory evaluations). 
• Protocol summary: updated median PFS assumptions and removed the text that mentions 
interim analysis. 
• Protocol summary: data analysis (updated PFS events to 110 for primary analysis, 
removed the text that mentions one sided level of significance and updated with 
randomization stratification factor for consistency with Section 12.5.1). 
• Section 1.1.2, Section 1.1.4.1.4 and Section 1.2: updated the overall survival data with 
recent data. 
• Section 1.1.2: amended ribociclib indication and usage as per FDA prescribing 
information, added ABC 5 guidelines with the recommendation for ribociclib use for 
premenopausal patients with ESMO-MCBS score 5 and EMA recommendations for 
ribociclib use. 
• Section 1.1.4.1.4: updated subgroup analysis of Asian patients (MONALEESA-7). 
• Section 3: updated survival follow up duration, and total enrollment period. 
• Section 3.1.2 and Section 3.1.3: updated end of study duration. 
• Section 3.1.3: clarified that survival follow-up will be conducted after the end of safety 
follow-up and updated the overall survival events. 
• Section 3.1.4, Section 3.17, Section 4.4, Section 4.5.1, Section 12 and Section 12.7: 
removed the text that mentions planned futility interim analysis. 
•  Section 3.1.7: updated definition of end of study and wording related to post trial access. 
• Section 4.3: updated Table 4-1 to add administration window for goserelin and dose 
frequency for vinorelbine. 
• Section 4.5.1: added guidance wording during public health emergencies. 
• Section 5.1: amended inclusion criterion 4 and 4c. 
• Section 5.2: exclusion criteria 2 was modified to clarify the duration of extended-field 
radiotherapy prior to randomization. 
• Section 6.1.1: updated Table 6-1 to add administration window for goserelin and dose 
frequency for capecitabine. 
• Section 6.1.4.1: added administration window for goserelin. 
• Section 6.1.4.2: added missing the information for gemcitabine dose, added additional 
wording regarding switch between Vinorelbine oral capsule and Vinorelbine IV infusion 
and corrected vinorelbine pharmaceutical dosage form and route of administration. 
• Section 6.1.7: corrected treatment duration. 
• Section 6.2.1: removal of censored reason for patients who received either megestrol 
acetate or medroxyprogesterone for more than one month of treatment. 
• Section 6.3.2: corrected wording regarding treatment assignment using IRT. 
• Section 6.5.1.3: added administration window for goserelin. 
• Section 6.7 and Section 7: added guidance wording during public health emergencies. 
• Section 8: corrected wording for patients who prematurely discontinue the study, updated 
visit window for EOT visit and safety follow up visit and administration window for 


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goserelin. Table 8-1 is updated to clarify survival follow up timeline, added administration 
window for goserelin and added guidance wording during public health emergencies. 
• Section 8.1: corrected typos for laboratory evaluations and ECG. 
• Section 8.3.1: clarified wording for treatment discontinuation and updated survival 
duration. 
• Section 8.3.2: added additional wording for imaging assessments for consistency with 
Table 8-2, corrected tumor evaluation criteria at EOT and updated Table 8-2 with 
additional wording for treatment phase for bone X-ray, CT or MRI and skin color 
photography. 
• Section 8.4: deleted hepatic safety markers and added pregnancy and coagulation to match 
with Table 8-5. Also, added guidance wording during public health emergencies in Table 
8-3. 
• Section 8.4.2: added guidance wording during public health emergencies in Table 8-5. 
• Section 8.4.2.3: added wording for clarity in case of positive pregnancy test. 
• Section 8.4.2.3, Section 8.4.3, Section 8.5 (Table 8-7) and Section 10.1.1: added guidance 
wording during public health emergencies. 
• Section 9.1.1: addition of discontinuation reasons according to Section 16.4.2 for 
consistency i.e., non-compliant with study treatment and no longer requires treatment. 
• Section 9.2: corrected end of study duration and number of PFS events for primary 
analysis. Also, updated wording related to safety evaluation following last dose or EOT 
visit and post-trial access. 
• Section 10.1.4: added follow-up information that pregnancy should be followed up to one 
year after the baby was due to be born. 
• Section 11.2: updated wording for management of database and quality control. 
• Section 12.4.2: number of PFS events for primary efficacy variable analysis was updated. 
• Section 12.4.3: added heading style (Handling of missing 
values/censoring/discontinuations) and description related to start of new anti-cancer 
treatment. 
• Section 12.4.4: added description related to additional sensitivity analysis. 
• Section 12.5.3: 
• removed ‘no formal statistical test will be performed for patient reported outcomes 
(PRO) data’. 
• added ‘time to deterioration in the PRO scales will be performed and compared 
between the two treatment arms’. 
 
 
• Section 12.8: sample size calculation section was updated based on the updated 
assumptions for median PFS. 


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• Section 15: updated list with 3 additional references and in alphabetical order. 
• Section 16.1: added text related to Table 16-1 and 16-2, respectively, for list of prohibited 
medications and medication to be used with caution during combined ribociclib, NSAI, 
and goserelin treatment in this study. 
• Section 16.1: updated Table 16-2 with the list of medications to be used with caution 
during study treatment as per program standard language. 
• addition of ‘dabrafenib’ and removal of ‘efavirenz’ under the category of moderate 
CYP3A4/5 inducers. 
• addition of ‘aprepitant’ and ‘perospirone’ under the category of sensitive CYP3A4/5 
substrates. 
• addition of ‘atorvastatin’ and removal of ‘atazanavir’ under the category of BSEP 
inhibitors. 
• addition of ‘irinotecan’ under the category of BCRP substrates. 
• Section 16.4.2: addition of discontinuation reasons according to Section 9.1.1 for 
consistency. 
• Section 16.5: reference list arranged according to alphabetical order. 
• Section 16.6: added heading style for Appendix 3. 
• Typographical and grammatical errors, and inconsistencies between different sections 
were addressed throughout the protocol. 
• The term “subject” was changed to “patient” throughout the protocol. 
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 and Pregnancy Follow up Consent. Sites are 
required to update and submit for approval a revised Informed Consents that takes into account 
the changes described in this protocol amendment. 


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Amendment 1 (27-Jan-2020) 
The study is currently open for enrollment with 66 patients enrolled to date.  
The current amendment is primarily intended for
clarify specific aspects of original protocol version, based 
on feedback and communications received from investigators and the participating countries. 
A summary of the key changes proposed in this amendment is listed below: 
 
 
 
 
 
 
• An additional exclusion criterion was added to exclude patients, who have disease 
recurrence during adjuvant tamoxifen treatment within 12 months period. 
• A new secondary objective “to compare 3-month treatment failure rate” was added to help 
in understanding the early efficacy of the regimen, as advised by the steering committee. 
• The clinical safety and efficacy data was updated for ribociclib in line with newly reported 
results of CLEE011E2301 (MONALEESA-7) and CLEE011F2301 (MONALEESA-3) 
studies. 
• Additional clarification was included on adjustment of ribociclib treatment cycles in the 
case of dose interruptions/re-initiation. 
• Additional wording for imaging tumor assessments was added for those patients who 
discontinued treatment. 
• Additional wording was added for combination chemotherapy arm patients to clarify that 
they might have additional biochemical assessments as per the local practice for such 
drugs and those are to be considered as standard of care. 
• Follow-up guidance for interstitial lung disease/pneumonitis was added. 
• Guidance for other adverse reactions was updated to include Toxic Epidermal Necrolysis 
(TEN). 
• Planned method of analysis for patient reported outcomes (FACT-B) was changed. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Throughout protocol: Typographical, inconsistencies between different sections and 
grammatical errors were addressed. 
• Throughout protocol: Added the wording “radiologically documented according to 
RECIST 1.1 criteria” throughout to clearly define disease progression. 
• Abbreviations: Added BSA, FFPE, modified RAP/SAP 
• Protocol summary: Added phase of the clinical trial 


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• Protocol summary: Added goserelin dose administration details. 
• Protocol summary was updated to maintain consistency with the main body of the 
protocol. 
• Section 1.1.1: the prevalence and mortality rates of breast cancer in Asia were updated to 
reflect the GLOBOCAN 2018 data. 
• Section 1.1.2 was updated to add latest overall survival data from CLEE011E2301 
(MONALEESA-7) study. 
• Section 1.1.4.1 was updated to reflect the latest health authority approval status of 
ribociclib. 
• Section 1.1.4.1.4 was updated to added latest clinical efficacy data from CLEE011E2301 
(MONALEESA-7) and CLEE011F2301 (MONALEESA-3) studies. 
• Section 1.1.4.6 was updated to add additional citations. 
• Section 1.2 was updated to accommodate the latest efficacy data emerged from the 
ongoing trials for ribociclib and palbociclib. 
• In Table 2-1, definition of secondary endpoint of time to treatment failure was updated to 
include “change to other anti-cancer therapy”. 
• Table 2-1 was updated to accommodate the additional secondary 
 
 objectives and endpoints. 
• Figure 3-1 was updated to mention that treatment phase of chemotherapy arm will be of 
21 days and the footnote was updated to make the radiological assessment schedule 
consistent with the other sections of protocol. 
• Section 3 was updated  
• to bring more clarity how long the patients can remain in the study if they 
permanently discontinue ribociclib 
 
 
• to update the number of sites and participating countries  
• composition of steering committee was updated to maintain the consistency with the 
other sections of protocol 
• Section 3.1.2.1 was modified to remove the text that mentions the efficacy follow up for 
patients who discontinued the protocol study treatment without disease progression and 
not censored yet. 
• Section 3.1.7 was updated to reflect the correct eCRF page that need to be completed at 
the end of study and the name of Managed Access Program” was also changed to 
“post-trial access”. 
• Table 4-1 was updated to provide more clarity that ribociclib 600 mg dose will be 
administered via 3 tables of 200 mg each. 
• Section 4.5.1 and Section 10.2.2 was updated to reflect the composition of steering 
committee to maintain the consistency with other sections of the protocol. 
• Section 5.1 was updated 
• The term “subject” was changed to “patient” 


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• Inclusion criterion 4 was modified to bring more clarity and maintain consistency 
with protocol title. 
• Inclusion criterion 5 was modified to remove the pre-specified concentration ranges 
for plasma estradiol and FSH 
• Inclusion criterion 8 was modified to add additional condition for total bilirubin in 
patients with liver metastases. 
• Inclusion criterion 8 was modified to remove sodium and phosphorus from the list of 
laboratory parameters that have to be in the normal range, before the first dose of 
study medication 
• Section 5.2 was updated 
• Exclusion criterion 1 was modified to exclude patients, who have disease recurrence 
during adjuvant tamoxifen treatment within 12 months period. 
• Exclusion criteria 4 was modified to exclude patients who participate in any other 
type of medical research that judged not to be scientifically or medically compatible 
with this study. 
• Exclusion criterion 10 was modified to update the unit for bilirubin in patients who 
have liver metastases. 
• A new exclusion criterion (criterion no. 14) “Patient is concurrently using hormone 
replacement therapy” was added. 
• Exclusion criterion 7 was modified to remove barrier methods of contraception. 
• Section 6.1 was modified to clarify that investigational drugs labels will be approved by 
the local regulatory authorities, if required by country regulation.  
• Table 6-1 and Section 6.1.4.1 was updated to clarify that goserelin dosing frequency will 
remain unchanged, regardless of ribociclib treatment cycle. 
• In Section 6.1.1 was modified to clarify that ribociclib will be used in accordance to 
protocol guidelines and all study treatment drugs (except ribociclib) should be used in 
accordance with the locally approved label. 
• Section 6.1.3 was updated to include beta-blocker in the list of exempted drugs that are 
allowed in this trial. 
• Section 6.1.6 was updated to clarify that leuprorelin or other LHRH agonists dosing will 
be as per the local approved label. 
• Section 6.2.15 was modified to mention that cumulative courses of RT should not 
encompass ≥ more than 25% of the irradiated bone marrow, instead of > 25% of the 
irradiated bone marrow. 
• Section 6.2.1.7 was added to clarify that the beta-blocker could be used to correct 
tachycardia considering the inclusion criteria and the prevalence of tachycardia in breast 
cancer population. 
• Section 6.3.2 and Section 11.2 were updated to remove the text related to IRT assisted 
randomization. 
• Section 6.5.1.1.1 was inserted to provide more clarity on adjustment of ribociclib 
treatment cycles in case of dose interruptions/re-initiation. 


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• Section 6.5.1.1.4 was inserted to provide follow-up guidance for interstitial lung 
disease/pneumonitis. 
• Section 6.5.1.1.5 was updated to clarify that ribociclib dose adjustment and management 
recommendations (provided in Table 6-6) are applicable for all other adverse events, 
including toxic epidermal necrolysis. 
• Section 6.5.3.2, Section 6.5.3.3, Section 6.5.3.5 was updated to clarify that for 
chemotherapy treatment to begin, blood tests may be performed that are part of local 
practice and standard of care. 
• Section 6.5.3.5 was updated to provide more clarity about the impact (on study) of 
vinorelbine treatment discontinuation due to hematologic toxicities and non-hematologic 
toxicities. 
• Table 6-11 was removed as Table 6-8 already provides the similar information for dose 
reductions of docetaxel. Thereafter, all table numberings are revised in the protocol. 
• Section 6.6.1 and Section 6.7.1.1 was updated to mention that treatment compliance will 
also be captured in the “site source document”, in addition to the “Drug Accountability 
Form”. 
 
 
 
• Section 8 was updated to remove the text that indicates missed or rescheduled visits would 
not lead to automatic discontinuation. Inserted a text clarifying that a visit window of ± 7 
days is allowed for biochemistry assessments. Additional modifications were also done for 
more clarity and to maintain the consistency with other section of the protocol. 
• Table 8-1 was updated to mark that  
 
 
• Information on estradiol and FSH will be remain in source documents only (S) and 
will not be entered into the database (D). 
• Footnote of Table 8-1 was updated  
• To mention that for patients on combination chemotherapy may have additional 
hematology and biochemical assessments as per the local practice for such drug and 
are considered as standard of care 
• To clarify that coagulation parameters of INR or PT are to be performed at every visit 
only for the patients receiving oral coumarin-derivate anticoagulants such as warfarin 
and phenprocoumon along with capecitabine as one of the medication in the 
combination chemotherapy group. 
• Section 8.1 was updated to clarify that  
• ECG should be performed within 7 days prior to randomization.  
• The modification also includes multiple evaluations of liver function and renal 
function is also allowed in addition to electrolytes and blood counts for screen failure 
patients. 
• Section 8.1.2 was updated to include visit date to maintain consistency with eCRF  
• Section 8.2 was updated to maintain consistency with eCRF. 
• Section 8.3.1 was updated to maintain consistency with the other sections of protocol.  


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• Section 8.3.2 was updated to clarify about the imaging tumor assessments for patients who 
discontinued treatment. 
• Section 8.3.2 was updated to remove text that indicated that repeat assessment will be 
performed to confirm CR and PR after the criteria for objective response are first met. 
• Section 8.4.2 was updated as there is no laboratory manual being used in this study. Also a 
text was inserted clarifying that a visit window of ± 7 days is allowed for biochemistry 
assessments. 
• Table 8-5 was updated to maintain consistency with eCRF in terms of laboratory 
parameters that are being assessed in the study. This table was also modified to remove 
sodium and phosphorus from the list of laboratory parameters  
• Section 8.4.2.1 and Section 8.4.2.2 were updated to clarify that patients enrolled in the 
chemotherapy treatments might have additional blood tests that are part of local practice 
and standard of care. 
• In Section 8.4.2.3 was updated to mention that there would be no need to repeat the 
pregnancy test if screening assessments were performed ≤ 7 days prior to the first dose of 
study treatments. 
• Section 8.4.2.4 was updated to capture the requirement of coagulation testing for patients 
receiving capecitabine. 
• Section 8.4.3 was updated to clarify that single reading of ECG is required. 
• Section 8.5 was updated to modify the window period for FACT-B questionnaire from 
3 days to 7 days. 
 
 
• Section 9.1.1 was updated to reflect the latest protocol standard language document. 
• Section 9.2 was updated to remove duplication. 
• Section 11.1 was updated to remove duplication. 
• Section 12.5.1 was updated to describe the statistical analysis plan for the newly added 
secondary efficacy objective of 3-month treatment failure rate. 
• Section 12.5.3 was updated as the planned method of analysis for FACT-B was changed 
to be aligned with endpoint defined in Section 2. 
 
 
• Section 16.4.2 was updated to revise the scheduled date of the end of treatment visit to be 
consistent with other sections of protocol. 
• Table 16-1 and Table 16-2 in Appendix 1 were updated to reflect the latest list of 
prohibited medication and medications to be used with caution during study drug 
treatment. 
• Appendix 3 was updated to replace FACT-B + 4 questionnaire with FACT-B 
questionnaire 
Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 


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The changes described in this amended protocol are substantial and require IRB/IEC approval 
prior to implementation. 


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1 
Introduction 
1.1 
Background  
1.1.1 
Epidemiology 
Breast cancer is the second most common cancer in the world and, by far, the most frequent 
cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012 (25% 
of all cancers), corresponding to a rate of 43 per 100,000 patients. Of these, approximately a 
quarter (24%) of all breast cancers were diagnosed within the Asia-Pacific region 
(approximately 404,000 cases at a rate of 30 per 100,000). Breast cancer ranks as the fifth cause 
of death from cancer overall. About 522,000 females (13 per 100,000 population) were 
estimated to have died from breast cancer globally during 2012, including almost 116,000 
deaths (22%) throughout the Asia-Pacific region at a rate of 8 per 100,000. It is the most 
common cancer in women both in more and less developed regions with slightly more cases in 
less developed (883,000 cases) than in more developed (794,000) regions. Worldwide, cancer 
rates are increasing and per the GLOBOCAN 2018 report on cancer incidence and mortality 
statistics, the 5-year prevalence is estimated to be 2,623,745 in Asia, with a mortality of 310,577. 
The percentage of patients with breast cancer aged younger than 50 years could be as high as 
42% in the Asia-Pacific region, and is almost 50% in the Middle East compared to 33% in the 
global scenario (El-Saghir et al 2007; GLOBOCAN 2018; Youlden et al 2014). 
Invasive breast cancer is classified by the presence or absence of estrogen receptor (ER), 
progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) antigen 
for prognostic and treatment purposes. Approximately two-thirds of breast cancers in women 
aged 50 years or younger are hormone receptor (HR)-positive (defined by expression of the 
estrogen and/or progesterone receptor) and human epidermal growth factor receptor 2 (HER2)-
negative (Howlader et al 2014). For first-line treatment of HR-positive, HER2-negative 
advanced breast cancer (ABC), although the recommendation is to provide endocrine therapy 
first in general (Rugo et al 2016), a high proportion of patients (younger than 50 years) are still 
being prescribed chemotherapy, which was associated with worse outcome, even after 
adjustment of relevant prognostic factors (Lobbezoo et al 2016). Therefore, dedicated trials in 
premenopausal breast cancer are required to establish the efficacy of endocrine treatment based 
therapy compared with chemotherapy in this population. 
1.1.2 
Treatment options for premenopausal women with hormone receptor 
positive (HR+), HER2-negative premenopausal advanced breast cancer 
Endocrine therapy remains the therapeutic backbone for the treatment of HR+, HER2-negative 
breast cancer. Based on current treatment guidelines (Gradishar et al 2017), for premenopausal 
women with HR+, HER2- negative, advanced breast cancer, the standard treatment options are 
selective ER modulators (tamoxifen or toremifene) or ovarian ablation or suppression plus 
endocrine therapy. 
The efficacy and safety of the combination of ribociclib and either tamoxifen or a nonsteroidal 
aromatase inhibitor (letrozole or anastrozole) and goserelin (Zoladex) as first line treatment was 
evaluated in MONALEESA-7 study, a phase III, multicenter study in pre- and perimenopausal 
women with HR+, HER2-negative advanced (metastatic or loco regionally recurrent) breast 


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cancer who have not received prior therapy for their disease. The study met its primary objective 
at the pre-planned interim analysis; progression-free survival (PFS) was significantly improved 
in the ribociclib arm (median: 23.8 months) compared with the placebo arm (median: 13.0 
months). Clinical benefit was evident relative to placebo plus letrozole with a 44.7% estimated 
risk reduction in the primary PFS endpoint as per investigator assessment evaluated by RECIST 
version 1.1 (HR=0.553, 95% confidence interval (CI): 0.441-0.694; p = 9.83×10–8) (Tripathy 
et al 2018). Overall survival (OS) was significantly longer in the ribociclib arm than in the 
placebo arm, with a 29% relative reduction in the risk of death (HR=0.712; 95% CI: 0.535, 
0.948). The one-sided stratified log-rank test P value was 0.00973, which crossed the pre-
specified stopping boundary (p=0.01018) to claim superior efficacy (Im et al 2019). The recent 
updated median overall survival was 58.7 months with ribociclib + endocrine therapy and 48.0 
months with placebo + endocrine therapy (HR, 0.76; 95% CI, 0.61-0.96), with a 24% relative 
reduction in the risk of death with ribociclib. It is the longest reported period in HR+/HER2-
negative advanced breast cancer (ABC) among all Phase III trials in this setting (Tripathy et al 
2020). 
Expanded indication based on MONALEESA-3 (CLEE011F2301) and MONALEESA-7 
(CLEE011E2301) approved by USFDA on 18-Jul-2018. The supplemental New Drug 
Application approval for Ribociclib (KISQALI®) is the first industry-wide approval using the 
USFDA’s Real Time Oncology Review and the Assessment Aid pilot programs and was 
approved within one month of submission. 
The USFDA also granted breakthrough therapy designation for MONALEESA-7 and priority 
review for the MONALEESA-3 and 7 for expanded indication. Ribociclib has been approved 
in combination with aromatase inhibitor in pre/perimenopausal or postmenopausal women and 
with fulvestrant pre- and/or postmenopausal women. Additional detail expanded indication are 
provided in Section 1.1.4.6. Furthermore, according to new updated ABC 5 guidelines using 
the current available data and follow-up, the ESMO-MCBS score was 5 (efficacy score 4 [PFS 
and OS]: 4; improved QoL) for the use of ribociclib combined with endocrine therapy in the 
first-line setting in pre-menopausal patients (Cardoso et al 2020). 
The USFDA has granted approval for ribociclib combination: 
• with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal 
women with HR+, HER2-negative advanced or metastatic breast cancer, as initial 
endocrine-based therapy; or 
• fulvestrant for the treatment of postmenopausal women with HR+, HER2-negative 
advanced or metastatic breast cancer, as initial endocrine based therapy or following 
disease progression on endocrine therapy. 
EMA has granted approval for ribociclib: 
• for the treatment of women with HR+, HER2-negative locally advanced or metastatic 
breast cancer in combination with an aromatase inhibitor or fulvestrant as initial 
endocrine-based therapy, or in women who have received prior endocrine therapy and  
• in pre- or perimenopausal women, the endocrine therapy should be combined with a 
LHRH agonist. 


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1.1.3 
Role of the CDK4/6 pathway in breast cancer 
While endocrine therapy is effective in treatment of HR+ advanced breast cancer, 
approximately 30-50% of patients may not respond to it due to a primary resistance. Moreover, 
many advanced breast cancer patients with initial response to endocrine therapy will acquire 
secondary resistance to these agents (Bachelot et al 2012; Nichols et al 2015). Co-targeting the 
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 endocrine therapy tumors by preventing or delaying the 
development of acquired resistance for endocrine treatments. 
Cell cycle progression is directly regulated by cyclin-dependent serine-threonine protein 
kinases (CDKs). Extracellular growth and adhesion signals increase the level and function of 
cyclin D proteins within the cell. In turn, the cyclin D proteins associate with and activate CDK4 
and CDK6 (Musgrove et al 2011). CDK4 and CDK6 phosphorylation leads to inactivation of 
the retinoblastoma protein (pRb) and thus releases E2F which in turn leads to the transcription 
initiation of proteins involved in cell cycle propagation and cell proliferation. The luminal A 
and B subtypes of breast cancer (85% of which are ER+/HER2-negative) have high rates of 
cyclin D/CDK activation; in the luminal A and B subtypes, cyclin D1 (CCND1) amplifications 
were observed in 29% and 58%, and CDK4 amplifications were observed in 14% and 25% 
respectively (Holm et al 2012; The Cancer Genome Atlas Network 2012). The luminal A 
subtype tumors also have loss of CDKN2A, which encodes p16Ink4a, a CDK inhibitor 
(Beroukhim et al 2010). The luminal subtypes also maintain expression of Rb, which is essential 
for benefit from treatment with a CDK4/6 inhibitor (Thangavel et al 2011). 
Dysregulation of cell cycle checkpoints is common in cancer. Modulating the cell cycle has 
always been an attractive therapeutic target in cancer, and previously published data have 
suggested that CDK4/6 inhibition may play a key role in the treatment of subsets of breast 
cancers. Patients with HR+ breast cancer exhibiting a gene expression signature of Rb loss had 
shorter recurrence-free survival following adjuvant tamoxifen (Bosco et al 2007). A tumor gene 
expression signature of E2F activation was associated with higher residual tumor cell 
proliferation following pre-surgical AI therapy. Therefore, activation of the CDK4/CDK6/E2F 
axis promotes endocrine resistance, and treatment with a CDK4/6 inhibitor or knockdown of 
CDK4 expression abrogates endocrine-resistant cell proliferation. 
In conclusion, loss of cell cycle control is a hallmark of cancer, and aberrations in the 
cyclin/CDK/Rb pathway are common in metastatic luminal breast cancer. Consequently, 
inhibition of this pathway at the level of CDK4/6 leads to reactivation of Rb and binding of 
E2F, thus leading to cell cycle arrest. Therefore, 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 as well as the do-novo endocrinal resistance. 
The marked efficacy of CDK4/6 inhibitors in combination with endocrine therapy in the 
treatment of both pre and post-menopausal patients with HR+, HER2-negative advanced breast 
cancer has been consistently documented in several recent phase III randomized trials. 
Importantly the PFS data as well as the overall response rate (ORR) data were quite favorable, 
when compared to what may be achieved by chemotherapy treatment in these patients.  


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1.1.4 
Introduction to investigational treatment(s) and other study 
treatment(s) 
This study includes ribociclib, goserelin, NSAI (letrozole or anastrozole), and chemotherapies 
(docetaxel, capecitabine, paclitaxel, gemcitabine, and vinorelbine) as treatments. 
1.1.4.1 
Ribociclib 
Ribociclib is an orally bioavailable and highly selective small molecule inhibitor with highly 
specific nanomolar inhibitory activity against CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme 
complexes with IC50’s of 0.01 and 0.039 µM in biochemical assays, respectively.  
Ribociclib (Kisqali®) in combination with an aromatase inhibitor (or letrozole, as specified by 
individual Health Authority marketing authorization) as initial endocrine-based therapy for the 
treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal 
growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer was approved 
by the USFDA on 13-Mar-2017, and by the European Commission on 22-Aug-2017 and a 
number of additional marketing authorizations in this indication have been approved globally. 
On 18-Jul-2018, the U.S. FDA expanded the indication for ribociclib in combination with an 
AI to include pre/perimenopausal women with HR-positive, HER2-negative advanced or 
metastatic breast cancer, as initial endocrine-based therapy and ribociclib in combination with 
fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or 
metastatic breast cancer, as initial endocrine-based therapy or following disease progression on 
ET 
(MONALEESA-7 
[CLEE011E2301] 
and 
MONALEESA-3 
[CLEE011F2301], 
respectively). This expanded indication was subsequently approved by the EU Commission on 
17-Dec-2018 and in several additional countries globally. Health authority reviews are currently 
ongoing, with additional marketing approvals expected in HR-positive, HER-2 negative 
advanced or metastatic breast cancer on an ongoing basis worldwide. Additional information 
on ribociclib approval is available in Section 1.1.2. 
1.1.4.1.1 Non-clinical experience 
Ribociclib inhibits the phosphorylation of Rb at CDK4/6-binding sites with an average IC50 of 
60 nM in Jeko-1 mantle cell lymphoma 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 retinoblastoma protein. 
Cardiac safety studies in vivo demonstrated QT prolongation with the potential to induce 
premature ventricular contractions at higher exposure levels. The effects of ribociclib on the 
bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa 
(atrophy), the kidney (concurrent degeneration and regeneration of tubular epithelial 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. 


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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 efflux transporter, this process is likely not clinically relevant 
due to the high passive permeability of ribociclib. 
1.1.4.1.2 Clinical experience  
Ribociclib is currently being investigated in patients with breast cancer and other solid tumors 
in multiple clinical trials at different phases of development. 
1.1.4.1.3 Clinical safety of ribociclib  
Clinical safety of ribociclib with endocrine agents such as letrozole, anastrozole, tamoxifen, 
exemestane and fulvestrant has been being evaluated in several phase I and III combination 
trials. Except in Japanese patients, the recommended dose of ribociclib in combination with 
these agents was declared as 600 mg every day on a 3 weeks on/1 week off schedule; in Japanese 
patients, 300 mg every day on the same dosing schedule was declared. 
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+, HER2-negative, advanced breast 
cancer. Most common treatment-emergent adverse events 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 adverse events reported in ≥ 5% of patients in the ribociclib arm 
were neutropenia (59.3%), leukopenia (21.6%), hypertension (9.9%), increased alanine 
aminotransferase (ALT) (9.3%), lymphopenia (6.9%) and increased aspartate aminotransferase 
(AST) (5.7%). Febrile neutropenia occurred in 1.5% of the patients in the ribociclib arm. Four 
patients (1.2%) met the biochemical and clinical criteria for Hy’s Law with 3 reported as 
treatment-related and all 4 returned to normal values after treatment discontinuation. Eleven 
patients (3.3%) presented on treatment QTc using Fridericia's formula (QTcF) prolongation 
> 480 msec. Serious adverse event were reported in 21.3% of patients in the ribociclib arm with 
7.5% of serious adverse events deemed by investigators as treatment-related. There were 3 fatal 
events in the ribociclib arm (disease progression, sudden death, and unknown cause) with 1 
adverse event (sudden death) reported as treatment-related in a patient who had grade 3 
hypokalemia and grade 2 QTcF prolongation (483 msec). Neutropenia, QT interval 
prolongation and hepatobiliary toxicity are considered to be important identified risks for 
ribociclib which appear to be manageable and reversible with adequate monitoring, interruption 
and/or reduction of ribociclib dosing.  


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In MONALEESA-7, AEs of any grade with ribociclib regardless of causality (reported in 
≥ 20% of patients) were neutropenia (75.8%), hot flashes (34%), nausea (31.6%), and 
leukopenia (31.3%). Febrile neutropenia occurred in 2.1% of patients. Increased ALT and AST 
(any grade) were reported in 12.8% and 11.9% of patients, respectively, with no cases of Hy’s 
Law (Tripathy et al 2018). 
In MONALEESA-7, a higher incidence of notable QTcF values and change from baseline QTcF 
(ΔQTcF) were observed in patients receiving tamoxifen compared to NSAI as the combination 
partner in both the placebo and ribociclib groups. Based on QTcF data with tamoxifen in 
MONALEESA-7, ribociclib will not be used combination with tamoxifen in this study. In 
patients receiving the combination of ribociclib, NSAI and goserelin, the mean ΔQTcF on Cycle 
1 Day 15, 2 hours post dose was 18.6 msec. The mean ΔQTcF values in MONALEESA-7 are 
consistent with MONALEESA-2 where ΔQTcF prolongation from baseline of 19.6 msec (90% 
CI: 18.0-21.2) was observed at Cycle 1 Day 15, 2 hours postdose in the ribociclib arm. 
In MONALEESA-3, the most common all-grade adverse events (AEs) reported in ≥ 30% of 
patients were neutropenia, nausea, and fatigue. The most common grade 3 AEs occurring in 
≥ 10% of patients were neutropenia and leukopenia. The only grade 4 event reported in ≥ 5% 
of patients was neutropenia. Febrile neutropenia occurred in 1.0% of patients in the ribociclib 
plus fulvestrant arm versus 0% of patients in the placebo plus fulvestrant arm. Most AEs 
observed were of mild or moderate severity, with no new safety signals observed. Although 
neutropenia was the most common all-grade and grade 3 or 4 AE, these events were generally 
uncomplicated. AE-related treatment discontinuations were rare, further supporting the 
manageable safety profile of ribociclib-based combinations. The incidence of QTcF 
prolongation observed with ribociclib plus fulvestrant was similar to that previously reported 
with ribociclib and there were no incidences of torsades de pointes (Slamon et al 2018).  
For a comprehensive review of safety profile of ribociclib in combination with endocrine agents 
refer to the ribociclib Investigator’s Brochure (IB). 
1.1.4.1.4 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+, HER2-negative, 
advanced breast cancer, ribociclib improved PFS (HR 0.56, 95% CI: 0.43-0.72, 
p = 0.00000329). The investigator-reported ORR 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 (FAS); 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).  
For the postmenopausal women with hormone receptor–positive, HER2-negative advanced 
breast cancer, ribociclib plus fulvestrant might represent a new first or second-line treatment 
option. Results from the recently completed MONALEESA-3 trial proved that ribociclib plus 
fulvestrant significantly improved the median progression-free survival compared with the 
placebo plus fulvestrant: 20.5 months (95% CI: 18.5-23.5 months) versus 12.8 months (95% 
CI: 10.9-16.3 months), respectively (hazard ratio = 0.593; 95% CI: 0.480-0.732; p<0.001) 
(Slamon et al 2018). A statistically significant improvement in overall survival benefit with 
addition of ribociclib was observed, with 28% reduction in the relative risk of death (HR: 0.724; 
95% CI: 0.568 – 0.924, p = 0.00455) (Slamon et al 2019). 


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Similarly, Ribociclib plus endocrine therapy could represent a new first-line treatment option 
in premenopausal women with hormone receptor–positive, HER2-negative advanced breast 
cancer. Results from the MONALEESA-7 trial demonstrated that median progression-free 
survival was significantly improved in the ribociclib plus endocrine therapy group (23·8 
months; 95% CI: 19·2–not reached) compared with the placebo plus endocrine therapy 
group13·0 months (11.0 to 16·4) (hazard ratio = 0·55, 95% CI: 0·44-0·69; p<0·0001) (Tripathy 
et al 2018). Results emerged out of the protocol-specified second interim analysis for overall 
survival demonstrate that the addition of ribociclib to endocrine therapy resulted in significantly 
longer overall survival than endocrine therapy alone. The estimated overall survival at 42 
months was 70.2% (95% CI: 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 
58.9) in the placebo group (hazard ratio for death = 0.71; 95% CI, 0.54 to 0.95; p = 0.00973 by 
log-rank test). The significantly longer progression-free survival in the ribociclib group than in 
the placebo group and the approximately 29% lower risk of death in the ribociclib group in this 
report show that there is a substantial clinical benefit of ribociclib plus endocrine therapy as 
compared with endocrine therapy alone (Im et al 2019). After a median of 53.5 months follow-
up, median overall survival for patients taking ribociclib + endocrine therapy was 58.7 months 
and 48.0 months for endocrine therapy alone (HR, 0.76; 95% CI, 0.61-0.96), with a 24% relative 
reduction in the risk of death with ribociclib. It is the longest reported period in HR+/HER2-
negative ABC among all Phase III trials in this setting (Tripathy et al 2020). 
Refer to the ribociclib Investigator’s Brochure for additional details on efficacy profile. 
1.1.4.1.5 Clinical pharmacokinetics of ribociclib  
Following oral dosing of the capsule formulation at 600 mg, ribociclib is rapidly absorbed with 
median time of maximum concentration (Tmax) of 2.40 h (range: 0.683 to 7.82 h). Steady-state 
plasma peak blood concentration (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 elimination half-life (T1/2) of ribociclib is 32.0 h (range: 8.06 to 97.9 h). 
Inter-patient variability in Cmax and area under the curve (AUC) is 62% and 66%, respectively, 
as assessed by geometric coefficient of variation (CV). LEQ803, an active metabolite of 
ribociclib, has similar pharmacokinetics (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. 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 
 increased ribociclib AUC by 3.2-fold following a single 
oral dose of 400 mg ribociclib (CLEE011A2101). Co-administration of a strong CYP3A4 
inducer 
 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
(CYP3A4 
substrate) with multiple doses of ribociclib (400 mg) increased
xposure by 3.8-fold. 
Co-administration of 
(CYP1A2 substrate) with multiple doses of ribociclib (400 mg) 
increased
xposure 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 drug-drug interactions (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 
and CLEE011A2103).  
Refer to the ribociclib Investigator’s Brochure for additional details. 
1.1.4.1.6 Clinical experience with ribociclib in Asian patients based on ongoing 
clinical trials  
The combination of ribociclib (600 mg) with letrozole (2.5 mg once a day) has been evaluated 
in an ongoing study [CLEE011A2301] involving 51 patients of Asian ethnicity: 28 in the 
ribociclib + letrozole arm and 23 in the placebo + letrozole arm (Section 1.1.4.1.4). A 
preliminary analysis of safety and efficacy in the non-Japanese Asian patients compared with 
the rest of the study population highlighted no substantial differences. Clinically meaningful 
PFS benefit with ribociclib plus letrozole was maintained in Asian patients (Hazard ratio: 0.378; 
95% CI: 0.166-0.906). The combination treatment was well tolerated in Asian patients, with a 
similar safety profile as observed in the full population (Yap et al 2016).  
In addition, a pan-Asian study, CLEE011A2115C, is being conducted to confirm the 
recommended dose, as well as to provide additional safety and efficacy data for the combination 
of ribociclib and letrozole when given as first line endocrine therapy for Asian patients with 
ER+, HER2- advanced breast cancer. At the dose escalation meeting on 13-Jun-2016, the 
recommended dose of ribociclib was determined as 600 mg in combination with letrozole for 
Asian non-Japanese patients (patients were from Hong Kong, Singapore, and 1 Chinese patient 
living in Japan).  
There are two other ongoing Phase III trials, which have included Asian patients: 
MONALEESA-3, ribociclib + fulvestrant in men and postmenopausal women with advanced 
breast cancer (1st or 2nd line); and MONALEESA-7, ribociclib + tamoxifen/NSAI + goserelin 
in pre/perimenopausal women with advanced breast cancer (1st line).  
The data from the patients enrolled in the MONALEESA-7 (LEE011E2301) study show that 
there was no major difference in the benefit risk profile of ribociclib between the patients from 
Asia-selected countries or from Korea with the global population. Pharmacokinetic parameters 
for ribociclib in combination with letrozole were consistent between Korean, Asian and the 
global population and did not indicate any ethnic sensitivity. The other factors that could be 
associated with ethnic sensitivity (such as disease characteristics and medical practice), did not 


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indicate any differences in the way that ribociclib acts in Asian, and specifically Korean, 
patients [MONALEESA-7 Ethnic Insensitivity Assessment and Bridging Data Report]. 
These 2 trials have completed and significant improvement in progression-free survival was 
observed in these trials. Additional details are provided in Section 1.1.4.1.4. 
A MONALEESA-7 subgroup analysis of Asian patients with HR+/HER2-negative ABC found 
an almost 3-fold improvement in median PFS for patients treated with ribociclib + NASI 
compared to NASI alone: median PFS was 30.4 months in the ribociclib + NASI arm and 
11.0 months in the placebo + NASI arm (HR, 0.470; 95% CI, 0.312-0.706). The Kaplan-Meier 
estimated overall survival at 36 months was 78.9% in the ribociclib group and 61.5% in the 
placebo group, a 56% relative reduction in the risk of death with ribociclib was observed. Both 
ORR and clinical benefit rate (CBR) were improved with the combination of ribociclib and 
NSAI compared to NASI alone (ORR: 66.2% vs. 36.8%, CBR: 86.2% vs. 63.2%). Adverse 
events in the Asian subgroup were consistent with the overall population, neutropenia was the 
only grade 3/4 adverse event observed in 78% of patients treated with ribociclib + NASI. The 
improvement observed in PFS and overall survival benefit for the Asian population were 
consistent with the overall NSAI population (Lu et al 2020). 
1.1.4.2 
Overview of non-steroidal aromatase inhibitors: letrozole and 
anastrozole 
Based on the clinical benefit shown in postmenopausal patients, aromatase inhibitors in 
combination with ovarian function suppression (OFS), using a GnRH to block the pituitary is 
usually an effective strategy and have been investigated in premenopausal patients with breast 
cancer in the (neo)adjuvant, adjuvant and advanced settings. Results from the randomized phase 
III trials SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane 
Trial) showed that adjuvant treatment with exemestane + OFS as compared with tamoxifen + 
OFS, significantly reduced recurrence in premenopausal women with HR+ early breast cancer. 
Results from both trials (N=5,738) showed statistically significant differences in disease free 
survival (DFS) at 5 years (91.1% in exemestane + OFS vs 87.3% in tamoxifen + OFS) and rate 
of freedom from breast cancer at 5 years (92.8% in exemestane + OFS vs 88.8% in tamoxifen 
+ OFS) (Pagani et al 2014). Studies exploring the combination of third generation AIs and 
goserelin in metastatic premenopausal BC patients are shown below in Table 1-1 (Montagna et 
al 2013). 


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Table 1-1 
Goserelin and third generation AIs in metastatic premenopausal BC 
patients 
Study 
N 
AI+goserelin (G) 
ORR 
(CR+PR) (%) 
CB 
(CR+PR+SD) 
(%) 
TTP 
(months) 
First line 
endocrine 
therapy 
(Forward et al 
2004) 
16 
Anastrozole+G 
6.2 
75 
N/R 
No 
(Cheung et al 
2010) 
36 
13 
Anastrozole+G 
Exemestane+G* 
36 
N/R 
67 
38 
12 
N/R 
Yes 
No 
(Carlson et al 
2010) 
35 
Anastrozole+G 
37 
72 
8.3 
Yes 
(Park et al 2010) 
35 
Letrozole+G 
46 
77 
9.5 
Yes 
(Yao et al 2011) 
52 
Letrozole+G 
21 
71 
10 
Yes/No 
(Roche et al 
2009) 
33 
Anastrozole+G 
55 
64 
13 
Yes 
(Nishimura et al 
2012) 
37 
Anastrozole+G 
19 
62 
7.2 
Yes/No 
ORR=Objective response rate, CR=Complete response, PR=Partial response, CB=Clinical benefit, SD=Stable 
disease, PD=Progressive disease, TTP=Time to progression, N/R=Not reported 
*In study by Cheung et al 2010, patients received treatment with exemestane after they received treatment with 
anastrozole. 
 
Although data are limited (Montagna et al 2013), clinical benefit of the combination of AIs and 
OFS in premenopausal women with advanced ER+ breast cancer has been shown in small phase 
II studies with letrozole and anastrozole. In one study (Cheung et al 2010), patients received 
exemestane, but only after they had received anastrozole, so the effect of single–agent 
exemestane has not been well characterized. Lastly, novel therapeutic approaches targeting 
promising pathways should be explored to further improve efficacy in premenopausal women 
with advanced HR+ breast cancer. 
1.1.4.3 Overview of Letrozole 
Letrozole (Femara®) is a nonsteroidal competitive inhibitor of the aromatase enzyme system 
with demonstrated efficacy in the treatment of postmenopausal patients with HR+ breast cancer. 
Letrozole acts by inhibiting in a highly selective fashion the conversion of adrenal androgens 
to estrogens, which is the primary source of estrogens in postmenopausal women. Letrozole is 
a highly selective inhibitor of aromatase that induces a 75% to 95% decrease of estrogen levels 
after two weeks of treatment using daily doses of 0.1 to 5 mg, with no significant clinical and 
laboratory toxicities or changes in levels of other hormones of the endocrine system as shown 
in early phase I (Lipton et al 1995; Trunet et al 1996). It is indicated for the adjuvant treatment 
of postmenopausal women with HR+ early breast cancer as well as the extended adjuvant 
treatment of patients who have received 5 years of tamoxifen therapy. It is also indicated for 
the treatment of advanced HR+ breast cancer, both in the first-line setting as well as in patients 
who have disease progression following anti-estrogen therapy. Letrozole, when given as 
(neo)adjuvant treatment to women with un-resectable hormone receptor positive early breast 
cancer, was associated with significantly higher response rate than tamoxifen (60% versus 48%, 
p = 0.004) and a higher percentage of patients underwent breast conservative surgery (48% 
versus 36%, p = 0.036) (Ellis et al 2001). 


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The most frequently reported adverse events that were significantly different from placebo for 
letrozole in the adjuvant and extended adjuvant setting include hot flashes, arthralgia/arthritis 
and myalgia. In the first line setting, the most frequently reported adverse events include 
musculoskeletal pain (bone/back pain and arthralgia), hot flashes, nausea and dyspnea and 
incidences of adverse events were similar for tamoxifen in this setting. In general, the observed 
adverse reactions were mild to moderate in nature.  
For information on letrozole and management of letrozole related adverse events refer to the 
Femara® Prescribing Information. 
1.1.4.4 
Overview of anastrozole 
Anastrozole (Arimidex®) is another selective non-steroidal aromatase inhibitor. It significantly 
lowers serum estradiol concentrations and has no detectable effect on formation of adrenal 
corticosteroids or aldosterone. It is also indicated for adjuvant treatment of postmenopausal 
women with early HR+ breast cancer and first line as well as second line treatment of 
postmenopausal women with advanced HR+ breast cancer. Current treatment guidelines 
consider there is no compelling evidence showing meaningful efficacy or toxicity differences 
between the 3 clinically approved AIs: letrozole, anastrozole and the steroidal AI (exemestane) 
(Gradishar et al 2017). 
The adverse reactions occurring with an incidence of ≥10% in women taking anastrozole 
included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and 
vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral 
edema, increased cough, dyspnea, pharyngitis and lymphedema. For information on anastrozole 
and management of anastrozole related adverse events refer to the Arimidex® Prescribing 
Information. 
1.1.4.5 
Overview of Goserelin 
Goserelin (Zoladex®) is a synthetic decapeptide analog of gonadotropin releasing hormone 
(GnRH) indicated for prostatic carcinoma, endometriosis, assisted reproduction, precocious 
puberty, and advanced breast cancer. Ovarian suppression of estrogen biosynthesis release with 
goserelin are effective in preventing relapse in premenopausal women with early stage ER+ 
breast cancer. A meta-analysis of four randomized trials comparing an LHRH analogue alone 
versus an LHRH analogue plus tamoxifen in premenopausal women with advanced breast 
cancer showed that the combination treatment was significantly superior to LHRH agonist alone 
[ORR 29.7 and 38.8%, (p = 0.03), median progression-free survival (PFS) was 5.4 and 
8.7 months (p = 0.0003), and median OS was 2.5 and 2.9 years (p = 0.02), respectively] (Klijn 
et al 2001).  
Adverse events occurring in > 20% of women included hot flushes, headache, sweating, acne, 
emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea and 
peripheral edema (Zoladex® Prescribing Information). 
1.1.4.6 
Rationale for the combination of ribociclib with NSAI plus goserelin:  
While endocrine therapy is effective in treatment of HR+ advanced breast cancer, 
approximately 30-50% of patients may not respond to it due to a primary resistance. 
Overexpression of cyclin D1 is seen in the majority of breast cancers, likely activating the 


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CDK4/CDK6/E2F axis and promoting endocrine resistance. Therefore, using a CDK4/6 
inhibitor to block this activity may enhance efficacy of endocrine treatment strategies (Yu et al 
2006). Moreover, many advanced breast cancer patients with initial response to endocrine 
therapy will acquire secondary resistance to these agents (Bachelot et al 2012; Nichols et al 
2015). Co-targeting the 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 endocrine therapy tumors by preventing or 
delaying the development of acquired resistance for endocrine treatments. So, with a greater 
understanding of the biologic pathways, inhibition of cyclin-dependent kinases 4 and 
6 (CDK4/6), could potentially overcome or delay resistance to endocrine therapy in hormone 
receptor-positive/HER2-negative patients with MBC led to approval of ribociclib, in 
combination with endocrine therapy (Hortobagyi et al 2016; Bartsch 2017; Slamon et al 2018; 
Tripathy et al 2018). 
In addition, the USFDA has recently (July 2018) granted approval for ribociclib combination: 
• with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal 
women with HR+, HER2-negative advanced or metastatic breast cancer, as initial 
endocrine-based therapy; or 
• fulvestrant for the treatment of postmenopausal women with HR+, HER2-negative 
advanced or metastatic breast cancer, as initial endocrine based therapy or following 
disease progression on endocrine therapy. 
1.1.4.7 
Docetaxel 
Docetaxel (Taxotere®), a cytotoxic taxane, is an anti-microtubule agent effective in the 
treatment of patients with breast cancer. The clinical profile of docetaxel as an effective 
cytotoxic agent in the treatment of metastatic breast cancer is well established 
(Lyseng-Williamson et al 2005). It is prepared by semi-synthesis beginning with a precursor 
extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel 
is (2R, 3S)-N-carboxy-3-phenylisoserine,N-tertbutyl ester, 13-ester with 5β-20-epoxy-
1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. 
Docetaxel acts by disrupting the microtubular network in cells that is essential for mitotic and 
interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of 
tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads 
to the production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells. 
In the US and Europe, docetaxel is currently approved for use in breast cancer, non-small cell 
lung cancer, prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of head and 
neck cancer. The most commonly reported adverse events for docetaxel as a single agent are 
neutropenia (reversible and not cumulative; the median day to nadir was 7 days and the median 
duration of severe neutropenia [< 500 cells/mm3] was 7 days), infections, anemia, febrile 
neutropenia, 
hypersensitivity, 
thrombocytopenia, 
neuropathy, 
dysgeusia, 
dyspnea, 
constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, 
mucositis, alopecia, skin reactions, and myalgia. The severity of adverse events of docetaxel 
may be increased when docetaxel is given in combination with other chemotherapeutic agents. 


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Further information regarding ‘ docetaxel ’  can be found at Taxotere® Prescribing 
Information. 
1.1.4.8 
Capecitabine 
Capecitabine (Xeloda®) is a fluoropyrimidine carbamate with antineoplastic activity, which 
functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). 
Capecitabine is activated via several enzymatic steps. The enzyme involved in the final 
conversion to 5-FU, thymidine phosphorylase (ThyPase), is found in tumor tissues, but also in 
normal tissues, albeit usually at lower levels (Xeloda® Prescribing Information) 
Capecitabine is indicated in combination with docetaxel for the treatment of patients with 
locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy that 
included an antracycline. Capecitabine is also indicated as monotherapy for the treatment of 
patients with locally advanced or metastatic breast cancer after failure of taxanes and an 
anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is 
not indicated. The dose of capecitabine approved by the USFDA for patients with locally 
advanced or metastatic breast cancer is 1,250 mg/m2 twice daily (bid), given intermittently for 
14 days on a 21-day cycle. Capecitabine has a favorable safety profile, with AEs readily 
managed by dose modification, and it offers the additional benefit of convenient oral dosing. 
Capecitabine is suitable for long-term administration and generally lacks cumulative toxicity 
with prolonged use (O’Shaughnessy et al 2012). 
As a monotherapy, capecitabine was extensively evaluated in the first line metastatic breast 
cancer in various phase II and phase III clinical trials. The ORR shown in these studies was in 
a range of 21 to 30% and PFS was between 2.8 to 7.1 months in patients with metastatic breast 
cancer unselected for ER status. The two phase III studies were conducted in unselected by ER 
status patients with metastatic breast cancer. In the ANZBCTG0001 study (N = 323) where 
patients with first-line mBC unsuited for more intensive chemotherapy were randomized to 
receive capecitabine monotherapy or cyclophosphamide, methotrexate and 5-fluorouracil 
(CMF). All patients had to have a relapse-free survival interval for at least 6 months following 
adjuvant chemotherapy and 80% of patients had received adjuvant endocrine therapy. The 
primary endpoint PFS was similar between two treatment arms (HR = 0.86; 95% CI: 0.67-1.10). 
Patients enrolled in the capecitabine arm had a median PFS of 7 months and median OS of 
22 months, compared to median PFS of 6 months and OS of 18 months in patients randomized 
to CMF arm. The OS difference was statistically significant in favor of capecitabine arm 
(HR=0.72; 95% CI: 0.55-0.94; log-rank p = 0.02) (O’Shaughnessy et al 2012). Another 
randomized Phase III study compared the efficacy and safety of first-line capecitabine with 
pegylated liposomal doxorubicin (PLD) in patients with mBC (Jäger et al 2010). The primary 
endpoint of time to progression (TTP) was similar with capecitabine and PLD (median TTP, 
7.1 months versus 6.2 months, respectively; HR = 1.21; 95% CI: 0.84-1.75; p = 0.31). 
Capecitabine also had efficacy similar to that of PLD in terms of OS (median OS time, 29.4 
months versus 22.4 months, respectively (HR = 1.17; 95% CI: 0.79-1.74; p = 0.44). 
Robert et al, reported a PFS of 6.2 months in ER-positive HER2 –negative breast cancer patients 
receiving capecitabine monotherapy (Robert et al 2011). 
Diarrhea, hand-foot syndrome (HFS), nausea, vomiting and stomatitis are common adverse 
reaction attributed to capecitabine treatment. Across the phase II/III breast cancer trials, HFS 


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and diarrhea were the most frequently reported grade 3 or 4 AEs; alopecia and 
myelosuppression were rare (O’Shaughnessy et al 2012). Further information regarding 
capecitabine can be found at Xeloda® Prescribing Information. 
1.1.4.9 
Paclitaxel 
Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of solid tumors, 
including breast cancer, ovarian cancer, and lung cancer. Paclitaxel is obtained via a 
semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β, 
20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester 
with (2R,3S)-N-benzoyl-3-phenylisoserine. The antitumor activity of paclitaxel is based on 
tubulin-binding and stabilization of non-functional microtubule bundles, thereby blocking 
normal mitotic spindle development and subsequent cell division (Ringel et al 1991).  
In breast cancer, paclitaxel is used both in combination with other agents and as single agent. 
A weekly (qw) over a three-weekly (q3w) administration schedule has been shown to be more 
effective in the metastatic as well as in the adjuvant setting after standard chemotherapy 
(Seidman et al 2008; Sparano et al 2008). In two large randomized Phase 3 studies the overall 
toxicity profile was similar between the qw and q3w schedule except for neuropathy (higher in 
qw arm) while other studies have described a more favorable toxicity profile with the qw 
administration (Eniu et al 2005). 
1.1.4.10 Gemcitabine 
Gemcitabine (gemcitabine HCl, 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer)) 
is a nucleoside analogue that exhibits antitumor activity. Gemcitabine exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the 
progression of cells through the G1/S-phase boundary. 
The cytotoxic effect of gemcitabine is attributed to its active metabolites difluorodeoxycytidine 
di- and triphosphate (dFdCDP, dFdCTP) into which gemcitabine is converted intracellularly. 
The dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool 
available for DNA synthesis; dFdCTP is incorporated into DNA, resulting in DNA strand 
termination and apoptosis. 
Gemcitabine is indicated either as a single agent or in combination with other cytotoxic drugs 
in a variety of indications including platinum resistant/refractory ovarian cancer, NSCLC, 
metastatic breast cancer as well as locally advanced (non-resectable Stage II or Stage III) or 
metastatic (Stage IV) adenocarcinoma of the pancreas. 
The most common adverse reactions for the single agent (≥ 20%) are nausea/vomiting, anemia, 
hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, 
rash, thrombocytopenia, dyspnea, and peripheral edema (Gemzar prescribing information 2018). 
1.1.4.11 Vinorelbine 
Vinorelbine (Navelbine®) is a semi-synthetic vinca alkaloid (5'nor-anhydrovinblastine) 
anti-mitotic chemotherapy drug. Vinorelbine destabilizes the microtubules. The antitumor 
activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase 
through its interaction with tubulin. Vinorelbine may also interfere with: 1) amino acid, cyclic 


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AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 
3) cellular respiration, and 4) nucleic acid and lipid biosynthesis (Navelbine® prescribing 
information 2018). In vitro studies showed a selective effect on non-neuronal microtubules, 
which may explain the decreased neurotoxicity of vinorelbine compared with other vinca 
alkaloids (Johnson et al 1996).  
Vinorelbine is indicated either as a single agent or in combination with other drugs as the first 
line treatment of stage 3 or 4 non-small cell lung cancer in the USA and in Europe, in addition 
to the NSCLC, vinorelbine is also indicated for the treatment of advanced breast cancer stage 3 
and 4 relapsing after or refractory to an anthracycline containing regimen. 
The most frequent adverse events associated with vinorelbine include alopecia, nausea, 
vomiting, neuropathy, neutropenia and leukopenia, venous reactions, and localized dermal 
necrolysis at the site of intravenous injection. Further information regarding vinorelbine can be 
found at Navelbine® prescribing information. 
1.1.5 
Potential for drug-drug interactions 
The combinations of ribociclib and a NSAI + goserelin is being evaluated in ongoing clinical 
trials and the currently available data does not suggests presence of a clinically relevant 
drug-drug interaction between ribociclib, letrozole and anastrozole (Syed 2017). Data from a 
clinical trial in patients with breast cancer and population PK analysis indicated no drug 
interaction between ribociclib and letrozole following co-administration of the drugs. Similarly 
for anastrozole, data from a clinical trial in patients with breast cancer indicated no clinically 
relevant drug interaction between ribociclib and anastrozole following co-administration of the 
drugs. 
In addition, the metabolism of goserelin is not CYP-mediated; rather hydrolysis of C-terminal 
amino acids is the major clearance mechanism. Based on the available information, goserelin 
is not expected to affect the metabolism of nor be affected by co-administered drugs (Zoladex® 
Prescribing Information). 
1.1.6 
Endocrine therapy versus chemotherapy: 
Recommendation for endocrine therapy versus chemotherapy as first-line treatment of hormone 
receptor-positive metastatic breast cancer (MBC) is endorsed by the main international 
guidelines such as ASCO and ESO-ESMO guidelines (Bonotto et al 2017). Endocrine therapy 
should be used as initial treatment except in cases of immediately life-threatening disease, 
tumors refractory to endocrine therapy, visceral crisis, or rapid progressive disease that mandate 
a high response rate treatment. Visceral crisis is deﬁned as severe organ dysfunction as assessed 
by signs and symptoms, laboratory studies, and rapid progression of disease. Visceral crisis is 
not the mere presence of visceral metastases but implies important visceral compromise leading 
to a clinical indication for a more rapidly efﬁcacious therapy, particularly since another 
treatment option at progression will probably not be possible (Cardoso et al 2017). Treatment 
recommendations should be based on type of adjuvant treatment, disease-free interval, and 
organ function (Rugo et al 2016). 
The preference of endocrine therapy is also supported by data showing a therapeutic benefit 
with less toxicity and better quality of life in comparison to chemotherapy. Ten-years (between 
2004 to 2014), retrospective, real world data in patients with luminal-like HER2-negative 


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metastatic breast cancer data, also confirmed that there is no significant difference in terms of 
survival (i.e. both PFS and OS) for chemotherapy versus endocrine therapy (Bonotto et al 2017). 
Historical literature suggests that neither survival nor quality of life (QoL) is improved by 
treating patients with chemotherapy when endocrine therapy has a reasonable chance of 
providing disease control (Rugo et al 2016). In the absence of visceral crisis (i.e., immediately 
life-threatening disease), endocrine therapy appeared to be the treatment of choice for visceral 
metastases in the same way as it was for non-visceral metastases (Robertson et al 2014). 
With respect to the option of combining the chemotherapy with the endocrine therapy, historical 
data suggest that sequential single-modality treatment is equivalent or preferred to combination 
therapy, although formal comparisons are weak with respect to clinically important end points 
including symptom control, PFS, and overall survival (OS). For these reasons, the 
recommended initial course of treatment for HR-positive MBC is endocrine therapy (Rugo et 
al 2016). 
Practical experience, evidences from the randomized trials, and systematic review of results of 
published randomized Trials has indicated that combining chemotherapeutic agent are 
associated with higher response rates and longer progress free survival than single-agent 
regimens. However, despite these superiorities, combination chemotherapeutic therapy neither 
improved overall survival nor improved the quality of life. The use of combination therapy 
often involves compromises with regard to dose and frequency of administration, and these 
compromises may negate the promise of synergy. Indeed, a combination regimen might impair 
rather than improve quality of life if it induces toxicity disproportionate to response (Sledge et 
al 2003). For patients with visceral crisis, symptomatic visceral metastasis with certain tumor 
load or rapid progression of disease or impending visceral compromise, combination 
chemotherapy is indicated because high response rate is needed. 
1.2 
Purpose 
A retrospective analysis of prescribing data in the Netherlands (N = 520) showed that one 
quarter of patients with ER+ breast cancer received chemotherapy as initial palliative treatment; 
in patients with visceral crisis or multiple metastases, the proportion treated with chemotherapy 
increased to one third (Lobbezoo et al 2016). In the same study, 20% (71/353) of patients older 
than 50 received chemotherapy as 1st line treatment, whereas 35% (45/239) of patients younger 
than 50 received chemotherapy as 1st line treatment. This can be explained by the perception 
that younger women have a more aggressive disease than older women. It is believed that the 
rates of first-line chemotherapy prescribed in younger women are likely to be even higher in 
Asia and Middle East than in Europe. Also, with the current treatment options there are limited 
data to answer whether first-line therapy for significantly symptomatic HR-positive MBC 
patients should be chemotherapy or endocrine therapy. All these leads to physicians in many 
countries to prefer the use chemotherapy over the endocrine therapy, in real-world clinical 
practice setting. Therefore, women with hormone receptor-positive HER2-negative disease, the 
question of whether to use chemotherapy or endocrine therapy as first-line treatment MBC 
remains, to date, partially unresolved. 
Now, especially with availability of new therapeutic agent like ribociclib, which demonstrated 
efficacy in combination as initial endocrine therapy, the question whether to use chemotherapy 
or endocrine therapy gains more importance for substantiation. The recent results from 


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MONALEESA-7 data demonstrated that for premenopausal women with ER+/HER2- ABC, 
median PFS with endocrine therapy was 13 months, which was extended to 2 years with the 
addition of a CDK4/6 inhibitor (ribociclib) (Tripathy et al 2018). The study also showed that 
for patients with measurable disease, the response rate of endocrine therapy plus CDK4/6 
inhibitor was 51%. Studies which evaluated combination chemotherapy in this patient group 
have demonstrated a response rate of 35 to 45%. Results from the overall survival demonstrate 
that the addition of ribociclib to endocrine therapy resulted in significantly longer overall 
survival than endocrine therapy alone with approximately 29% lower risk of death. This 
demonstrate that there is a substantial clinical benefit of ribociclib plus endocrine therapy as 
compared with endocrine therapy alone (Im et al 2019). The recent updated median overall 
survival was 58.7 months with ribociclib + endocrine therapy and 48.0 months with placebo + 
endocrine therapy (HR, 0.76; 95% CI, 0.61-0.96), with a 24% relative reduction in the risk of 
death with ribociclib. It is the longest reported period in HR+/HER2-negative ABC among all 
Phase III trials in this setting (Tripathy et al 2020). Therefore, the current standard 1st line 
treatment for premenopausal ER-positive HER2-negative metastatic breast cancer patients who 
are not associated with a critical clinical condition should be ovarian suppression plus endocrine 
therapy and ribociclib, rather than of chemotherapy. 
Palbociclib, a CKD 4/6 inhibitor, when combined with endocrine treatment and compared with 
capecitabine in Young-PEARL study, palbociclib demonstrated a longer PFS (20.1 vs. 14.4 
months; 95% CI: 0.437 to 0.994) (Park et al 2019). For patients with visceral crisis, or 
aggressive disease which mandated rapid disease control, combination chemotherapy would be 
needed according to current guidelines. Although combining multiple chemotherapy agents 
provided significant clinical benefits by providing the superior time to disease progression, 
ranging from 6 months to approximately 8 months. The median time to disease progression was 
6.1 months in the capecitabine plus docetaxel combination arm and 4.2 months with docetaxel 
alone (O’Shaughnessy et al 2002). Similarly, the PFS was 5.9 months for gemcitabine plus 
paclitaxel versus 3.9 months for paclitaxel (Albain et al 2008). For patients who received 
doxorubicin plus paclitaxel, the estimated median time to progression was 8.3 months, 
significantly longer than the estimated median of 6.2 months for patients who received 5-
fluorouracil, doxorubicin, and cyclophosphamide (Jassem et al 2001). However, in first line 
setting, four phase III clinical trials consistently demonstrated that CDK4/6 inhibitor plus 
endocrine therapy could generate a tumor response rate higher than 50% (in measurable lesions), 
which is higher than what has been reported by most of the chemotherapy regimens in phase III 
studies. The purpose of this trial is to compare the two treatment modalities in the patients with 
aggressive disease in HR+/HER2- metastatic pre/peri-menopausal breast cancer setting. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Primary Objective:  
Primary Endpoint: 
 
Analysis 


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To determine whether treatment 
with NSAI + goserelin+ ribociclib 
prolongs PFS compared to 
treatment with combination 
chemotherapy in premenopausal 
or perimenopausal women with 
HR+, HER2 negative locally 
advanced or metastatic breast 
cancer. 
Progression-free survival is defined as the 
time from the date of randomization to the 
date of the first documented progression as 
per local review and according to RECIST 
1.1 or death due to any cause. 
Refer to 
Section 12.4.1 
Secondary Objectives:  
Secondary Endpoints:  
 
To compare time to treatment 
failure (TTF) between the two 
treatment arms. 
Time to treatment failure is defined as the 
time from the date of randomization/start of 
treatment to the earliest of date of 
progression, date of death due to any 
cause, change to other anti-cancer 
therapy, or date of discontinuation due to 
reasons other than ‘Protocol violation’ or 
‘Administrative problems’. 
Refer to 
Section 12.5.1 
To compare 3-month treatment 
failure rate between the two 
treatment arms.  
Treatment failure rate is defined as the 
proportion of patients who discontinued the 
study treatment due to progressive 
disease, death due to any cause, change 
to other anti-cancer therapy, or 
discontinuation due to reasons other than 
protocol violation or administrative 
problems. 
Refer to 
Section 12.5.1 
To determine whether treatment 
with NSAI + goserelin + ribociclib 
increases overall response rate 
(ORR), clinical benefit rate (CBR), 
and Time to response (TTR) 
compared to treatment with 
combination chemotherapy. 
• 
Overall response rate (ORR) is defined 
as the proportion of patients whose 
best overall response is either CR or 
PR, as per local review and according 
to RECIST 1.1. 
• 
Clinical benefit rate is defined as the 
proportion of patients with a best 
overall response of CR, or PR or stable 
disease, lasting for a duration of at 
least 24 weeks, as defined by RECIST 
1.1. 
• 
Time to response is defined as the time 
from the date of randomization to the 
first documented response of either CR 
or PR, which must be subsequently 
confirmed, as defined by RECIST 1.1. 
Refer to 
Section 12.5.1 
To compare the overall survival 
(OS) between two treatment arms. 
Overall survival is defined as the time from 
the date of randomization to the date of 
death due to any cause. 
Refer to 
Section 12.5.1 
To evaluate the safety of ribociclib 
in combination with NSAI and 
goserelin, and combination 
chemotherapies. 
Frequency/severity of adverse events, lab 
abnormalities. 
Refer to 
Section 12.5.2 
To compare patient reported 
outcomes for health-related quality 
of life in the two treatment arms. 
Change from baseline in the global health 
status/QOL scale score by using FACT-B 
questionnaires. 
Refer to 
Section 12.5.3 


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3 
Study design 
This is a randomized, phase II, open label, multi-center trial comparing the combination of 
NSAI (letrozole or anastrozole) + goserelin + ribociclib versus combination chemotherapy 
(either of docetaxel + capecitabine, paclitaxel + gemcitabine or capecitabine + vinorelbine). 
Premenopausal or perimenopausal women with HR+, HER2-negative, advanced breast cancer 
with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and fulfill at 
least one of the following criteria will be considered for this study: symptomatic visceral 
metastases, or rapid progression of disease or impending visceral compromise, or markedly 
symptomatic non visceral disease.  
Approximately, 222 eligible women patients will be competitively enrolled and randomly 
assigned to one of the below treatment arms in 1:1 ratio:  
• Ribociclib arm: NSAI + goserelin + ribociclib (N = 111)  
• Combination chemotherapy arm: Either of docetaxel + capecitabine, paclitaxel + 
gemcitabine or capecitabine + vinorelbine based chemotherapy treatment (N = 111). The 
choice of which chemotherapy combination will be used on study will be decided by the 
study investigator; once patients’ initiate the treatments, switching to another combination 
chemotherapies will not be allowed. 
Randomization will be stratified by (1) the presence of liver metastases (present or absent) (2) 
DFI <2 years (yes or no, de novo stage 4 is defined as DFI >2 years). 


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Figure 3-1 
Schematic representation of the study design 
 
 
a. End of treatment (EOT) is defined as until disease progression (radiologically documented 
according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study 
treatment for any other reason, including consent withdrawal, patient is lost to follow-up, or the 
sponsor terminates the study, whichever occurs first. 
b. After discontinuation of study treatment, all patients will be followed for safety for 30 days except in 
case of death, lost to follow-up or withdrawal of consent. 
c. Survival follow-up will be done every 16 (± 4) weeks until the EOS, which is defined by the following: 
at least 46 months from first patient first visit (FPFV) or when required numbers of OS events have 
been reached (80% of 222 patients have died), whichever occurs first. 
Note: Efficacy follow up is through tumor assessment and for FACT-B Questionnaire at every 6 weeks 
after randomization for the first 12 weeks and every 8 weeks for the next 32 weeks and at every 
12 weeks thereafter until disease progression, death, withdrawal of consent, loss to follow-up, or 
patient/guardian decision. 
The study will consist of a 28-day screening phase (after signing the study informed consent 
form (ICF)), treatment phase (includes EOT visit and safety follow-up) and survival follow up 
as described in Figure 3-1. Patients will receive study treatment until the following (whichever 
occurs first): disease progression, unacceptable toxicity, death, or discontinuation from the 
study treatment for any other reason, including consent withdrawal, patient is lost to follow-up, 
or the sponsor terminates the study. 
Patients will be followed for survival regardless of treatment discontinuation for any reason 
(except if consent is withdrawn, patient is lost to follow-up or until death) and regardless of 
achieving the primary endpoint, until the deaths, withdrawal of consent, loss to follow-up, or 
patient/guardian decision. Patients’ permanently discontinuing ribociclib, but not any other 
treatment could remain on study until primary endpoint is achieved. 
Discontinuation of the NSAI will necessitate the end of treatment. Patients discontinuing 
goserelin after at least 1 year of study treatment, which is due to menopausal secondary to 
oophorectomy or aging, could remain on treatment; however early discontinuation of goserelin 
will necessitate the end of the treatment.  
 
 


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It is anticipated that patients will be recruited in approximately in 55 sites in 13 countries in 
approximately 30 months’ time. 
A Steering Committee has been established, comprising of investigators, Novartis personnel 
participating in the trial, and one patient, who is not a trial participant to ensure transparent 
management of the study according to the protocol through recommending and approving 
modifications as outlined in Section 10.2.2. 
3.1.1 
Screening phase 
Premenopausal or perimenopausal women with HR+, HER2-negative advanced breast cancer 
will be screened for eligibility within a 28-day screening window prior to starting study 
treatment on study baseline (Cycle 1 Day 1). During this time, the inclusion and exclusion 
criteria will be assessed and all screening assessments, laboratory tests, and procedures will be 
performed. Results of all screening and baseline (Cycle 1, Day 1) evaluations must be reviewed 
by the investigator or his/her designee prior to patient enrollment into the study in order to 
assure that all inclusion and exclusion criteria have been satisfied. No re-screening of patients 
is allowed in this study. 
All study patients must be thoroughly informed about all aspects of the study, including the 
study agents, visit schedule, required evaluations, and all regulatory requirements for informed 
consent. The signed informed consent must be obtained to participate in this study prior to the 
performance of any study-related activities. If the patient is unable to read, an impartial witness 
should be present during the entire informed consent discussion. Eligibility will be determined 
according to the inclusion/exclusion criteria as described in Section 5. A list of procedures to 
be performed at the time of screening is summarized in Table 8-1. Patients must meet all 
eligibility criteria to be considered for enrollment in the study. 
3.1.2 
Treatment phase 
On completion of all screening procedures, patient eligibility will be checked and the eligibility 
check will be embedded to the Interactive Response Technology (IRT) system. Please refer and 
comply with detailed guidelines in the IRT manual. Interactive Response Technology system 
will confirm the inclusion of eligible patients and randomly assign patients to one of the two 
treatment arms in a 1:1 ratio. 
Patients may continue study treatment until the following (whichever occurs first): disease 
progression (radiologically documented according to RECIST 1.1 criteria), occurrence of 
unacceptable toxicity, death, or discontinuation from the study treatment for any other reason, 
including consent withdrawal, patient is lost to follow-up, or the sponsor terminates the study. 
End of study is defined in Section 3.1.7. 
Patients will be followed for survival, at every 16 (± 4) weeks, regardless of treatment 
discontinuation for any reason (except if consent is withdrawn, patient is lost to follow-up or 
until death) and regardless of achieving the primary endpoint, until at least 46 months from the 
first patient first visit (FPFV) date or when required numbers of OS events have been reached 
(80% of 222 patients have died) (whichever occurs first). 


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3.1.2.1 
Safety and efficacy follow-up 
After discontinuation of study treatment, all patients will be followed up for safety for 30 days 
except in case of death, loss to follow-up or withdrawal of consent. Patients whose treatment is 
interrupted or permanently discontinued due to an AE, including abnormal laboratory value, 
must be followed until resolution or stabilization of the event, whichever comes first. This could 
include all study assessments appropriate to monitor the event.  
During the safety follow-up, the information of subsequent one line of anti-neoplastic therapy 
initiated immediately after study treatment discontinuation will be collected.  
3.1.3 
Survival follow-up 
All patients will be followed for survival once they discontinue study treatment and end of 
efficacy evaluations after at least 46 months from FPFV, or when OS events have been reached 
(80% of 222 patients have died) (whichever occurs first). Survival follow-up will be conducted 
every 16 (± 4) weeks or earlier if a survival update is required to meet safety or regulatory needs, 
after the safety follow-up visit. Survival information can be obtained by clinical visits or 
telephone calls until death, the patient is lost to follow-up, or the patient withdraws consent for 
survival follow-up. 
3.1.4 
Timing of interim analyses and design adaptations 
No interim analysis is planned.  
3.1.5 
Treatment period 
Patients will be treated with NSAI + goserelin + ribociclib or combination chemotherapies 
(either docetaxel + capecitabine or paclitaxel + gemcitabine or capecitabine + vinorelbine, as 
per investigator’s choice) until disease progression, unacceptable toxicity, death, withdrawal of 
consent by the patient, patient is lost to follow up, death, discontinuation from the study 
treatment due to any other reason or the sponsor terminates the study. For details of assessments, 
refer to Table 8-1. 
3.1.6 
Definition of end of treatment 
An end of treatment (EOT) will be on the first occurrence of any of the following: disease 
progression (radiologically documented according to RECIST 1.1 criteria), unacceptable 
toxicity, death, or discontinuation from the study treatment for any other reason, including 
consent withdrawal, patient is lost to follow-up, or the sponsor terminates the study. 
3.1.7 
Definition of end of the study 
The end of study will be after 46 months from first patient first visit date or when required 
number of OS events have been reached (80% of 222 patients have died), whichever occurs 
first. A End-of-study (EOS) completion eCRF page should be completed at the end of study for 
every individual patient. 
If the primary endpoint, is statistically significant at the primary PFS analysis, data collection 
will continue during survival follow-up and End of Study will be declared after 46 months from 
FPFV or 80% of 222 patients have died (whichever occurs first). 


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If the primary endpoint, PFS, is not statistically significant at the primary PFS analysis then 
End of Study will be declared and all patients will discontinue all components of study therapy 
and will complete the safety follow-up period (30 days after EOT visit). 
Patients continuing to derive benefit from study treatment at the end of the study in the opinion 
of the investigator may be transferred to a post-trial access (PTA) following the local country 
Health Authority regulation(s) and patient’s consent, if ribociclib is either not commercially 
available or not reimbursed to the patients in the country by the time the study is completed. If 
at the end of the study, patients continuing to derive benefit from comparator treatment in the 
opinion of the investigator will transitioned onto the commercial available product(s), which 
should be accessible via their healthcare provider in the respective countries. If the comparator 
treatment is commercially available but not reimbursed, an alternative option may be discussed 
between the investigator and Novartis team. 
3.1.8 
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 9.2 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 Institutional Review boards (IRBs) and/or ethics committees of the early termination 
of the trial. 
4 
Rationale 
4.1 
Rationale for study design 
This is a randomized, open label, two-arm study with the objective to compare the effect of 
combination of NSAI (letrozole or anastrozole) + goserelin+ ribociclib versus combination 
chemotherapy in premenopausal or perimenopausal patients with advanced breast cancer. The 
randomized, multi-center, parallel group design is the gold standard design for clinical trials as 
it minimizes treatment assignment bias, balancing both known and unknown prognostic factors 
in the assignment of treatments.  
A randomization ratio of 1:1 is selected for this phase II trial, which will allow an evaluation of 
objectives. As in this study treatment blinding cannot be implemented, open-label design is 
opted. 
Randomization will be stratified by the following factors: 
1. the presence of liver metastases (present or absent)  
2. DFI < 2 years (yes or no). 
The stratification factors are selected because of their well-recognized prognostic value. 
4.2 
Rationale for choice of control drugs or combination drugs 
Recent clinical data indicate that inhibitors of CDK4/6 are effective in combination with 
endocrine therapies in advanced ER+ breast cancer, including in combination with letrozole or 


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with NSAI (Section 1.1.2). Ovarian suppression of estrogen release with luteinizing 
hormone-releasing hormone (LHRH) agonists such as goserelin is effective in preventing 
relapse in premenopausal women with early stage ER+ breast cancer (Klijn et al 2001). 
Similarly, the efficacy of chemotherapeutic agent selected in this study are well established in 
this clinical settings (Section 1.1.4.7 to Section 1.1.4.11). 
4.3 
Rationale for dose/regimen and duration of treatment 
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 and approved in several countries worldwide when combined with endocrine 
therapy in clinical trials in patients with HR+, HER2-negative advanced breast cancer 
(Section 1.1.4.1.3 and Section 1.1.4.1.4). 
The treatment doses will be according to their approved label. Based on available data from 
preliminary results of patients treated with the combination of ribociclib at 600 mg and 
letrozole, anastrozole, and goserelin, the combination is tolerable and there is no clinically 
relevant drug interaction between ribociclib and these above mentioned drugs (Section 1.1.5). 
Therefore, these doses will be used in this study. 
Similarly, in the combination chemotherapies arm, the doses are in accordance with product 
labeling. The treatment information, including co-therapies are presented in Table 4-1. 
Table 4-1 
Treatment information 
Compound 
(generic) 
Dose and dosage form 
Frequency 
Ribociclib Arm 
Ribociclib 
600 mg (200 mg x 3) Tablets 
Days 1-21 of each 28 day cycle 
Letrozole (NSAI) 
2.5 mg Tablets 
Daily (all days of every cycle 
without interruption). 
Anastrozole (NSAI) 
1 mg Tablets 
Daily (all days of every cycle 
without interruption) 
Goserelin 
3.6 mg Subcutaneous implant 
Day 1 of each 28 day cycle (an 
administration window of ± 3 days 
is allowed) 
Combination chemotherapy treatment Arm 
Docetaxel + 
capecitabine 
Docetaxel: 60 - 75 mg/m² on day 1 
(IV Infusion) 
 
Capecitabine: 1600 - 2500 
mg/m²/day (Tablet) 
Docetaxel once, on day 1 of the 
3-weeks cycle 
Capecitabine twice daily, on days 
1 to 14 of each cycle, followed by 
a 1-week rest period, in 3 weeks 
cycle. 
Paclitaxel + gemcitabine 
Paclitaxel: 175 mg/m2 (IV Infusion) 
 
 
 
Gemcitabine: 1000 - 1250 mg/m2 
(IV Infusion) 
Paclitaxel via 3-hour intravenous 
(IV) infusion on Day 1 in 3-weeks 
cycles. 
Gemcitabine at via 30-minute IV 
infusion on Day 1 and Day 8 in 
3-weeks cycles 


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Paclitaxel: 80 - 90 mg/m2 
(IV Infusion) 
 
 
Gemcitabine: 800 -1250 mg/m2 
(IV Infusion) 
Paclitaxel via 1-hour intravenous 
(IV) infusion on Day 1 and Day 8 in 
3-weeks cycles 
Gemcitabine at via 30-minute IV 
infusion on Day 1 and Day 8 in 
3-weeks cycles 
Capecitabine + 
vinorelbine 
Capecitabine: 1600 - 2500 mg/m2 
/day (Tablet) 
 
Vinorelbine 60 to 80 mg/m2/day 
(oral) or 25 to 30 mg/m2 (IV 
infusion) 
Capecitabine twice daily on days 1 
to 14, followed by a 1-week rest 
period,, in 3-weeks cycle 
Vinorelbine, once, on Day 1 and 
Day 8 in 3-weeks cycles 
4.4 
Purpose and timing of interim analyses 
No interim analysis is planned. 
4.5 
Risks and benefits 
4.5.1 
Potential risks to clinical trial participants 
The study will be submitted for approval to local Independent Review Boards prior to any 
patient being enrolled. Patients in this study will be carefully monitored for key toxicities that 
have been observed with study drugs with periodic laboratory assessment and 
electrocardiogram (ECG).  
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive management of 
study-drug induced adverse events are provided for all the investigational drugs in Section 6.5. 
A Steering Committee has been established comprising of investigators, Novartis personnel 
participating in the trial and one patient, who is not participating in this trial to ensure 
transparent management of the trial according to the protocol through recommending and 
approving modifications as outlined in Section 10.2.2. A Novartis Safety Management Team 
periodically reviews and evaluates all emerging data across the ribociclib program for potential 
safety signal assessment in a timely manner.  
Women of child bearing potential must be informed that taking the study treatment 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 requirements outlined in the 
exclusion criteria. If there is any question that the patient will not reliably comply, they should 
not be entered or continue in the study. This study does not cause any risk for the male partners 
of the female participants. 
Risks of imaging procedures 
Tumor response will be assessed locally, according to the Novartis guideline version 3.2 
(Appendix 2) based on RECIST Version 1.1 (Eisenhauer et al 2009). Imaging assessments will 
be performed 
• at screening within 28 days prior to randomization and  


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• subsequently at every 6 weeks after randomization/start of treatment for the first 12 weeks 
and  
• at every 8 weeks for the next 32 weeks and  
• at every 12 weeks thereafter until progression (radiologically documented according to 
RECIST 1.1 criteria) or death, withdrawal of consent, loss to follow-up, patient/guardian 
decision. Please refer to Table 8-1 for details of assessments.  
A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, or FDG-PET) will be performed. If a patient has PET study or whole body bone 
Magnetic resonance imaging (MRI) within 42 days (6 weeks) before signing informed consent, 
she do not need an additional bone scan.  
Patients will receive radiation when X-ray and computed tomography (CT) scans is done. The 
radiation received during one examination is the same as 2 - 10 years of normal radiation 
received in everyday life, depending on the body parts included. Although repeated radiation 
may damage body tissues and slightly increase the chances of having cancer, however patients 
should not expect an increased risk from the imaging being done for this study. Patient enrolled 
in this study are those with aggressive disease status. Therefore, close monitoring of disease 
status through imaging study is necessary for the safety of the patient. 
Patients’ visit(s) to study sites for any assessments during public health emergencies, may 
increase the risk to patients to be impacted by public health issue. In these situations, it will be 
Principal Investigators’ responsibility to make judgments which will be in the best interest of 
patient’s health. 
4.5.2 
Potential benefits to clinical trial participants 
All women patients with HR+/HER2- breast cancer enrolled in this study will receive either 
ribociclib + NSAI (letrozole or anastrozole) + goserelin or combination chemotherapy (either 
combination of docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + 
vinorelbine). The patients in the experimental arm will receive ribociclib in addition to the 
standard of care NSAI + goserelin. Addition of a ribociclib has already demonstrated clinical 
benefit without losing the benefit of the back bone therapy. Whereas, the patients in the control 
arm will receive chemotherapies that are approved and widely used in regular clinical practices 
for this study indication. 
5 
Population 
The study will include approximately 222 premenopausal or perimenopausal, adult, women 
with HR+, HER2-negative, advanced breast cancer and have not received neither prior 
hormonal therapy nor any chemotherapies in advance breast cancer setting. To be considered 
for this study, the patients must have an advanced disease status that need combination 
chemotherapy according to PI’s judgment. The investigator or designee must ensure that only 
patients who meet all the following inclusion and none of the exclusion criteria are offered 
treatment in the study.  
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 


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1. Patient is an adult female ≥ 18 years old and < 60 years old at the time of informed 
consent. Written informed consent must be obtained prior to any screening procedures. 
2. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor 
positive and/or progesterone receptor positive breast cancer based on the most recently 
analyzed tissue sample and all tested by local laboratory. ER should be more than 10% ER 
positive or Allred ≥ 5 by local laboratory testing. 
3. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or 
an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or 
SISH) test is required by local laboratory testing and based on the most recently analyzed 
tissue sample. 
4. Women with inoperable locally advanced or metastatic breast cancer not amenable to 
curative therapy. Patients must fulfill at least one of the following criteria to be considered 
that combination chemotherapy is needed according to PI’s judgment. However, for 
patients who are eligible under inoperable locally advanced breast cancer or criteria 4c, 
the recruitment is stopped to enrich patient population with visceral metastases. 
a. Symptomatic visceral metastases 
b. Rapid progression of disease or impending visceral compromise.  
c. Markedly symptomatic non visceral disease if the treating physician opts to give 
chemotherapy for rapid palliation of patients’ symptoms. 
5. Patient is premenopausal or perimenopausal at the time of study entry. 
a. Premenopausal status is defined as either: 
• Patient had last menstrual period within the last 12 months. 
OR 
• If on tamoxifen within the past 14 days, plasma estradiol and FSH are in the 
premenopausal range, according to local laboratory definition. 
• In case of therapy induced amenorrhea, plasma estradiol and/or FSH are in the 
premenopausal ranges according to local laboratory definition. 
• Patients who have undergone bilateral oophorectomy are not eligible. 
b.  Perimenopausal status is defined as neither premenopausal nor postmenopausal (see 
exclusion criteria 5) 
6. Patients must have not received neither prior hormonal therapy nor chemotherapy for 
advanced breast cancer, except LHRH agonist. Patients who received ≤ 14 days of 
tamoxifen or a NSAI (letrozole or anastrozole) with or without LHRH agonist for 
advanced breast cancer prior to randomization are eligible. Patient must have measurable 
disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (a lesion at a 
previously irradiated site may only be counted as a target lesion if there is a clear sign of 
progression since the irradiation) 
7. Patient has an ECOG performance status 0 to 2. For patients with ECOG 2, the poor 
performance status should be due to breast cancer other than underlying medical disease. 
8. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by local laboratory): 
a. Absolute neutrophil count ≥ 1.5 × 109/L 
b. Platelets ≥ 100 × 109/L 


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c. Hemoglobin ≥ 9.0 g/dL 
d. Estimated glomerular filtration rate ≥ 30 mL/min by a Cockcroft-Gault formula.  
e. Total bilirubin < ULN except for patients with Gilbert's syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN or total 
bilirubin ≤ 1.5 ULN in patients with liver metastases. 
f. Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver metastasis, 
who are only included if the AST is < 5 × ULN and Alanine transaminase 
(ALT) < 2.5 × ULN, except for patients with liver metastases, who are only included 
if the ALT is < 5 × ULN.  
9. Patient must have the following laboratory values within local normal range or corrected 
to within local normal range with supplements before the first dose of study medication: 
• 
Potassium 
• 
Magnesium 
• 
Total Calcium (corrected for serum albumin) 
10. Standard 12-lead ECG values assessed by the local laboratory 
• 
QTcF interval at screening < 450 msec (QT interval using Fridericia’s correction) 
• 
Mean resting heart rate 50-99 bpm (determined from the ECG) 
11. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or 
patient has had a hysterectomy. 
12. Must be able to swallow investigational tablets or capsules. 
13. Patients must be able to communicate with the investigator and comply with the 
requirements of the study procedures. 
14. Must be willing to remain at the clinical site as required by the protocol. 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patient has received prior systemic anti-cancer therapy (including hormonal therapy and 
chemotherapy, or any CDK4/6 inhibitor for advanced breast cancer.  
• Patients who received (neo)adjuvant therapy for breast cancer are eligible. If the prior 
(neo)adjuvant therapy included aromatase inhibitors, the treatment free interval must 
be greater than 12 months from the completion of aromatase inhibitor treatment until 
randomization. 
• If patients have disease recurrence during adjuvant tamoxifen treatment, disease free 
interval (defined as duration between the date of patient received complete tumor 
resection for primary breast cancer lesion to the date of disease recurrence 
documented) must be greater than 12 months. 
• Patients who are receiving ≤ 14 days of tamoxifen or NSAI or LHRH agonists ≤ 28 
days for advanced breast cancer prior to randomization are eligible. 
2. Patient has received extended-field radiotherapy ≤ 2 weeks prior to randomization or limited 
field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or 
better from related side effects of such therapy (with the exception of alopecia or other 
toxicities not considered a safety risk for the patient at investigator's discretion). Patient 


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from whom ≥ 25% (Ellis 1961) of the bone marrow has been previously irradiated are also 
excluded. 
3. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with 
the exception of adequately treated, basal or squamous cell skin carcinoma, or curatively 
resected cervical cancer in situ. 
Note: CNS involvement must be ruled out by assessments if a patient has any signs or 
symptoms indicating potential CNS metastases. 
4. Participation in other studies involving investigational drug(s) within 30 days prior to 
randomization or within 5-half-lives of the investigational product, (whichever is longer) 
or participation in any other type of medical research judged not to be scientifically or 
medically compatible with this study. If the patient is enrolled or planned to be enrolled in 
another study that does not involve an investigational drug, the agreement of the Novartis 
study medical lead is required to establish eligibility. 
5. Patient is postmenopausal. Postmenopausal status is defined either by: 
• Prior bilateral oophorectomy 
OR 
• Age ≥ 60 years 
OR 
• Age < 60 years and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol 
in the postmenopausal range per local normal range. 
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and 
estradiol serum levels are needed to ensure menopausal status  
(Denlinger et al 2017). 
6. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or 
breast-feed during the study 
7. 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 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 
• Total hysterectomy or tubal ligation at least 6 weeks before taking study treatment 
• Male partner sterilization (at least 6 months prior to screening). For female patients on 
the study the vasectomized male partner should be the sole partner for that patient 
• Placement of an intrauterine device 
Note: Use of oral (estrogen and progesterone), transdermal, injected, implanted hormone 
containing intrauterine systems (IUS) or any other hormonal methods of contraception is not 
allowed in this study. If local regulations deviate from the contraception methods listed above 
to prevent pregnancy, local regulations apply and will be described in the ICF. 
8. Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality, including any of the following: 


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• History of documented myocardial infarction, angina pectoris, symptomatic 
pericarditis, or coronary artery bypass graft within 6 months prior to study entry 
• Documented cardiomyopathy 
• 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 hypocalcemia, 
hypokalemia or hypomagnesemia, history of cardiac failure, or history of 
clinically significant/symptomatic bradycardia 
• Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by 
safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting 
study drug) 
• Inability to determine the QTcF interval 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade AV block (e.g., bifascicular block, 
Mobitz type II and third degree AV block) 
• Systolic blood pressure >160 or <90 mmHg 
9. Patients who have lung metastases with oxygen demand in resting status. 
10. Patients who have liver metastases with bilirubin >1.5 ULN. 
11. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria: 
• At least 4 weeks from prior therapy completion (including radiation and/or surgery) to 
starting the study treatment. 
• Clinically stable CNS tumor at the time of screening and not receiving steroids and/or 
enzyme inducing anti-epileptic medications for brain metastases. 
• Leptomeningeal metastases is not allowed, even with stable clinical condition.  
12. Patient has impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection), as decided 
by the investigator. 
13. Patient has a known history of human immunodeficiency virus (HIV) infection (testing 
not mandatory). 
14. Patient is concurrently using hormone replacement therapy. 
15. Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator's judgment, cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol: (e.g. 
chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, 
bacterial or viral infections, etc.). 
16. Patient is currently receiving any of the following substances and cannot be discontinued 
7 days prior to Cycle 1 Day 1: 


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• Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, 
pummelos, star fruit, Seville oranges) and their juices that are strong inducers or 
inhibitors of CYP3A4/5, 
• Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5. 
17. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects. 
18. 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: a short duration (< 5 days) of 
systemic corticosteroids; any duration of topical applications (e.g., for rash), inhaled sprays (e.g., 
for obstructive airways diseases), eye drops or local injections (e.g., intra-articular). 
19. Patient with a known hypersensitivity to any of the excipients of ribociclib, anastrozole, 
letrozole, goserelin, the chemotherapy drug that is going to be used, or to any of the other 
ingredients of the study medication (including peanut and soy). 
20. Not able to understand and to comply with study instructions and requirements. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
6 
Treatment 
6.1 
Study treatment 
For this study, the terms “investigational drug” refers to Novartis study drug ribociclib 
(LEE011). The other drugs to be used in this study are letrozole, anastrozole, goserelin, and 
combination chemotherapies. Goserelin could be substituted by leuprorelin (leuprolide) as 
requested by the principal investigator with informing the study team before randomization. 
The combination chemotherapies will be used in this study are either combination of docetaxel 
+ capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine. 
Novartis will supply ribociclib (LEE011) as 200 mg tablets as individual patient supply 
packaged in bottles. All other investigational drugs will be procured locally as they are 
commercially available drugs according to local practice and regulation and will be labeled as 
“clinical trial use only” and label will be approved by the local regulatory authorities, if required 
by country regulation. Storage conditions are described in the medication label. All treatment 
medications should be used in accordance with the locally approved label. Medication labels 
will comply with the legal requirements of the country and be printed in the local language. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record Case Report/Record Form (eCRF). 


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6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
dosage form and 
route of 
administration  
Frequency and/or 
Regimen 
Supply 
type 
Sponsor 
(global 
or local) 
Ribociclib arm (endocrine treatments) 
Ribociclib (LEE011) 
600 mg 
(200 mg × 3) 
Tablets for oral use 
Days 1-21 of each 28 day 
cycle  
Open 
label 
supply 
Sponsor 
(global) 
Letrozole 2.5 mg 
Tablets for oral use 
Daily (all days of every 
cycle without interruption). 
Sponsor 
(local) 
Anastrozole 1 mg 
Tablets for oral use 
Daily (all days of every 
cycle without interruption). 
Goserelin 3.6 mg 
Subcutaneous implant 
Day 1 of each 28 day cycle 
(regardless of ribociclib 
treatment cycle) with an 
administration window of ± 
3 days 
Control arm (combination chemotherapies) 
Docetaxel 
(60 
– 
75 mg/m²)/capecitab
ine 
(1600 
– 
2500 mg/m²/day)  
Docetaxel: 
IV Infusion 
Capecitabine: 
Tablets 
for oral use 
Docetaxel once, on day 1 of 
the 
3-weeks 
cycle, 
Capecitabine twice daily, on 
Days 1 to 14, followed by a 
1-week rest period, in 3 
weeks cycle. 
Open 
label 
supply  
Sponsor 
(local) 
Paclitaxel (175 mg/
m2)/ 
gemcitabine 
(1000 - 1250 mg/m2) 
 
OR 
 
Paclitaxel (80 
- 
90 mg/m2)/ 
gemcitabine 
(800 - 1250 mg/m2) 
IV infusion 
 
Paclitaxel 
via 
3-hour 
intravenous (IV) infusion on 
Day 1 in 3-weeks cycles. 
Gemcitabine 
at 
via 
30-minute IV infusion on 
Day 1 and Day 8 in 3-weeks 
cycles 
Paclitaxel via 1-hour 
intravenous (IV) infusion on 
Day 1 and Day 8 in 3-
weeks cycles.  
Gemcitabine at via 
30-minute IV infusion on 
Day 1 and Day 8 in 
3-weeks cycles 
Capecitabine (1600 
- 2500 mg/m2/day)/ 
vinorelbine (60 to 
80 mg/m2/day [oral] 
or  
(25 to 30 mg/m2 
[IV infusion]) 
Capecitabine: 
Tablets 
for oral use 
Vinorelbine: Capsule for 
Oral use/IV infusion  
Capecitabine twice daily on 
day 1 to 14, followed by a 
1-week rest period, in 
3-weeks cycle 
Vinorelbine, once, on Day 1 
and Day 8 in 3-weeks cycles  


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Ribociclib, letrozole, anastrozole and goserelin will be administered as a flat-fixed dose, and 
not by body weight or body surface area. Whereas, combination chemotherapies (docetaxel + 
capecitabine, paclitaxel + gemcitabine, capecitabine + vinorelbine) will be administered by 
body surface area. The dose of study medication will be adapted during the study in case the 
change (increase or decrease) in body surface area exceeds 10% of the body surface area 
compared to Visit 2 or the last dose adjustment due to a change in the patient’s body surface 
area. All study treatment drugs must be administered together at approximately the same time 
(or within few hours for chemotherapy) each day. All oral study treatment drugs can be 
administered with or without food. Except ribociclib, all study treatment drugs should be used 
in accordance with the locally approved label. Ribociclib will be used in accordance to protocol 
guidelines. The investigator or responsible site personnel should instruct the patient to take the 
study drugs as per protocol (promote compliance). Patients will be instructed to return unused 
study drugs to the site at the end of each cycle. The site personnel will ensure that the 
appropriate dose of each study drug is administered and that the drug accountability is 
performed. 
6.1.2 
Treatment arms/group  
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1: 
• Ribociclib arm: NSAI + goserelin + ribociclib. Other endocrine therapy should be 
stopped. Goserelin could be substituted by leuprorelin as requested by PI. 
• Combination chemotherapy arm: docetaxel + capecitabine, paclitaxel + gemcitabine or 
capecitabine + vinorelbine based chemotherapy treatment. The chemotherapy regimen 
will be decided by the treating physician. The patients who will be administered with 
chemotherapy, will be allowed to receive granulocyte-colony stimulating factor (GCSF) as 
per treating physician decision, but if patients receive endocrine therapy prior to 
randomization, endocrine therapy should be stopped. 
6.1.3 
Additional study treatments  
No other treatment beyond investigational drug and control drug are included in this trial, except 
bone targeted agents such as bisphosphonate, denosumab, or beta-blocker. 
6.1.4 
General dosing guidelines 
6.1.4.1 
Ribociclib treatment arm: 
The study treatments should be taken as follows: 
• Ribociclib is dosed orally for the first 21 days out of a 28 day cycle.  
• Letrozole, or anastrozole are dosed orally daily (28 days out of the 28 day cycle).  
• Goserelin is continuously released via a subcutaneous implant injected on Day 1 of each 
28 day cycle (regardless of ribociclib treatment cycle) with an administration window of 
± 3 days. 
For patients who is receiving LHRH agonist before randomization, goserelin is still need to be 
given on cycle 1 day 1. 
• Patients should be instructed to take the study drug combination of ribociclib with a 
large glass of water (~250 mL or ~8 oz) at the same time each day, patients can 


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determine if they prefer morning or early afternoon dosing, but should maintain a 
consistent time. Evening doses are strongly not recommended. In general, ribociclib 
letrozole or anastrozole tablets may be taken without regard to meals. Please see 
Section 6.1.5 below for additional guidelines for scheduled visit days. 
• Patients receiving ribociclib must avoid consumption of grapefruit, grapefruit hybrids, 
pomelos/pummelos, star-fruit, Seville oranges or products containing their juice during the 
entire study and preferably 7 days before the first dose of study medications and during 
the study, due to potential CYP3A4 interaction with the study medications. These foods 
are known as CYP3A4 inhibitors and have a potential to increase exposure to ribociclib. 
Orange juice is allowed. 
• Patients should be instructed to swallow the capsules and 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. 
• 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. 
• Goserelin implant should be administered as a subcutaneous injection in Day 1 of each 28 
day cycle (regardless of ribociclib treatment cycle) with an administration window of 
± 3 days using an aseptic technique under the supervision of a physician. Administration 
technique should be in accordance with the locally approved label (SmPC). 
• Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or 
those with a known risk of QT prolongation are not permitted. 
• Multivitamins are permitted. 
• All pre-medication given during the study must be recorded on the Concomitant 
Medication page of the eCRF. 
• Other concomitant medication given during the study must be recorded on the 
Concomitant Medication page of the eCRF. 
6.1.4.2 
Combination chemotherapies arm 
• Docetaxel + capecitabine combination: Docetaxel should be administered at the dose of 60 
to 75 mg/m² once on day 1 of the 3-week cycle whereas, the capecitabine should be 
administered at dose of 1600 to 2500 mg/m²/day twice daily on days 1 to 14. 
• Paclitaxel + gemcitabine combination: Paclitaxel should be administered either on Day 1 
(at dose of 175 mg/m2) via an approximately 3 hour infusion, or on Day 1 and 8 (at dose 
of 80 - 90 mg/m2) via an approximately 1 hour infusion in each cycle. Gemcitabine at dose 
of 1000 to 1250 mg/m2 or 800 to 1250 mg/m2 dose should be administered via 30 minute 
infusion on Day 1 and Day 8 in 3-week cycles. 
• Capecitabine + vinorelbine combination: Capecitabine should be administered at the dose 
of 1600 to 2500 mg/m2/day twice daily days 1 to 14 on a 3-weeks cycle and vinorelbine 
(either 60 to 80 mg/m2/day [for oral capsule] or 25 to 30 mg/m2 [for IV infusion]), once 
daily, on Day 1 and Day 8 (Note: switch between Vinorelbine oral capsule and 
Vinorelbine IV infusion is allowed). 


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• The capecitabine dose (capsule for oral use) must be taken with food or within 30 minutes 
after a breakfast/meal with approximately 200 ml of water. The vinorelbine tablets could 
be administered with some food, or after the meal. 
• For patients with bilirubin >1 × ULN, the initial dose of docetaxel should be administered 
at the dose of 30 to 37 mg/m² once on day 1 of the 3 week cycle. For patients with 
bilirubin level >1.25 × ULN, the initial dose of paclitaxel, could be administered at the 
dose of 135 mg/m² once on day 1 of the 3 week cycle, or 65 mg/m² on Day 1 and 8 of the 
3 week cycle. No need to modify the initial dose of gemcitabine, capecitabine, and 
vinorelbine based on base line bilirubin level. 
• The patients who will be administered with combination chemotherapies, will be allowed 
to receive GCSF as per treating physician decision. 
• Patients who will be administered with oral chemotherapies should be specially instructed 
to swallow the capsules and 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. 
• 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. 
• No herbal medications-are permitted. 
• Multivitamins are permitted. 
• All pre-medication given during the study must be recorded on the Concomitant 
Medication page of the eCRF. 
• Other concomitant medication given during the study must be recorded on the 
Concomitant Medication page of the eCRF. 
Paclitaxel pre-medication 
Standard pre-medication should be administered according to local practice. The following 
treatment is recommended (Seidman et al 2008): 
• Dexamethasone 10-20 mg or equivalent, one dose before paclitaxel 
• Diphenhydramine 50 mg (αH1 receptor), one dose before paclitaxel 
Either ranitidine 50 mg or cimetidine 300 mg (H2 receptor), one dose before paclitaxel. 
Standard premedication treatment should be given 30 to 60 minutes before the paclitaxel 
infusion or according to local standard of care. 
Docetaxel pre-medication 
Standard pre-medication should be administered according to local practice. The following 
treatment is recommended (Taxotere® Prescribing Information): 
• Dexamethasone 16 mg per day (e.g., 8 mg twice daily, or other steroid with equivalent 
potency) for 3 days starting 1 day prior to docetaxel administration. 


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6.1.5 
Additional dosing guidelines for scheduled visit days 
On days with fasting, (overnight fasting defined as at least 8-12 hours) biochemistry and/or lipid 
profile samples as outlined in Table 8-1, the following additional guidelines should be followed: 
• The patient must be fasting overnight for all cycle visits for at least 8-12 hours prior to the 
blood collection for chemistry parameters, and fasting glucose samples. Water is allowed 
during all fasting periods; however coffee, tea and juice are not permitted during the 
fasting period. After the fasting blood sample is obtained in the clinic, the patient may 
consume breakfast, if desired. 
• If a pre-dose ECG measurement should be collected, then the ECG measurement should 
occur before dosing of the study treatment and the information will be recorded in the 
eCRF. 
6.1.6 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.5. 
During the study, patients in the combination chemotherapy arm should continue to receive 
chemotherapy until disease progression (radiologically documented according to RECIST 1.1 
criteria) or unacceptable toxicity. When one of the combination chemotherapy drugs has to be 
stopped because of toxicity, the patient may be continued on the other better tolerated 
chemotherapy drug (monotherapy) (the patients can’t switch to another combination 
chemotherapies). After switching to monotherapy, the patient will be continued with 
monotherapy for 2 cycles and if the patients does not recover from the toxicity symptom of 
previous combination chemotherapy, the patient will be continuing with the monotherapy. 
Patients for whom even the monotherapy has to be stopped because of toxicity are allowed to 
switch to endocrine therapy, and will be defined as an event for secondary endpoint, time to 
treatment failure. However, they should not receive the CDK4/6 inhibitor, or switch to a 
different chemotherapy agent. If patient received CDK4/6 inhibitor, or switch to a different 
chemotherapy agent without evidence of disease progression, their data will be censored for the 
primary endpoint, and will be defined as an event for secondary endpoint: time to treatment 
failure.  
Patients in the ribociclib arm will be censored for the primary endpoint, and will be defined as 
event for secondary endpoint of time to treatment failure if they switch to a different endocrine 
therapy, or to chemotherapy, unless they have an event (e.g., disease progression). Switching 
between letrozole or anastrozole (both NSAI) is allowed in case of toxicity related to AI such 
as arthralgia. Switch goserelin to leuproreline or other LHRH agonists will be allowed after 
discussion with and approved by study team. Leuprorelin or other LHRH agonists dosing will 
be as per the local approved label. 
6.1.7 
Treatment duration 
Patients will receive trial treatment until the following (whichever occurs first), disease 
progression (radiologically documented according to RECIST 1.1 criteria), unacceptable 
toxicity, death, or discontinuation from the study treatment for any other reason, including 
consent withdrawal, patient is lost to follow-up, or the sponsor terminates the study. Patients 
will be followed for survival, at every 16 (± 4) weeks, regardless of treatment discontinuation 
for any reason (except if consent is withdrawn, patient is lost to follow-up or until death) and 


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regardless of achieving the primary endpoint, after at least 46 months from first patient first 
visit (FPFV), or when 80% of OS events have been reached (whichever occurs first). For 
patients who in the opinion of the investigator are still deriving clinical benefit from study 
treatment, every effort will be made to continue provision of study treatment. For additional 
detail, please refer to Section 3.1.7. 
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
Megestrol acetate and medroxyprogesterone treatment for any reason are not allowed in both 
arm.  
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. 
Please consult the list of prohibited medications (Table 16-1) and the list of use with caution 
medications for further guidance (Table 16-2). The patient must be told to notify the 
investigational site about any new medications she takes after the start of the study treatment. 
All medications (other than study drugs), and significant non-drug therapies (including 
vitamins, herbal medicines, physical therapy and blood transfusions) administered within 30 
days of study entry and during the study must be 
listed on the Concomitant 
medications/Significant non-drug therapies eCRF. If patients take concomitant medications 
chronically, any change in dose schedule of concomitant medication throughout the study 
period should be clearly documented. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the patient is already 
enrolled, contact Novartis to determine if the patient should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action  
For the ribociclib treatment arm: 
The list of prohibited medications and the list of medications that are to be used with caution 
during combined ribociclib, NSAI, and goserelin treatment are provided, respectively, in Table 
16-1 and Table 16-2 in Appendix 1. 
This list is not comprehensive and is only meant to be used as a guide. Please contact the medical 
monitor with any questions. These medications should be excluded if possible. If they must be 
given based on the investigator’s judgment, then use with caution and consider a ribociclib 
interruption if the concomitant medication is only needed for a short time: 
• Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib 
exposure, respectively). 
• Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib 
may increase exposure to these medications). 
• Strong inhibitors of BSEP (based on in vitro data co-administration with ribociclib may 
lead to intrahepatic cholestasis). 


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• Sensitive substrates of the renal transporters, MATE1 and OCT2 (ribociclib has the 
potential to increase exposure to substrates of these transporters, although no animal or 
clinical data are available to support these statements). 
• Sensitive substrates of transporter BCRP (ribociclib has the potential to increase exposure 
to substrates of these transporters, although no animal or clinical data are available to 
support these statements). 
• Medications that carry a possible risk for QT prolongation (may precipitate QT 
prolongation and TdP). 
• Substrates metabolized predominantly by CYP2C19 or CYP2A6 with a narrow 
therapeutic index (that could be affected by letrozole). 
For the combination chemotherapy arm: 
Patients receiving capecitabine 
• Oral coumarin-derivate anticoagulants such as warfarin and phenprocoumon should be 
avoided in patients receiving capecitabine as study treatment. If patient needs to take 
coumarin-derivate anticoagulants anticoagulant response (INR or prothrombin time) 
should be monitored frequently in order to adjust the anticoagulant dose based on 
capecitabine prescribing information. Altered coagulation parameters and / or bleeding, 
including deaths have been reported during concomitant use. 
• Aluminium hydroxide- and magnesium hydroxide-containing antacid (such as Maalox) 
should not be administrated immediately after capecitabine because of their effect on the 
pharmacokinetics of capecitabine. 
• The level of phenytoin should be carefully monitored in patients receiving capecitabine 
and phenytoin dose may need to be reduced. 
• Care should be also exercised when capecitabine is co-administered with CYP2C9 
substrates. 
Patients receiving gemcitabine 
No specific drug interaction studies have been conducted for gemcitabine. Thus, no 
recommendations or prohibited concomitant medications are provided in the gemcitabine 
prescribing information. 
Patients receiving docetaxel 
In vitro studies have shown that the metabolism of docetaxel may be modified by the, 
concomitant administration of compounds that induce, inhibit, or are metabolized by 
cytochrome P450 3A4, such as ketoconazole. Caution should be exercised with these drugs 
when treating patients receiving docetaxel as there is a potential for a significant interaction.  
Patients receiving paclitaxel 
• Care should be exercised when paclitaxel is concomitantly administered with known 
substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. 


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• Care should also be exercised when paclitaxel is concomitantly administered with known 
substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers 
(e.g., rifampin) of CYP2C8. 
Patients receiving vinorelbine 
• Administration of vinorelbine to patients with prior or concomitant radiation therapy may 
result in radiosensitizing effects. 
• Caution should be exercised in patients concurrently taking drugs known to inhibit drug 
metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. 
6.2.1.2 
Use of bone targeted agents 
Bisphosphonates and denosumab are generally allowed with the following comments: 
• Adjuvant bisphosphonate/denosumab therapy is allowed as per local and ASCO 
guidelines. 
• Chronic concomitant bisphosphonate/denosumab therapy for the prevention of bone 
metastasis is not permitted. 
• Bisphosphonate/denosumab therapy for the treatment of osteoporosis is permitted. 
• Bisphosphonate/denosumab therapy for the prevention of skeletal related events for 
patients with bone metastases is permitted. 
• If bisphosphonate/denosumab therapy is to be started after the first dose of study drug, 
prior consultation and approval by Novartis is required and the reason for its use must be 
clearly documented. 
Patients taking concomitant medication chronically could be maintained at the same dose, or 
could be decrease in dose or prolong in dose schedule, and dose schedule throughout the study 
period, as medically feasible. Increase the dose or shortening the dose schedule is not allowed, 
unless approved by Novartis after consultation, with the reason documented. 
6.2.1.3 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially reducing ribociclib drug exposure to sub-
therapeutic levels. Systemic corticosteroid treatment should not be given in ribociclib arm 
during the study, except for: 
• Topical applications (e.g., rash), inhaled sprays (e.g., for obstructive airways diseases), 
eye drops or local injections (e.g., intra-articular). 
• A short duration (<5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency 
of 4 mg dexamethasone (e.g. for chronic obstructive pulmonary disease, or as an 
antiemetic). 
6.2.1.4 
Hematopoietic growth factors 
The patients who are enrolled in combination chemotherapy arm will be allowed to receive 
GCSF as per treating physician decision. Prophylactic use of GCSF with ribociclib is not 
recommended. 


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6.2.1.5 
Palliative radiotherapy 
Palliative radiation is permitted. It should not be delivered to a target lesion. Cumulative courses 
of RT should not encompass ≥ 25% of the irradiated bone marrow (See Appendix 4). If 
palliative radiotherapy is initiated after start of study treatment, the reason for its use must be 
clearly documented and progression as per RECIST 1.1 must be ruled out. 
No dose modification of study treatment is mandated during palliative radiotherapy. 
6.2.1.6 
Use of antiemetic medications 
Ribociclib has low to minimal emetogenic potential according to a definition of antineoplastic 
agent emetogenicity (Grunberg et al 2011). Antiemetic therapy can be used according to 
clinical guidelines for antineoplastic medications with low to minimal emetogenic potential 
for treatment and/or prevention of nausea and vomiting as a result of study treatment (NCCN 
Clinical Practice Guidelines in Oncology, Antiemesis 2016; Roila et al 2016). 
Potential drug interaction between ribociclib and antiemetic medications should always be 
taken into consideration. Example of a  prohibited antiemetic medication is ondansetron 
that in combination with ribociclib may precipitate 
TdP. Refer to Section 6.2.1 and 
Section 6.2.2 for a list of medications that are allowed or prohibited to be used with ribociclib. 
Antiemetic therapy can be used according to clinical guidelines for patient receiving 
chemotherapy. 
6.2.1.7 
Use of beta-blocker 
During the screening, if the patients’ heat rate is above 100/min, beta-blocker will be allowed. 
Thereafter, if the patients’ heart rate is under control, ECG shows no QTcF prolongation and 
the patient is clinically and hemodynamically stable, they will be allowed to participate in the 
study. 
6.2.2 
Prohibited medication 
The following medications are prohibited during combined ribociclib, NSAI, and goserelin 
treatment in this study (Table 16-1 in Appendix 1, this list is not comprehensive and is only 
meant to be used as a guide. Please contact the medical monitor with any questions). 
• Strong inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease 
ribociclib exposure, respectively). 
• Substrates of CYP3A4/5 with a narrow therapeutic index (ribociclib may increase 
exposure to these medications resulting in toxicity to these medications). 
• Medications with a known risk for QT prolongation and/or TdP (may precipitate QT 
prolongation and TdP in combination with ribociclib). 
• Other investigational and antineoplastic therapies. 
• Herbal preparations/medications and dietary supplements that are strong inhibitors or 
inducers of CYP3A4/5 or those with a known risk of QT prolongation. These include but 
are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 


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Patients should stop using these preparation/medications at least 7 days prior to first dose 
of study treatment. 
6.2.3 
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 (please refer to 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. 
6.2.4 
Concomitant medications associated with menopausal status 
It is important to consider potential drug-drug interactions when using concomitant medications 
associated with hot flushes and other anticipated symptoms associated with this indication/use 
of endocrine therapy. Please refer to Table 16-1 in Appendix 1 for further information on 
prohibited concomitant medications. 
6.2.5 
Rescue medication  
Granulocyte-colony stimulating factor treatment is allowed for patient with neutropenia 
induced by chemotherapy, or neutropenic fever induced by study drugs in both arms. GCSF 
treatment is not recommended for patient with neutropenia without infection in patients receive 
ribociclib treatment. Appropriate treatment for study drug related AEs such as antibiotics for 
infection should be initiated according to the local guideline and treating physician’s decision. 
When the prohibited medication is definitely needed to be used as a rescue medication for 
specific clinical situation, the relevant study drug such as ribociclib should be temporarily stop. 
6.3 
Subject numbering, treatment assignment, randomization  
6.3.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient 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 Patient 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 patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient number 
available. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 


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not be reused for any other patient and the Patient number for that individual must not be 
changed. If the patient fails to be randomized or start treatment for any reason, the reason will 
be entered into the Screening Disposition page. IRT must be notified within 2 days that the 
patient was not randomized. 
6.3.2 
Treatment assignment, randomization 
Patients will be randomized to one of the two treatment arms in a ratio of 1:1. 
Randomization will be stratified by the following factors:  
1. the presence of liver metastases (present or absent) 
2. disease free interval (defined as duration between the date of patient received complete 
tumor resection for primary breast cancer lesion to the date of disease recurrence 
documented) < 2 years (yes or no, de novo stage 4 disease is defined as DFI >2 years) 
At Baseline (Cycle 1, Day 1) all eligible patients will be randomized via IRT to one of the 
treatment arms. The investigator or his/her delegate will contact the IRT after confirming that 
the patient fulfills all the inclusion/exclusion criteria.  
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. IRT assigns 
medication kit numbers (only for ribociclib) in every dispensing visit. The randomization 
scheme for patients will be reviewed and approved by a member of the Randomization Office. 
6.4 
Treatment blinding  
Treatment will be open to patients, investigator staff, persons performing the assessments, and 
the Novartis clinical trial team. 
6.5 
Dose escalation and dose modification 
Dose escalation is not applicable in this study, unless it is due to the improvement of 
hyperbilirubinemia. 
6.5.1 
Dose modifications - Ribociclib treatment arm 
Investigators are permitted to interrupt and/or reduce the ribociclib dose in order to allow 
patients to continue treatment. Dose modifications should be considered for patients who do not 
tolerate the protocol-specified dosing schedule for ribociclib or where clinical judgment of the 
treating physician determines that ribociclib dose interruptions and/or reductions are 
recommended based on the individual benefit/risk assessment. Dose reductions are not planned 
for goserelin, or NSAIs. Any changes to the dose or interruption of dosing must be recorded on 
the Dosage Administration Record eCRF. All patients will be followed for adverse events and 
for serious adverse events for 30 days following the last dose of study drug. 
6.5.1.1 
Ribociclib 
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of ribociclib therapy. Refer to Table 6-2 for guidance. No 
dose re-escalation is permitted. 


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Table 6-2 
Dose modification guideline-Ribociclib 
 
Dose 
Number of Tablets & strength 
Starting dose 
600 mg 
3 × 200 mg Tablets 
First dose reduction 
400 mg 
2 × 200 mg Tablets 
Second dose reduction 
200 mg 
1 × 200 mg Tablets 
Recommendations for dose reduction, interruption or discontinuation of ribociclib in the 
management of adverse reactions are summarized in Table 6-3, Table 6-4, Table 6-5, and 
Table 6-6. 
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 9.2, treatment must be 
discontinued. If dosing was interrupted for >28 days due to ribociclib-related toxicity, ribociclib 
must be discontinued. 
If a patient inadvertently doses on a rest day (e.g., days 22 to 28 of any given cycle), ribociclib 
will be interrupted to ensure 7 consecutive rest days and avoid overdose. The visit schedule will 
be adjusted accordingly. 
6.5.1.1.1 Recommendations on adjustment of ribociclib treatment cycles in the case 
of dose interruptions/re-initiation 
Delayed start of a cycle: 
In the case of ribociclib being withheld at Cycle (x) D1 based on investigator’s judgement, the 
patient should reinitiate ribociclib on a 3 week ON/ 1 week OFF schedule once the 
assessment(s) are within acceptable levels according to Section 6.5.1. The visit schedule should 
be adjusted based on the ribociclib treatment schedule. 
Mid-cycle dose interruption: 
In the case of ribociclib being withheld for <7 days during any cycle, patient should reinitiate 
ribociclib to complete the 21 calendar day treatment (3 weeks ON) followed by 1 week OFF 
schedule. 
In the case of ribociclib being withheld for ≥ 7 days during any cycle, patient should reinitiate 
ribociclib to a new 28 calendar day treatment schedule (3 weeks ON/ 1 week OFF) once the 
assessment(s) are within acceptable levels according to Section 6.5.1. The visit schedule should 
be adjusted based on the ribociclib treatment schedule.  


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Table 6-3 
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions 
Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Thrombocytopenia 
Grade 1(≥ 75 × 109/L) 
No dose adjustment required. 
Grade 2 (≥ 50 × 109/L – <75 × 109/L) 
Dose interruption until recovery to grade ≤1. 
Re-initiate ribociclib at the same dose. 
Grade 3 (≥ 25 × 109/L - <50 × 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 × 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 × 109/L) 
No dose adjustment required. 
Grade 2 (≥1.0 - <1.5 × 109/L) 
No dose adjustment required. 
Grade 3 (≥0.5 - <1.0 × 109/L) 
• Dose interruption until recovery to ≥1.0 × 109/L. Re-
initiate ribociclib at the same dose level. 
• If toxicity recurs at grade 3: temporary dose interruption 
until recovery to ≥ 1.0 × 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 × 109/L) 
Dose interruption until recovery to ≥ 1.0 × 109/L. 
Re-initiate ribociclib at the next lower dose level. 
Febrile neutropenia 
Grade 3 
ANC <1.0 × 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 × 109/L 
and no fever. Restart at the next lower dose level. 
If febrile neutropenia recurs, discontinue ribociclib. 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue ribociclib. 
Anemia 
(Hemoglobin) 
Grade 1 (≥ 10.0 – LLN g/dL) 
No dose adjustment required. 
Grade 2 (≥ 8.0 – <10.0 g/dL) 
No dose adjustment required. 
Grade 3 (<8.0 g/dL) 
Dose interruption until recovery to grade ≤ 2. 
Re-initiate ribociclib at the same dose. 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue ribociclib. 
 


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Table 6-4 
Ribociclib dose adjustment and management recommendations for 
hepatic toxicities (CTCAE v4.03) 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1 (>ULN – 1.5 × ULN) 
(confirmed 48-72h later) 
Maintain dose level with LFTs monitored every two weeks 
Grade 2 (>1.5 – 3.0 × 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 × 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 × 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 gallbladder or bile duct disease, hyperbilirubinemia 
due to the indirect component only (i.e. direct bilirubin component ≤ 1 × ULN) due to hemolysis or Gilbert 
Syndrome, other pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other 
hepatotoxic drugs. 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only. Bilirubin 
will be fractionated if elevated. 


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HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
AST or ALT 
AST or ALT without bilirubin elevation > 2 x ULN 
Same grade as baseline or increase from 
baseline grade 0 to grade 1 (confirmed 
48 – 72 h later) 
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or every two weeks in 
case of increase from baseline grade 0 to 1 
Increase from baseline grade 0 or 1 to grade 
2 (>3.0 – 5.0 × ULN) 
• Dose interruption of ribociclib 
• If resolved to ≤ baseline grade in ≤ 21 days, then 
maintain dose level 
• If resolved to ≤ baseline grade in >21 days or toxicity 
recurs, then reduce 1 dose level 
• Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
• If toxicity recurs after two dose reductions or recovery to 
≤ baseline grade is >28 days, discontinue ribociclib 
Increase from baseline grade 0 or 1 to grade 3 
(> 5.0 – 20.0 × ULN) 
• Dose interruption of ribociclib until resolved to ≤ 
baseline grade, then lower 1 dose level of ribociclib 
• Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
• If recovery to ≤ baseline grade is > 28 days, discontinue 
ribociclib 
• If toxicity recurs, discontinue ribociclib 
Increase from baseline grade 2 to grade 3 (> 
5.0 – 20.0 × ULN) 
• Dose interruption of ribociclib until resolved to ≤ 
baseline grade, then lower 1 dose level of ribociclib 
• Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
• If toxicity recurs after two dose reductions or recovery to 
≤ baseline grade is > 28 days, discontinue ribociclib. 
Grade 4 (>20.0 × 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 × ULN combined with total 
bilirubin >2 × ULN without evidence of 
cholestasis 
Or 
For patient with elevated AST or ALT or total 
bilirubin at baseline: [AST or ALT >2 × 
baseline AND >3.0 × ULN] OR [AST or ALT 
8.0 x ULN] whichever is lower- combined 
with [total bilirubin > 2 × baseline AND >2.0 
× ULN] 
• Discontinue ribociclib 
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose 
interruption/reduction. They include but are not limited to: concomitant medications, herbal preparations or 
dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive liver metastasis, and 
alcohol intake. 
6.5.1.1.2 Additional follow-up for hepatic toxicities 
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered as clinically important events.  
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 


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• For patients with normal ALT and AST and TBIL value at baseline: AST or 
ALT >3.0 × ULN combined with TBIL >2.0 × ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or 
ALT >2 × baseline AND >3.0 × ULN] OR [AST or ALT >8.0 × ULN], whichever is lower, 
combined with [TBIL >2 × baseline AND >2.0 × ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation >2.0 × ULN with R value <2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the 
ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and <5) liver injury. In the absence 
of cholestasis, these patients must be immediately discontinued from study drug treatment, 
and repeat Liver Function Tests as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 
2 or higher), creatine kinase, prothrombin time (PT) or INR and GGT. For patients with Gilbert 
Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to 
changes in direct bilirubin only. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values. 
• Obtaining a more detailed history of current symptoms. 
• Obtaining a more detailed history of prior and/or concurrent diseases, including history of 
any pre-existing liver conditions or risk factors. 
• Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., 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 a liver biopsy, as clinically indicated to assess pathological change and 
degree of potential liver injury. 


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All cases of DILI confirmed on repeat testing meeting the laboratory criteria defined above, 
with no other alternative cause for LFT abnormalities identified, should be considered as 
“medically significant”, thus meeting the definition of SAE (Section 10.1.3), 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. 


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6.5.1.1.3 Additional follow-up for QTc prolongation 
Table 6-5 
Ribociclib dose adjustment and management recommendations for 
QTcF prolongation (CTCAE v4.03) 
Grade 
Dose Modification 
For All Grades 
1. 
Check the quality of the ECG and the QT value and repeat if needed. 
2. 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If 
outside of the normal range, interrupt ribociclib administration, correct 
with supplements or appropriate therapy as soon as possible, and 
repeat electrolytes until documented as normal. 
3. 
Review concomitant medication usage for the potential to inhibit 
CYP3A4 and/or to prolong the QT interval. 
4. 
Check compliance with correct dose and administration of ribociclib. 
1 
QTcF 450-480 ms 
Perform steps 1-4 as directed in “For All Grades”. No dose adjustment 
required. 
2 
QTcF 481-500 ms 
1. 
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
2. 
Perform a repeat ECG within one hour of the first QTcF of ≥ 481 ms. 
Repeat ECG as clinically indicated until the QTcF returns to < 481ms, 
restart LEE011 with dose reduced by 1 dose level. Refer to table 6.2 
for dosing schedule. 
3. 
If QTcF ≥ 481 ms recurs, ribociclib should be reduced by 1 dose level. 
Refer to Table 6-2 for dosing schedule. 
4. 
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due to 
QTcF ≥ 481 ms 
3 
QTcF ≥ 501 ms on at least two 
separate ECGs 
1. 
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.”  
2. 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
3. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified 
specialist) and repeat cardiac monitoring as indicated until the QTcF 
returns to < 481 ms. 
4. 
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level. 
Refer to Table 6-2 for dosing schedule. 
5. 
If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in 
“For All Grades,” discontinue ribociclib. 
6. 
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due 
to QTcF ≥ 501 ms 
7. 
If QTcF of ≥ 501 ms recurs, discontinue ribociclib. 
4 
[QT/QTcF ≥ 501 or > 60 
ms change from 
baseline] and 
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia] 
1. 
Discontinue ribociclib. Perform steps 1-4 as directed in “For All 
Grades.” 
2. 
Obtain local cardiologist (or qualified specialist) consultation and 
repeat cardiac monitoring as indicated until the QTcF returns to <481 
ms. 
6.5.1.1.4 Additional follow-up for interstitial lung disease/pneumonitis 
To minimize the risk of ILD/pneumonitis, monitor patients for pulmonary symptoms indicative 
of ILD/pneumonitis, which may include hypoxia, cough, and dyspnea. In patients who develop 
Grade 1 ILD/Pneumonitis, no dose adjustment is required. Initiate appropriate medical therapy 
and monitor as clinically indicated. In patients who developed ILD/Pneumonitis Grade 2,  dose 
should be interrupted until recovery to Grade ≤ 1, and then ribociclib can be resumed at the next 


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lower dose level. For Grade 3 or 4 permanently discontinue ribociclib. An individualized 
benefit-risk assessment should be performed before resuming ribociclib. 
6.5.1.1.5 Guidance for all other adverse reactions 
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium 
for all adverse reactions, if indicated. If electrolyte values are outside of the normal range, 
interrupt ribociclib administration, correct electrolytes with supplements or appropriate 
therapy as soon as possible, and repeat electrolyte testing until documented normalization of 
the electrolytes. For all other adverse events, including Toxic Epidermal Necrolysis (TEN), 
which is a grade 4 event by CTCAE, please follow recommendations in Table 6-6. 
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. 
6.5.1.2 
Non-steroidal aromatase inhibitors 
The established clinical dose of letrozole (2.5 mg/day) and anastrozole (1 mg/day) will be used 
and no dose modification of letrozole or anastrozole is planned in this study. For information 
on NSAIs (letrozole or anastrozole) and management of related adverse events refer to the 
Femara® Prescribing Information or Arimidex® Prescribing Information. 
6.5.1.3 
Goserelin 
The established clinical dose of goserelin (3.6 mg subcutaneous injection on Day 1 of each 28 
day cycle with an administration window of ± 3 days) will be used and no dose modification of 
goserelin is planned in this study. For information on goserelin and management of goserelin 
related adverse events refer to the Zoladex® Prescribing Information. 
6.5.2 
Adjustment of starting dose in special populations - Renal impairment 
for Ribociclib treatment arm 
Insufficient data are available to provide a dosage recommendation for ribociclib in patients 
with renal impairment. A study in non-cancer patients with varying degrees of renal impairment 
and matched patients with normal renal function is ongoing (CLEE011A2116). Refer to 
[Ribociclib Investigators Brochure] for more details. Based on rat ADME data, ribociclib was 
predominantly excreted in the in the bile as metabolites, with limited excretion of unchanged 
drug in urine. 


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Studies with goserelin in female patients with renal impairment do not indicate a need for dose 
adjustment with the use of the depot formulation (Zoladex® Prescribing Information). 
Renal impairment does not affect letrozole or anastrozole PK in humans (Femara® Prescribing 
Information, Arimidex® Prescribing Information). 
Patients with baseline renal impairment or with AST/ALT or bilirubin values beyond certain 
thresholds as specified in the eligibility criteria are excluded from the study. Patients who 
experience renal impairment (not due to other contributing factors) of grade 2 or higher during 
the treatment period should discontinue treatment and should be followed for safety 
assessments. 
6.5.3 
Dose modifications – combination chemotherapies arm 
Any changes to the dose or interruption of dosing must be recorded on the Dosage 
Administration Record eCRF. All patients will be followed for adverse events and for serious 
adverse events for 30 days following the last dose of study drug. Deviation of the dose 
modification/discontinuation from the protocol recommendation is allowed only if the benefit 
of deviation outweighs the risk as judged by PI, and appropriate prophylaxis management is 
incorporated into next cycle of treatment. Documentation of the judgment is needed before 
starting the treatment deviated from the protocol recommendation. 
6.5.3.1 
Paclitaxel 
Guidelines for dose modification and dose interruption of paclitaxel are described in Table 6-7 
below. 


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Table 6-7 
Dose modifications for suspected toxicities related to paclitaxel 
Toxicity 
Grade 
Actions 
Non-hematological 
1 or 2 
- Continue paclitaxel therapy 
 
3 or 4 
(excluding 
alopecia 
and fatigue) 
- Delay paclitaxel until toxicity improves to grade ≤ 1 
- Restart paclitaxel at 20% reduced dose  
- If toxicity requires more than 3 weeks from last planned 
administration to improve to grade ≤ 1, discontinue paclitaxel 
Hematological 
1 or 2 
- Continue paclitaxel therapy 
Hematological 
- ANC ≤ 1.0 × 109/L 
(1,000/mm3) 
- Platelets 
≤ 50 × 109/L 
(75,000/mm3) 
- Hemoglobin ≤ 8.0 
g/Dl despite 
transfusion 
3 or 4 
- Delay paclitaxel treatment until neutrophils ≥ 1.5 ×109/L 
(1,500/mm3), platelets ≥ 100 ×109/L (100,000/mm3) and Hgb ≥ 9 g/dL 
- If recovery occurs ≤ 7 days restart at same dose and schedule 
- If recovery requires >7 days reduce paclitaxel dose by 20%  
- If toxicity requires more than 3 weeks from last planned 
administration to improve to grade ≤ 1, discontinue paclitaxel  
Bilirubin, cre, AST, 
and ALT 
1 or 2 (see 
below for 
bilirubin and 
renal function) 
- Continue paclitaxel therapy  
 
3 or 4 
(or for bilirubin 
or creatinine 
≥ 2 × ULN; or 
calculated Cr 
clearance ≤ 40 
Ml/min) 
- Delay paclitaxel treatment until toxicity improves to grade ≤ 1 
- Restart paclitaxel at same dose 
- If toxicity recurs reduce paclitaxel dose by 20%  
- If toxicity requires more than 3 weeks from last planned 
administration to improve to grade ≤ 1, discontinue paclitaxel 
treatment  
6.5.3.2 
Docetaxel 
Guidelines for dose modification and dose interruption of docetaxel are described in Table 6-8 
below. 
Any dose reduction or dose delay of chemotherapy is based upon the severity of a toxicity, as 
graded by NCI Clinical Toxicity Criteria (NCI-CTCAE, version 4.03). Once a dose has been 
reduced during a treatment cycle, re-escalation will not be permitted during any subsequent 
cycles. Re-challenging the patient with docetaxel chemotherapy subsequent to study drug 
maintenance treatment initiation with study drug will not be allowed.  
Blood tests may be performed weekly, as per the local practice and standard of care, to assess 
in the first cycle of chemotherapy if study treatment can begin. Please refer to Table 6-8 for 
recommended docetaxel dose adjustments. Hematological testing may be performed on Day 10 
(± 3 days) of each cycle to establish the nadir values and to avoid the re-occurrence of any grade 
3-4 neutropenia or febrile neutropenia. Dose delays or reductions to docetaxel will be 
implemented based on these values AND/OR the Day 1 values at the start of each cycle 
(Table 6-8). 


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Table 6-8 
Criteria for cycle delay and/or dose reductions of docetaxel 
RECOMMENDED DOCETAXEL DOSE MODIFICATIONS1 
Worst Toxicity 
CTCAE Grade* (Value) 
DOCETAXEL 
 
HEMATOLOGIC 
Neutropenia (ANC) – Grade 4 (ANC <0.5 
× 109/L) for more than one week 
Delay treatment until resolution or toxicity returns to Grade 1, then 
administer reduced dose by 20% for 1st occurrence, discontinue 
docetaxel2 at 2nd occurrence 
Febrile neutropenia – (ANC < 1.0 × 109/L 
and fever ≥ 38.5°C) for more than one 
week 
Delay treatment until resolution, then administer reduced dose by 
20% for 1st occurrence, discontinue docetaxel2 at 2nd occurrence 
 
Platelets – Grade 4 (<25.0 × 109/L) 
Delay treatment until resolution, then administer reduced dose by 
20% for 1st occurrence, discontinue docetaxel2 at 2nd occurrence 
METABOLIC/LABORATORY 
Alkaline phosphatase – Grade 3 (> 5.0 -
20.0 × ULN) 
Delay treatment until resolution, then reduced dose by 20% for 1st 
occurrence, discontinue docetaxel2 at 2nd occurrence 
Alkaline phosphatase – Grade 4 (>20.0 × 
ULN) 
All sites: Permanently discontinue docetaxel2 
ALT/SGPT – Grade 3 (>5.0 – 20.0 × ULN) Delay treatment until resolution, then administer reduced dose by 
20% for 1st occurrence, discontinue docetaxel2 at 2nd occurrence 
ALT/SGPT – Grade 4 (>20.0 × ULN) 
All sites: Permanently discontinue docetaxel2 
AST/SGOT – Grade 3 (> 5.0 - 20.0 × 
ULN) 
Delay treatment until resolution, then administer reduced dose by 
20% for 1st occurrence, discontinue docetaxel2 at 2nd occurrence 
AST/SGOT – Grade 4 (> 20.0 × ULN) 
All sites: Permanently discontinue docetaxel2 
Bilirubin – Grade 3 (>3.0 – 10.0 × ULN) 
Delay treatment until resolution, then administer reduced dose by 
20% for 1st occurrence, discontinue docetaxel2 at 2nd occurrence 
Bilirubin – Grade 4 ( >10.0 × ULN) 
All sites: Permanently discontinue docetaxel2 
Skin 
Severe or cumulative cutaneous 
reactions  
Delay treatment until resolution or toxicity returns to Grade 1, then 
administer reduced dose by 20% for 1st occurrence, discontinue 
docetaxel2 at 2nd occurrence 
Peripheral Nervous System 
Peripheral neuropathy Grade 3 or 4 
All sites: Permanently discontinue docetaxel2 
ALL OTHER non-hematologic ADVERSE EVENTS 
Grade 3 or 4  
 
Delay treatment until resolution or toxicity returns to Grade 1, then 
administer reduced dose by 20% for 1st occurrence, discontinue 
docetaxel2 at 2nd occurrence 
1 Docetaxel dose reduction from 75 mg/m2 to 60 mg/m2 is based on the following published studies Chen et al. 
2006 and Shim et al 2005. 
2 If study treatment is stopped due to toxicity attributed specifically to docetaxel, the patient may continue to 
receive study drug as maintenance treatment until documented disease progression, unacceptable toxicity 
occurs or consent is withdrawn. Maintenance treatment with study drug can commence once docetaxel related 
toxicities have resolved at the next scheduled cycle visit. Docetaxel chemotherapy will not be administered 
during maintenance treatment in this study. Re-challenging the patient with docetaxel chemotherapy 
subsequent to study drug maintenance treatment initiation will not be allowed. 
*Common Toxicity Criteria for Adverse Events (NCI-CTCAE Version 4.03). 
Hepatic Impairment 


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Patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN 
should not receive docetaxel. 
6.5.3.3 
Gemcitabine 
For gemcitabine dose modifications/reductions, dosage adjustment will be based on the degree 
of hematological toxicity experienced by the patient (Table 6-9). Patients receiving gemcitabine 
should be monitored, as per the local practice and standard of care, prior to each dose with a 
complete blood count, including differential and platelet count. If marrow suppression is 
detected, treatment should be modified or suspended according to the guidelines below: 
Table 6-9 
Gemcitabine dosage reduction guidelines 
Treatment Day 
Absolute granulocyte 
count (×106/L)  
Platelet count 
(×106/L)  
% of full dose 
Day 1 
≥ 1500 
and ≥ 100,000 
100% 
 
less than 1500 
or less than 
100,000 
Hold 
Day 8 
≥ 1200 
>75,000 
100% 
 
1000-1199 
50,000-75,000 
75% 
 
700-999 
≥ 50,000 
50% 
 
<700 
<50,000 
Hold 
 
For non-hemorrhagic adverse events, gemcitabine should be permanently discontinued for 
unexplained dyspnea or other evidence of severe pulmonary toxicity, severe hepatic toxicity, 
hemolytic-uremic syndrome, capillary leak syndrome, and posterior reversible encephalopathy 
syndrome, Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) 
non-hematological toxicity until resolved. 
6.5.3.4 
Capecitabine 
Local label should be used for capecitabine dose modifications for the management of adverse 
reactions or as described in Table 6-10.


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Table 6-10 
Recommended dose modifications of capecitabine for both hematological and non-hematological toxicity 
Toxicity  
NCIC 
Grades* 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
During a 
course of 
therapy 
Dose adjustment for 
next 
treatment (% of starting 
dose) 
During a 
course of 
therapy 
Dose 
adjustment 
for next 
treatment (% 
of starting 
dose) 
During a 
course of 
therapy 
Dose 
adjustment 
for next 
treatment (% 
of starting 
dose) 
During a course 
of therapy 
Dose 
adjustment for 
next 
treatment (% of 
starting dose) 
1st appearance 
Maintain 
dose 
level. 
Maintain dose level. 
Interrupt until 
resolved to 
grade 0-1. 
100% 
Interrupt until 
resolved to 
grade 0-1. 
75% 
Discontinue 
permanently  
OR 
If physician deems 
it to be in the 
patient's best 
interest to 
continue, interrupt 
until resolved to 
grade 0-1. 
50% 
2nd appearance 
- 
75% 
50% 
Discontinue 
permanently 
 
- 
3rd appearance 
- 
50 
Discontinue 
permanently. 
- 
- 
4th appearance 
- 
Discontinue 
treatment 
permanently. 
- 
- 
- 
* Common Terminology Criteria for adverse events v4.0 or toxicity management per local label was used, except for the hand-and-foot syndrome 
 


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6.5.3.4.1 Adjustment of starting dose in special populations 
Renal impairment 
No adjustment to the starting dose of capecitabine is recommended in patients with mild renal 
impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In 
patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a 
dose reduction to 75% of the capecitabine starting dose is recommended. Subsequent dose 
reduction should be made if grade 2 to 4 adverse events occurred, Table 6-10. 
Cockroft and Gault Equation: 
 
 
 
 
 
(140 – age [yrs]) (body wt [kg]) 
Creatinine clearance for males = 
————————————— 
 
 
 
 
 
(72) (serum creatinine [mg/dL]) 
Creatinine clearance for females = 0.85 × male value 
Severe renal impairment 
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance 
below 30 mL/min by Cockroft and Gault equation. 
Hepatic impairment due to liver metastasis 
Patients with mild or moderate hepatic impairment due to liver metastasis should be monitored 
carefully while administered capecitabine. No starting dose reduction is necessary. 
6.5.3.5 
Vinorelbine 
Hematologic toxicity: 
Complete blood counts, as per the local practice and standard of care, will be obtained to assess 
for hematologic toxicity. Dose modifications may be made on the basis of the blood counts on 
the day of the scheduled treatment. 
On Day 1 vinorelbine will be administered as long as absolute granulocyte count is 
≥ 1.5 × 109/L and platelets are > 100.0 × 109/L. If these treatment parameters are not met 
treatment will be delayed 1 week. If recovery takes >2 weeks, the patient will be discontinued 
from vinorelbine treatment, but not from the study entirely. On Day 8 the parameters in Table 
6-11 will apply: 
Table 6-11 
Absolute granulocyte and platelet count parameters (Days 8) 
Absolute Granulocyte Count (×109/L) 
Platelet count (×109/L) 
Dose of Vinorelbine 
>1.5 
>100.0 
Full dose 
1.0-1.499 
75.0 -99.0 
15 mg/m2 
<1.0 
<75.0 
Hold 
Peripheral neuropathy (sensory or motor) toxicity: 
• Grade 0-1: No Change 


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• Grade 2-4: Hold therapy and re-evaluate weekly; resume at 15 mg/m2 for all subsequent 
treatment when toxicities have resolved or improved to an acceptable level. 
Patients who experience Grade 2 or greater neurological toxicity should have vinorelbine held 
until symptoms are Grade 0-1. 
Other non-hematologic toxicities: 
For other Grade 3 and 4 toxicities, treatment should be held until the toxicity resolves to baseline 
or an acceptable level, then reinstituted (if medically appropriate) at the next lower dose level. 
If treatment is withheld for longer than 2 weeks, the patient will be discontinued from 
vinorelbine treatment, but not from the study entirely. 
Hepatic insufficiency: 
1. Total serum bilirubin 2.1 to 3 mg/dL: Give 50% of starting dosage 
2. Total serum bilirubin greater than 3 mg/dL: Give 25% of starting dosage 
3. Hepatic impairment with concomitant neutropenia: Give the lowest suggested dose 
adjustment for given degree of neutropenia or hepatic impairment. 
6.5.4 
Follow-up for toxicities  
Patients who complete treatment or whose treatment is interrupted or permanently discontinued 
due to an adverse event or abnormal laboratory value must be followed at least once a week for 
4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event. All 
patients will be followed up for safety for 30 days following the last dose of study treatment. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form and site source document. This information must be captured in the source 
document at each patient visit. Compliance will be assured by administrations of the study 
treatment under the supervision of investigator or his/her designee. 
6.6.2 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group, third 
party, and investigational site as appropriate. Study drug destruction at the investigational site 
will only be permitted, if permitted by local regulations. 
6.7 
Preparation and dispensation 
Patients, enrolled in the ribociclib arm, will be provided with an adequate supply of study drugs 
for self-administration at home, including instructions for administration, until at least their next 
scheduled study visit. Patients will receive ribociclib on an outpatient basis. The investigator 
shall provide the patient with instructions for ribociclib administration according to the protocol. 
For the patients assigned to receive chemotherapies as IV infusions, infusions will be prepared 
by a site pharmacists. If the patients are assigned to receive the chemotherapies orally (as tablets 


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and capsules), site pharmacists or designee will provide an adequate supply of the study drugs 
to the patients, including instructions for administration, until at least their next scheduled study 
visit. Letrozole, anastrozole, goserelin and chemotherapies combinations (capecitabine + 
vinorelbine, paclitaxel + gemcitabine, and docetaxel +capecitabine) should be dispensed as 
mentioned in Section 6.1.1. The investigator or responsible site personnel must instruct the 
patient or caregiver to take the study drugs as per protocol. Study drug(s) will be dispensed to 
the patient by authorized site personnel only. All dosages prescribed to the patient and all dose 
changes during the study must be recorded on the Dosage Administration Record CRF. 
Investigator staff will identify the study medication kits to dispense to the patient by contacting 
the IRT (applicable for patients in the ribociclib arm only) and obtaining the medication 
number(s). The study medication has a 2-part label (base plus tear-off label), immediately 
before dispensing the medication kit to the patient, site personnel will detach the outer part of 
the label from the packaging and affix it to the source document. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, delivery of IMP directly 
to a participant’s home may be permitted (if allowed by Local or Regional Health Authorities 
and Ethics Committees as appropriate) in the event the Investigator has decided that an on-site 
visit by the participant is no longer appropriate or possible, and that it is in the interest of the 
participant’s health to administer the study treatment even without performing an on-site visit. 
• Ribociclib: The dispatch of ribociclib from the site to the participant’s home remains 
under the accountability of the Investigator. Each shipment/provisioning will be for a 
maximum of 1 month supply until Cycle 11 and 3 months supply thereafter. In this case, 
regular phone calls or virtual contacts (every 4 weeks or more frequently if needed) will 
occur between the site and the participant for instructional purposes, safety monitoring, 
drug accountability, investigation of any adverse events, ensuring participants continue to 
benefit from treatment and discussion of the participant´s health status until the 
participants can resume visits at the study site. 
• For other study drugs (letrozole/anastrozole): Access to these drugs through a 
pharmacy outside of study site should be ensured by investigator or his/her team.  If these 
are prescription only drugs in the country, investigator may consider sending prescriptions 
over the email to the patient or patient’s relative.  
• For goserelin/leuprorelin: Procedure for subcutaneous implant for these drugs can be 
performed by another medical professionals outside of study site. Detailed treatment plan 
(dose, schedule) should be transferred to the other breast cancer treating physician by 
principal investigator. The process for assuring oversight of the same including 
communication to confirm patients’ safety and any treatment should be documented.   
• Patients receiving oral chemotherapy drugs: Prescription delivery to such patients can 
be arranged or prescription can be issued from another qualified breast cancer treating 
physician or medical oncologists authorized by the principal investigator. All details 
should be transferred for the chemotherapy treatment (dose, schedule) to the qualified 
physician outside study site, and process for assuring oversight should be documented. In 
addition, any certified source documents (including any other medication records) should 
be retrieved and maintained in patients’ medical record or charts at study site.  


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• For patients who are receiving intravenous chemotherapy drugs: In these cases, 
patient is not able to self-administer the drug. Risk-benefit of the patient coming to the 
facility before conducting the on-site visit should be assessed & documented during public 
health emergencies situation. If on-site visit is not possible and the administration of the 
intravenous chemotherapy is necessary per patient’s overall health status, it may be 
performed by another qualified breast cancer treating physician or medical oncologists 
authorized by principal investigator. All details about the chemotherapy treatment (dose, 
schedule) to this qualified physician outside study site should be transferred by principal 
investigator. The process for assuring investigator oversight, including communication to 
confirm patients’ safety and any treatment should be documented. In addition, any 
certified source documents (including any other medication records) should be retrieved 
and maintained in patients’ medical record or charts at study site. 
If patient is not able to continue chemotherapy drugs (IV/Oral) due to public health emergencies 
situations, then principal investigator should imply his/her best clinical judgement while 
evaluating patient and make the decisions related to continuation of patient in the study. 
6.7.1 
Handling of study treatment and additional treatment  
6.7.1.1 
Handling of study treatment  
Study treatment must be received by a designated person 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. Ribociclib will be supplied centrally by Novartis and the other study 
medications (letrozole, anastrozole, goserelin, capecitabine, vinorelbine, paclitaxel, 
gemcitabine, and docetaxel) will be sourced locally. Upon receipt, all study treatment must be 
stored according to the instructions specified on the labels and in the [Investigator’s Brochure]. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log, and site source document. Monitoring of drug 
accountability will be performed by monitors during site visits or remotely and at the 
completion of the trial. Patients will be asked to return all unused study treatment and packaging 
at the end of the study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all 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. 
Table 6-12 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Ribociclib 
tablets in bottles 
Labeled as ‘Ribociclib 200 mg’ 
Study treatment packaging has a 2-part label. 


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Study treatments 
Packaging 
Labeling (and dosing frequency) 
Anastrozole 
Refer to local product information 
Refer to local product information 
Letrozole 
Goserelin 
Docetaxel 
Paclitaxel 
Gemcitabine 
Vinorelbine 
Capecitabine 
6.7.1.2 
Handling of additional treatment  
No other treatment beyond investigational drug and control drug are included in this trial. 
6.7.2 
Instruction for prescribing and taking study treatment 
Details have been provided in Section 6.1. 
7 
Informed consent procedures  
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/ independent ethics committee (IEC)-approved informed consent. 
If applicable, in cases where the patient’s representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that may challenge the ability to obtain a standard written informed 
consent due to limits that prevent an on-site visit, Investigator may conduct the informed 
consent discussion remotely (e.g. telephone, videoconference) if allowable by a local Heath 
Authority. However signing of ICF should be completed at the study site after informed consent 
discussion has been conducted and patient agrees to participate in the study. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the ribociclib can be found in the 
IB. For the other investigational drugs, information about other common side effects can be 
found in respective product’s approved label. This information will be included in the patient 


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informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the patient. 
Women of child bearing potential must be informed that taking the study treatment 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 requirements 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. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
 
 
 
 
 
 
 
8 
Visit schedule and assessments 
Table 8-1 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 
database (D) or remain in source documents only (S) (“Category” column). Patients should be 
seen for all visits/assessments as outlined in the assessment schedule or as close to the 
designated day/time as possible.  
Patients who prematurely discontinue the study for any reason should be scheduled for the EOT, 
followed by safety follow-up and survival follow up visits and all of the assessments listed in 
Table 8-1 will be performed. At these visits, dispensed investigational product should be 
reconciled, and the adverse event and concomitant medications will be recorded on the CRF. 
Allowed visit windows are specified as follows: 
• Patients meeting all entry criteria will be randomized and will be administered the first 
dose of study treatment preferably on the day of randomization, but no later than 3 days 
after randomization. 
• A general ± 3 day window is permitted on assessments. A visit window ± 7 days is 
allowed on biochemistry assessments. Restrict the use of windows before Cycle 3 Day 1 
when feasible. 
• A general ± 3 days is allowed for goserelin administration. 
• A visit window of + 3 days is allowed for EOT visit, ± 3 days for safety follow up visit. 


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• Radiological assessments and patient reported outcomes must be performed as outlined in 
Table 8-1. A visit window of ± 7 days is allowed.  
• The whole body bone scan should be performed within 42 days or 6 weeks prior to 
randomization. 
• Height, weight, vital signs, physical exam, ECOG performance status, hematology, 
biochemistry, should be performed within 14 days of randomization. 
• Note: If the physical examination, ECOG performance status, and/or laboratory screening 
assessments were performed ≤ 7 days prior to the first dose of study treatments, then they 
do not need to be repeated on Cycle 1 Day 1.  
• The ECG should be performed within 7 days prior to randomization. 
• Patients’ eligibility to participate in the study will be confirmed before randomization is 
performed and study drug is administered. 
• Testing of FSH and/or estradiol (if necessary for determining pre-menopausal status for 
eligibility) and serum pregnancy test (β-Hcg) (unless the patient has had a hysterectomy) 
must occur within 28 days before starting study treatment. 
All other screening assessments must be completed within 28 days before randomization 
(Cycle 1, Day 1). Every effort should be made to follow the schedule outlined in Table 8-1. 


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Table 8-1 
Assessment Schedule  
 
Category 
Reference 
to protocol 
section 
Screening Phase 
Treatment Phase 
Survival Follow up 
Visit name 
 
 
Screening 
Cycle 
1 
Cycle 2 Cycle 3 to Cycle 12 
In 
every 
3rd 
Cycles 
(Cycle 
15, 18, 
21...) 
End of 
study 
treatment 
(EOT) 
within 15 
days from 
the last 
dose 
Safety 
follow 
up 
EOT + 
30 
days 
Survival Follow up 
(occurs every 16 (± 4) 
weeks after safety 
follow up visit) 
Treatment days 
 
 
-28 to 
-1 
-14 to -1 
1 
1
5 
1 
15 
1 
1 
 
 
N/A 
Screening 
Study Informed Consent, 
 
D 
7 
X 
 
 
 
 
 
 
 
 
 
 
IRT Screening (after ICF 
signature) 
S 
8.1 
X 
 
 
 
 
 
 
 
 
 
 
Screening phase disposition 
D 
8.1 
X 
 
 
 
 
 
 
 
 
 
 
Patient History 
Demography 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria 
D 
5.1 
and 
5.2 
X 
X 
 
 
 
 
 
 
 
 
 
Relevant medical history / current 
medical conditions 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
ER and PgR status 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
HER2 status 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of cancer 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 


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Category 
Reference 
to protocol 
section 
Screening Phase 
Treatment Phase 
Survival Follow up 
Visit name 
 
 
Screening 
Cycle 
1 
Cycle 2 Cycle 3 to Cycle 12 
In 
every 
3rd 
Cycles 
(Cycle 
15, 18, 
21...) 
End of 
study 
treatment 
(EOT) 
within 15 
days from 
the last 
dose 
Safety 
follow 
up 
EOT + 
30 
days 
Survival Follow up 
(occurs every 16 (± 4) 
weeks after safety 
follow up visit) 
Treatment days 
 
 
-28 to 
-1 
-14 to -1 
1 
1
5 
1 
15 
1 
1 
 
 
N/A 
Prior / concomitant medication 
D 
8.2 
Continuous – up to 30 days after last dose 
 
Randomization 
Eligibility checklist (within IRT) 
S 
8.1.1 
 
 
X 
 
 
 
 
 
 
 
 
IRT – randomization 
D 
8.1 
 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
Physical examination 
S 
8.4 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Performance status (ECOG) 
D 
8.4.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
D 
8.4 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
D 
8.4 
 
X 
X 
 
X 
 
X 
As 
clinicall
y 
indicate
d 
X 
 
 
Vital signs 
D 
8.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory assessments 
Hematology2 
D 
8.4.2.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biochemistry (including fasting 
glucose)2 
D 
8.4.2.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FSH  
S 
8.4.2.3 
X 
 
 
 
 
 
 
 
 
 
 
Plasma estradiol  
S 
8.4.2.3 
X 
 
 
 
 
 
 
 
 
 
 


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Category 
Reference 
to protocol 
section 
Screening Phase 
Treatment Phase 
Survival Follow up 
Visit name 
 
 
Screening 
Cycle 
1 
Cycle 2 Cycle 3 to Cycle 12 
In 
every 
3rd 
Cycles 
(Cycle 
15, 18, 
21...) 
End of 
study 
treatment 
(EOT) 
within 15 
days from 
the last 
dose 
Safety 
follow 
up 
EOT + 
30 
days 
Survival Follow up 
(occurs every 16 (± 4) 
weeks after safety 
follow up visit) 
Treatment days 
 
 
-28 to 
-1 
-14 to -1 
1 
1
5 
1 
15 
1 
1 
 
 
N/A 
Coagulation 3 
D 
8.4.2.4 
 
 
Please refer to 8.4.2.4 
Tumor Assessment 
Tumor Assessment 
D 
8.3.2 
X 
 
Every 6 weeks for the first 12 weeks and at every 8 weeks for the next 32 
weeks, and at every 12 weeks thereafter until disease progression, death, 
withdrawal of consent, loss to follow-up, patient/guardian decision, and at 
EOT1. If PR/CR is reported, confirmation of response is required; 
confirmatory assessment should be performed ≥ 4 weeks after response is 
first documented. 
 
Whole body bone scan 
D 
8.3.2 
X (within 42 days 
prior to 
randomization) 
- 
Safety 
ECG (standard 12-lead) 
D 
8.4.3 
 
X 
(Days -7 
to Days -
1) 
 
X 
X 
 
 
 
X 
 
 
Serum Pregnancy Test  
D 
8.4.2.3 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy test  
D 
8.4.2.3 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Concomitant 
medications/procedures 
D 
6.2.1 
X 
 
Continuous 
X 
X 
 


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Category 
Reference 
to protocol 
section 
Screening Phase 
Treatment Phase 
Survival Follow up 
Visit name 
 
 
Screening 
Cycle 
1 
Cycle 2 Cycle 3 to Cycle 12 
In 
every 
3rd 
Cycles 
(Cycle 
15, 18, 
21...) 
End of 
study 
treatment 
(EOT) 
within 15 
days from 
the last 
dose 
Safety 
follow 
up 
EOT + 
30 
days 
Survival Follow up 
(occurs every 16 (± 4) 
weeks after safety 
follow up visit) 
Treatment days 
 
 
-28 to 
-1 
-14 to -1 
1 
1
5 
1 
15 
1 
1 
 
 
N/A 
Adverse events 
D 
10 
X 
 
Continuous 
X 
X 
 
End of Phase Disposition 
D 
8  
 
 
 
X 
 
 
Patient Reported Outcome 
FACT-B 
D 
8.5 
X 
 
Every 6 weeks for the first 12 weeks and at every 8 weeks for the 
next 32 weeks, and at every 12 weeks thereafter until disease 
progression, death, withdrawal of consent, loss to follow-up, 
patient/guardian decision, and at EOT 
X 
 
Treatment 
NSAI 
D 
6.1 
 
 
Daily 
 
 
 
Goserelin 
D 
6.1 
 
 
Day 1 of each cycle with an administration window 
of ± 3 days 
 
 
 
Ribociclib 
D 
6.1 
 
 
Days 1-21 of each cycle 
 
 
 
Combination Chemotherapies  
D 
6.1 
 
 
Please refer to “Treatment Information” Table 4-1. 
 
 
 
Discontinuation 
IRT – discontinuation 
S 
9.2 
 
 
 
 
 
 
 
 
X 
 
 


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Category 
Reference 
to protocol 
section 
Screening Phase 
Treatment Phase 
Survival Follow up 
Visit name 
 
 
Screening 
Cycle 
1 
Cycle 2 Cycle 3 to Cycle 12 
In 
every 
3rd 
Cycles 
(Cycle 
15, 18, 
21...) 
End of 
study 
treatment 
(EOT) 
within 15 
days from 
the last 
dose 
Safety 
follow 
up 
EOT + 
30 
days 
Survival Follow up 
(occurs every 16 (± 4) 
weeks after safety 
follow up visit) 
Treatment days 
 
 
-28 to 
-1 
-14 to -1 
1 
1
5 
1 
15 
1 
1 
 
 
N/A 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
3.1.2.1 
 
 
 
 
 
 
 
 
 
X 
 
Survival follow-up 
D 
3.1.3 
 
 
 
 
 
 
 
 
 
 
X 
1 The tumor evaluation at EOT is ONLY required for patients who discontinued the study treatments before the first scheduled post-baseline tumor assessment (week 6) 
OR for patients whose previous tumor assessment did not demonstrate PD and was done more than 21 days prior to end of treatment visit. 
2 Hematology and biochemical parameters need to be performed as indicated in the VES. Patients on combination chemotherapy may have additional hematology and 
biochemical assessments as per the local practice for such drug and are considered as standard of care. 
3 Coagulation parameters of INR or PT are to be performed at every visit only for the patients receiving oral coumarin-derivate anticoagulants such as warfarin and 
phenprocoumon along with capecitabine as one of the medication in the combination chemotherapy group. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as the situation dictates. If allowed by local Health Authority and depending on 
operational capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff to the participant´s home, can replace on-site study visits, for the duration of 
the disruption until it is safe for the participant to visit the site again. Patients can be contacted more frequently than is required by the study protocol, with frequency 
selected according to circumstances and including the individual patient’s vulnerability to pandemic or epidemic. All modes of patient contact (virtual or writing) should 
have a proper source documentation for the trial. 


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8.1 
Screening 
Molecular pre-screening 
Not applicable  
Screening 
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to randomization or within 1 to 14 days prior to randomization for selected assessments (see 
Table 8-1 for list of assessments to be performed); the ECG should be performed within 7 days 
prior to randomization. 
Note: Any screening assessment that is done outside the screening window (Day -28 to 
Day -1 or Day -14 to Day -1 as applicable) must be repeated prior to randomization. 
For laboratory evaluations used to determine eligibility, one 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 (multiple evaluations for serum electrolytes, blood counts and 
biochemistry parameters such as liver function and renal function are allowed). If the repeated 
laboratory result does not meet the criteria, the patient will be considered a screening failure. 
No re-screening of patients is allowed in this study.  
During the screening, if the patients’ heart rate is above 100/min, beta-blocker will be allowed. 
Thereafter, if the patients’ heart rate is under control, ECG shows no QTcF prolongation (>450 
msec) and the patient is clinically and hemodynamically stable, they will be allowed to 
participate in the study. Assessments of patient reported outcomes should be collected prior to 
any clinical assessments, drug dosing or diagnostic testing. 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization (and 42 days for the whole body bone scan), including before 
signing the main study ICF can be considered as the baseline images for this study. 
8.1.1 
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. 
8.1.2 
Information to be collected on screening failures 
Patients who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, visit date, 
informed consent, and Inclusion/Exclusion pages must also be completed for screen failure 
patients. No other data will be entered into the clinical database for patients who are screen 
failures, unless the patient experienced a serious adverse event during the screening phase (see 
SAE section (Section 10.1.3) for reporting details). 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. 


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Patients who are randomized and fail to start treatment, e.g. patients randomized in error, will 
be considered an early terminator and will be recorded in the IRT, along with reason for early 
termination. The reason for early termination should be recorded on the appropriate Case Report 
Form. 
8.2 
Subject demographics/other baseline characteristics 
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
The data that will be collected on patient characteristics at screening includes: 
• Demography (Age, sex, race, ethnicity). 
• Diagnosis and extent of cancer (including staging at study entry and histology/cytology) 
• Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History eCRF should include the toxicity grade. No 
additional medical assessments will be performed to confirm the current medical 
condition. 
• ER, PgR, and HER2 status. 
• All prior antineoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for cancer prior to the 
administration of study drug. 
• All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded on the Prior and Concomitant medication or 
Surgical and medical procedures eCRF page and updated on a continual basis if there are 
any new changes to the medications. 
• Patient-reported outcome questionnaires (FACT B) (See Section 8.5). 
Furthermore the following assessments will be performed: 
• Vital signs 
• Height, weight 
• Physical examination 
• Performance status (ECOG) 
• Laboratory evaluations (hematology, chemistry) 
• ECG 
• Radiological assessments (e.g. CT Scan) 
8.3 
Efficacy  
8.3.1 
Efficacy Assessment 
Tumor assessments will be performed: 
• at screening (Day -28 to -1) and  


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• at every 6 weeks after randomization/first dose for the first 12 weeks and  
• at every 8 weeks for the next 32 weeks and  
• at every 12 weeks thereafter until disease progression (radiologically documented 
according to RECIST 1.1 criteria) or death, withdrawal of consent, loss to follow-up, 
patient/guardian decision 
• at End of Treatment (EOT): Only required for patients who discontinued the study 
treatments before the first scheduled post-baseline tumor assessment (week 6) OR 
patients whose previous tumor assessment did not demonstrate PD and was done more 
than 21 days prior to end of treatment visit 
At the Screening (Day -28 to Day -1), if any site has any record of CT scan that is performed 
within 28 days prior to randomization for a particular patient, the CT scan need not be re-
performed for that patient and that image can be considered as the baseline images for this 
study.  
Following treatment discontinuation, all patients (except if consent is withdrawn or patient is 
lost to follow-up) will be followed for survival at least every 16 (± 4 weeks after the safety 
follow-up visit), until at least either 80% deaths have been documented or at least 46 months 
elapsed since FPFV, whichever occurs first.  
8.3.2 
Imaging tumor assessments 
Tumor response will be assessed locally according to the Novartis guideline version 3.2 
(Appendix 2) based on RECIST 1.1 (Eisenhauer et al 2009). The imaging assessment collection 
plan is presented in Table 8-2. 
Patients must have at least one documented measurable lesion (per RECIST v1.1) or in the 
absence of measurable disease, have at least one predominantly lytic bone lesion at study entry.  
Imaging assessments will be performed at screening within 28 days prior to randomization and 
subsequently at every 6 weeks for the first 12 weeks and at every 8 weeks for the next 32 weeks 
and at every 12 weeks thereafter (± 7 days), until disease progression (radiologically 
documented according to RECIST 1.1 criteria), death, withdrawal of consent, loss to follow-up, 
or patient/guardian decision. Imaging assessment performed during the screening phase 
(between Day -28 to Day -1) should be considered as the baseline image. The details of 
assessments is provided in Table 8-1. The interval between imaging assessment should be 
respected regardless of whether study treatment is temporarily withheld. Additional imaging 
assessments may be performed at any time during the study at the investigator’s discretion to 
support the efficacy evaluations for a patient, as necessary. Clinical suspicion of disease 
progression at any time requires a physical examination and imaging assessments to be 
performed promptly rather than waiting for the next scheduled imaging assessment. After 
baseline, all assessments should be performed within ± 7 days of the scheduled day of 
assessment. The same method of assessment and the same technique should be used to 
characterize each individual and reported lesion at baseline and during follow up. Each lesion 
that is measured at baseline must be measured by the same method (either same imaging method 
or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 


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imaging assessments should be performed in accordance with the original imaging schedule. 
To the extent possible, each lesion should be assessed using the same imaging method 
throughout the study. 
All patients will undergo CT or MRI of the chest, abdomen and pelvis at baseline and 
subsequent scheduled visits per Table 8-1. The preferred imaging methodology is CT with 
intravenous (i.v.) contrast. However, if at baseline, a patient is known to have a contraindication 
to CT i.v. contrast media or develops a contraindication during the trial, a non-contrast CT of 
chest (MRI is not recommended due to respiratory artifacts) plus contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET)) should be 
acquired at baseline for all patients if not collected previously within 42 days (6 weeks) prior 
to randomization. Skeletal lesions identified on the whole body bone scan at baseline, which 
are not visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at baseline 
and followed at scheduled visits using localized CT, MRI or X-ray. Whole body bone scans 
need not be repeated after baseline unless clinically indicated. 
Color photography, including a metric ruler to estimate the size of the lesion, must be acquired 
for all skin lesions present at screening. These should be followed throughout the study 
according to the schedule outlined in Table 8-1. 
Other metastatic disease sites will be followed by CT or MRI, as clinically indicated. 
Chest X-ray or ultrasound should not be used to assess tumor lesions. 
Combined Positron Emission Tomography (PET)/CT may be used only if the CT component is 
of similar diagnostic quality as a CT performed without PET, including the utilization of oral 
and i.v. contrast media. At the discretion of the Investigators, FDG-PET scans may be 
performed to document progressive disease per RECIST 1.1 (Appendix 2). If possible, a single 
radiologist should perform all tumor response evaluations for an individual patient. Any lesions 
in previously irradiated areas should not be considered measurable unless they have 
experienced progression since the radiotherapy. Any pre-existing radiographic findings which 
may mimic metastatic disease and any prior radiotherapy should be recorded in the eCRF. 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization (and 42 days for the whole body bone scan), including before 
signing the main study ICF can be considered as the baseline images for this study. 
If an off-schedule imaging assessment is performed to confirm response or if progression is 
suspected, subsequent imaging assessments should be performed in accordance with the 
original imaging schedule. 
Physical exam tumor assessments, photography, pathology/histology and cytology results, as 
well as information regarding prior interventions, pre-existing radiographic findings that mimic 
metastatic disease at baseline/screening and on-study interventions should be captured in the 
appropriate eCRFs and may be -for additional review if appropriate. 
A tumor evaluation at EOT is required: 


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• for patients who discontinue treatment before first scheduled post-baseline tumor 
assessment (week 6) or 
• for patients whose previous tumor assessment did not demonstrate PD and was done more 
than 21 days prior to end of treatment visit. 
Efficacy assessments should continue as per the scheduled visit provided in Table 8-1. 
Table 8-2 
Imaging Assessment Collection Plan  
Procedure 
Screening: day −28 to day -1 
Treatment phase* 
End of 
treatment* 
CT or MRI (Chest, 
Abdomen, Pelvis) 
Mandated  
Every 6 weeks for the first 
12 weeks and  
at every 8 weeks for the 
next 32 weeks,  
and at every 12 weeks 
thereafter (± 7 days) until 
disease progression 
(radiologically documented 
according to RECIST 1.1 
criteria), death, withdrawal 
of consent, loss to follow-
up, or patient/guardian 
decision 
Mandated 
Brain CT or MRI 
Only if suspected brain 
metastases 
Only if suspected brain metastases 
Whole body bone 
scan** 
Mandated, within 42 days 
(6 weeks) prior to 
randomization.  
As clinically indicated 
As clinically 
indicated 
Bone X-ray, CT or 
MRI 
Only if skeletal abnormalities 
identified by whole body bone 
scan (or skeletal survey) at 
screening, which are not 
visible in the chest, abdomen, 
pelvis CT/MRI. 
If bone lesion at screening, 
every 6 weeks for the first 
12 weeks and at every 
8 weeks for the next 
32 weeks, and at every 
12 weeks thereafter 
(± 7 days), until disease 
progression (radiologically 
documented according to 
RECIST 1.1 criteria), 
death, withdrawal of 
consent, loss to follow-up, 
or patient/guardian 
decision 
Mandated 
only if bone 
lesion at 
screening 


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Procedure 
Screening: day −28 to day -1 
Treatment phase* 
End of 
treatment* 
Skin color 
Photography 
Only if skin lesions at 
screening 
If skin lesions at screening, 
every 6 weeks for the first 
12 weeks and at every 
8 weeks for the next 
32 weeks, and at every 
12 weeks thereafter 
(± 7 days), until disease 
progression (according to 
RECIST 1.1 criteria), 
death, withdrawal of 
consent, loss to follow-up, 
or patient/guardian 
decision 
Mandated if 
skin lesions at 
screening 
CT or MRI of any 
disease outside of 
chest, abdomen 
and pelvis (e.g., 
neck) 
Only if suspected lesion at 
screening 
If lesion identified at 
screening, every 6 weeks 
for the first 12 weeks and 
at every 8 weeks for the 
next 32 weeks, and at 
every 12 weeks thereafter 
(± 7 days) until disease 
progression (radiologically 
documented according to 
RECIST 1.1 criteria), 
death, withdrawal of 
consent, loss to follow-up, 
or patient/guardian 
decision  
Mandated if 
lesion at 
screening 
*Tumor evaluation at EOT is required for patients who discontinue study treatment before the first 
scheduled post-baseline tumor assessment (week 6) and for patients whose previous tumor 
assessment did not demonstrate PD and was done more than 21 days prior to end of treatment 
visit. 
** Whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, sodium fluoride positron emission tomography (NaF PET) or fluorodeoxyglucose (FDG) 
PET. 
Note: All scans will be read locally  
8.3.3 
Appropriateness of efficacy assessments 
Tumor response measurements are standard and will be assessed according to the Novartis 
guideline version 3.2 (Appendix 2) based on RECIST Version 1.1 (Eisenhauer et al 2009). 
8.4 
Safety 
Safety will be monitored by assessing physical examinations, ECOG performance status, height 
and weight, vital signs, ECG, patient reported outcomes, laboratory assessments including 
hematology, biochemistry, pregnancy, and coagulation parameters such as INR or PT (to be 
performed only for the patients receiving capecitabine as one of the medication in the 
combination chemotherapy group along with oral coumarin derivate anticoagulants such as 
warfarin and phenprocoumon) as well as collecting of the adverse events at every visit. All the 
safety assessment will be performed according to the visit schedule as outlined in Table 8-1. 


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For details on AE collection and reporting, refer to Section 10.1. 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. The list of the physical 
assessments planned for this study are provided in Table 8-3. 
Table 8-3 
Physical Assessments 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological review. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed. 
- 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures 
medical history. Significant findings made after first administration of 
investigational drug which meet the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital sign 
Vital signs include blood pressure and pulse measurements and body 
temperature. After the patient has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood pressure 
will be measured three times using an automated validated device, with an 
appropriately sized cuff. The repeat sitting measurements will be made at 1 – 2 
minute intervals and the mean of the three measurements will be used. In case the 
cuff sizes available are not large enough for the patient’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
Height and 
weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured. 
 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, regular phone or virtual calls 
can occur (every 4 weeks for ribociclib arm and every 3 weeks for combination chemotherapy arm or 
more frequently if needed) for safety monitoring and discussion of the participant´s health status until it 
is safe for the participant to visit the site again. 
Physical assessment/s can be performed by another qualified breast cancer physician or medical 
oncologist outside study site. The process for assuring oversight of the same, including communication 
to confirm patient safety should be in place. All relevant source documents certified by other breast 
cancer treating physician/s or medical oncologist/s should be retrieved and maintained in patients’ 
medical record or charts at study site. Decisions related to patients’ discontinuation for treatment will 
be based on investigators’ full review of results of laboratory and safety assessment, patient’s physical 
assessment of health status, clinical judgment and/or patient’s own decision. 
8.4.1 
Performance status 
The performance status will be assessed according to the ECOG performance status scale (Oken 
et al 1982) following the schedule given in Table 8-4. 


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Table 8-4 
ECOG performance status 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.4.2 
Laboratory evaluations 
Clinical laboratory analyses (hematology and chemistry) are performed by the local laboratory. 
Visit windows of ± 3 days are allowed for all visits except at Cycle 1 Day 1; a visit window ± 
7 days is allowed on biochemistry assessments. 
Novartis must be provided with a copy of the laboratory’s certification (if applicable), and a 
tabulation of the normal ranges and units of each parameter collected in the eCRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 
reported via an updated tabulation indicating the new effective date. Additionally, if at any time 
a patient has laboratory parameters obtained from a different (outside) laboratory, Novartis must 
be provided with a copy of the certification and a tabulation of the normal ranges and units for 
this laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
patients in the study and evaluating any abnormalities for clinical significance. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (At 
decided by the investigator) 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 adverse event eCRF page. Laboratory data will be summarized using the 
CTCAE version 4.03. Additional analyses are left to the discretion of the investigator. 


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Table 8-5 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
White blood cell count (WBC) with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), hemoglobin 
(Hgb) and platelet count. 
Biochemistry with 
fasting glucose 
Potassium, uric acid, urea or BUN, creatinine, fasting glucose, calcium, 
corrected calcium, magnesium, and albumin. 
AST (SGOT), ALT (SGPT), total bilirubin, direct bilirubin, GGT and 
alkaline phosphatase, Amylase, lipase and LDH. 
Coagulation  
PT International normalized ratio [INR] or protrombin time. Please refer 
to Section 8.4.2.4. 
Pregnancy Test 
FSH, estradiol (for premenopausal patients only), serum pregnancy, 
and urine pregnancy test (dipstick) 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, Laboratory panels (e.g. 
Biochemistry and Hematology) can be performed at a certified local laboratory outside study site by 
supplying the patient with a lab request form, if feasible. All local lab reports (along with reference 
ranges) done outside of study site should be collected and filed in the patient medical records or 
charts at the study site. 
Principal investigator should exercise discretion to consider other safety assessments that need to be 
conducted outside of the study site to ensure the patient’s safety. 
8.4.2.1 
Hematology 
Hematology tests are to be performed according to the visit schedules outlined in Table 8-1. 
Patients on combination chemotherapy may have additional hematology assessments as per the 
local practice for such drug and are considered as standard of care.  
For details of the Hematology panel, refer to Table 8-5. 
Note: If the laboratory screening assessments were performed ≤ 7 days prior to the first dose of 
study treatments (for both ribociclib and combination chemotherapies), then they do not need 
to be repeated on Cycle 1 Day 1. 
Hematology should be assessed on the scheduled day, even if study drug is being withheld. 
8.4.2.2 
Biochemistry 
Biochemistry tests are to be performed according to the visit schedules outlined in Table 8-1. 
Patients on combination chemotherapy may have additional biochemical assessments as per the 
local practice for such drug and are considered as standard of care. 
For details of the biochemistry panel refer to Table 8-5. 
Note: If the laboratory screening assessments were performed ≤ 7 days prior to the first dose of 
study treatments (for both ribociclib and combination chemotherapies), then they do not need 
to be repeated on Cycle 1 Day 1. 
Biochemistry should be assessed on the scheduled day, even if study drug is being withheld. 


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8.4.2.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. FSH, 
estradiol, and serum or urine pregnancy tests (patients who have undergone a hysterectomy do 
not need pregnancy tests performed) are to be performed according to the Visit Schedules 
outlined in Table 8-1. If the laboratory screening assessments were performed ≤ 7 days prior to 
the first dose of study treatments (for both ribociclib and combination chemotherapies), then 
urine pregnancy test need not be repeated on Cycle 1 Day 1. At screening, a serum pregnancy 
test should be performed regardless of the age of the patients, while at baseline, during the 
study, and at the end of study, urinary pregnancy tests (dipstick) are sufficient. A positive 
pregnancy test requires immediate interruption of study treatment until the assessment is 
confirmed by the Principal Investigator. If positive, the patient must be discontinued from the 
study and perform EOT visit. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, patient can perform the 
urine pregnancy test at home and report the result to the site. Patient should be instructed to 
perform the urine pregnancy test first and only if the test result is negative proceed with the 
administration of the study treatment. A communication process should be established with the 
participant so that the site is informed and can verify the pregnancy test results (following 
Country specific measures). 
8.4.2.4 
Coagulation 
At every visit, INR or PT are to be performed only for the patients receiving capecitabine (as 
one of the medication in the combination chemotherapy group) along with oral 
coumarin-derivate anticoagulants such as warfarin and phenprocoumon.  
Oral coumarin-derivate anticoagulants such as warfarin and phenprocoumon should be avoided 
in patients receiving capecitabine as study treatment. If patient needs to take coumarin-derivate 
anticoagulants anticoagulant response (INR or prothrombin time) should be monitored 
frequently in order to adjust the anticoagulant dose based on capecitabine prescribing 
information. Altered coagulation parameters and / or bleeding, including deaths have been 
reported during concomitant use. 
8.4.3 
Electrocardiogram (ECG) 
Standard 12 lead ECG must be recorded after 10 minutes rest in the supine position, prior to 
each time point indicated in Table 8-6. The QTcF should be used for clinical decisions. Single 
reading of ECG is required at schedule days, including at the screening phase. Eligibility will 
be based on the ECGs conducted at screening. The preferred sequence of cardiovascular data 
collection during study visits is ECG collection first, followed by vital signs, and blood 
sampling. 
Table 8-6 
Timing of study procedures  
Cycle 
Patients 
Day 
Time 
ECG Type 
Screening 
All 
-7 to -1 
Anytime 
12 Lead 
1 
All 
Day 15 
Pre-dose1 
12 Lead 


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2 
All 
Day 1 
Pre-dose1 
12 Lead 
EOT 
Anytime 
12 Lead 
Unscheduled ECG 
Anytime 
12 Lead 
1The exact date of dosing must be recorded on the appropriate eCRF 
*Single reading of ECG is required for all cycles 
If any of the readings include an abnormal ECG or an average QTcF value of ≥ 481 is obtained 
at any time after randomization, study treatment must be interrupted, repeat ECG and follow 
management guidelines detailed in Section 6.5.1 (for ribociclib treatment arm) and in 
Section 6.5.3 (for combination chemotherapies arm). 
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected. Local cardiologist ECG assessment may be performed at any time during 
the study at the discretion of the investigator. 
Each ECG tracing should be labeled with the study number, patient initials (where regulations 
permit), patient number, date, and kept in the source documents at the study site. Clinically 
significant ECG abnormalities present at screening 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. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, ECGs (as required) can 
be performed by a qualified healthcare professional outside study site by providing the patient 
with a requisition form, if feasible. ECG tracings/reports done outside of study site should be 
collected and filed in the patient medical records or charts at the study site. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
8.5 
Patient reported outcomes (PRO) 
FACT-Breast (FACT-B) is a breast cancer-specific module to explore patient-reported outcome 
measures of health-related quality-of-life, functioning, disease symptoms and treatment-related 
side effects. The FACT-B (Brady et al 1997) is a recognized, reliable and valid instrument 
frequently used in clinical trials of patients with advanced or metastatic breast cancer. The 
English FACT-B version 4 are divided into five subscales, namely physical (PWB), 
social/family (SWB), emotional (EWB), functional well-beings (FWB), and the additional 
concerns for breast cancer (BCS) (Cheung et al 2014). The Scores will be added to create 
subscale and overall scores. 
The FACT-B quality of life questionnaire (see Appendix 3) will be administered at study site 
before any study drug administrations at the visits indicated in Table 8-1 utilizing paper 
questionnaire for data collection. After that, all the answers provided by the patient will be 
transcripted into the eCRF by the investigator or delegated study personal. Collection of the 
FACT-B PRO has up to -7 day window unless otherwise indicated. 


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All questionnaires should be administered in the patient’s local language at the beginning of the 
study visit prior to any interaction with the study investigator including any tests, treatments or 
receipt of results from any tests to avoid biasing the patient’s perspective. This is to avoid 
potentially biasing patients or their responses to study questionnaires. Patients should be given 
sufficient space and time to complete the study questionnaire and the administered 
questionnaire should be reviewed for completeness. If missing responses are noted, patients 
should be encouraged to complete any missing responses. Attempts should be made to collect 
responses to the questionnaire for all patients, including from those who discontinue prior to 
the study evaluation completion visit, however, if patients refuse to complete the questionnaire, 
this should be documented in study source records. A patient’s refusal to complete the study 
questionnaire is not considered a protocol deviation. 
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records. 
If an AE or SAE is confirmed then the physician should record the event as instructed in 
Section 10 of this protocol. Investigators should not encourage the patients to change responses 
reported in questionnaires. 
Table 8-7 
Patient reported outcomes collection plan 
Patient Questionnaire 
Cycle 
Day 
Time 
FACT-B 
Screening 
-28 to Day -1 
Prior to any clinical 
assessments, drug 
dosing or diagnostic 
testing. 
Subsequent cycles 
Every 6 weeks for the first 12 
weeks and at every 8 weeks for 
the next 32 weeks, and at 
every 12 weeks thereafter until 
disease progression, death, 
withdrawal of consent, loss to 
follow-up, patient/guardian 
decision. 
End of treatment 
Day of EOT visit 
Safety follow-up 
Day of Safety follow-up visit 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, FACT-B data may be collected 
remotely (e.g. telephone interviews) if allowed by local regulations and site personnel has the 
knowledge and expertise to perform it. 
 
  


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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Both patient and investigator may voluntarily discontinue from the study treatment for any 
reason at any time. 
The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would negatively impact the patient’s well-being. 
Study treatment must be discontinued under the following circumstances: 
• Adverse Event (including, but not limited to QTcF ≥ 501 msec, confirmed at repeated 
ECG measurements and recurrent after dose adjustment was performed; documented 
episode of ventricular tachycardia, or ventricular fibrillation) 
• Lost to follow-up 
• Physician decision 
• Progressive Disease  
• Any other protocol deviation that results in a significant risk to the patient’s safety 
• Study terminated by sponsor 
• Technical problems 
• Non-compliant with study treatment 
• No longer requires treatment 
Patients must be withdrawn from the study treatment if any of the following occur: 
• Pregnancy 
• Death 
• Patient/Guardian decision 
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation: 
• Adjustments to study treatment due to toxicity that result in discontinuation. Please refer to 
Section 6.5.1 (for ribociclib treatment arm) and Section 6.5.3 (for combination 
chemotherapies arm) 
• Use of prohibited medication. Please refer to Section 6.2.2. 


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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the patient’s premature discontinuation of study treatment 
and record this information. 
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, and letter) should be 
made to contact the patient/pre-designated contact as specified in the lost to follow-up section. 
This contact should preferably be done according to the study visit schedule. 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. Patients who 
discontinue study treatment should undergo an EOT visit followed by a 30 day safety follow-up 
visit. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
For the detail of information to be collected, refer to Table 8-1. The investigator must also 
contact the IRT to register the patient’s discontinuation from study treatment. 
9.1.2 
Withdrawal of informed consent  
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
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Novartis will continue to retain and use all research results (data) 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). 
9.1.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed. Patients lost to follow-up should be recorded as such on the 
appropriate Disposition CRF. 
9.1.4 
Early study termination by the sponsor  
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should this be necessary, the 
patient should be seen as soon as possible and the same assessments should be performed as 
described in Section 9.2 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 or sponsor depending on 
the local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial. 
9.2 
Study completion 
An end of treatment (EOT) visit will be performed when the patient permanently discontinues 
all study treatment and the end of treatment procedures are completed.  
End of study will be either on completion of at least 46 months from FPFV or when 80% of OS 
events have been reached, whichever occurs first. All randomized and/or treated patients should 
have a safety follow-up visit conducted 30 days after EOT visit. The information collected is 
kept as source documentation. All SAEs reported during this time period must be reported as 
described in Section 10.1.3. Documentation of attempts to contact the patient should be 
recorded in the source documentation. 
The primary analysis will occur when approximately the required 110 of PFS events is reached. 
After the primary analysis of PFS, the study will remain open provided the PFS demonstrates 
treatment benefit. Patients still being followed on the study after the primary analysis time point 
will continue as per the schedule of assessments. The study will end once the final OS analysis 
is performed approximately after 46 months from FPFV or when the 80% patient dies 
(whichever comes first). If the primary analysis of PFS does not demonstrate treatment benefit, 
the follow-up for OS will end. 
On EOT, patients should be scheduled for an EOT visit within 15 days following the date study 
treatment is permanently discontinued, at which time all of the assessments listed for the EOT 


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visit will be performed. For details of assessments, refer to Table 8-1. If the decision to 
discontinue the patient occurs at a regularly scheduled visit, that visit may become the EOT 
visit rather than having the patient return for an additional visit. An End of treatment disposition 
eCRF page should be completed, giving the date and reason for stopping the study treatment.  
If a withdrawal occurs, or if the patient fails to return for visits, the investigator must determine 
the primary reason for a patient’s premature withdrawal from the study and record this 
information on the EOT eCRF page. The EOT visit is not considered the end of the study. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations up to 45 days (within 15 days 
after the last dose and 30 days after the EOT visit) following the last dose of study treatment. 
The Investigator must contact the IRT to register the patient’s discontinuation. 
Patients continuing to derive benefit from study treatment at the end of the study in the opinion 
of the investigator may be transferred to a PTA following the local country Health Authority 
regulation(s) and patient’s consent, if ribociclib is either not commercially available or not 
reimbursed to the patients in the country by the time the study is completed. If at the end of the 
study, patients continuing to derive benefit from comparator treatment in the opinion of the 
investigator will transition onto the commercial available product(s), which should be 
accessible via their healthcare provider in the respective countries. If the comparator treatment 
is commercially available but not reimbursed, an alternative option may be discussed between 
the investigator and Novartis team. 
10 
Safety monitoring and reporting  
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.3): 


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1. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for 
an adverse event, the severity of mild, moderate, severe, and life-threatening, 
corresponding to Grades 1 – 4, will be used. CTCAE Grade 5 (death) will not be used in 
this study but is collected as seriousness criteria; rather, information about deaths will be 
collected though a Death form. 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient. 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a SAE (see Section 10.1.3 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy). 
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown). 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
• its outcome i.e., its recovery status or whether it was fatal 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for 30 days following the last dose of study 
treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 


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visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. Novartis must be provided with a copy of the certification and a 
tabulation of the normal ranges and units for this laboratory as well. The investigator is 
responsible for reviewing all laboratory reports for patients in the study and evaluating any 
abnormalities for clinical significance. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should 
be followed until they have returned to normal or an adequate explanation of the abnormality 
is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a serious adverse event unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 
If any information for the patient harboring infection related to pandemic or epidemic (e.g. 
COVID-19) becomes known to investigator or his/her team through patient/care-giver, it should 
be informed to Novartis team. If a patient is confirmed positive for pandemic and/or epidemic 
infection, it should be recorded as an adverse event. Any events associated with it should be 
recorded/reported either as non-serious AE or SAE based on the seriousness criteria of the event. 


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10.1.2 
Adverse events of special interest 
Adverse events of special interest 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.  
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. Adverse events of special interest are discussed in detail in the IB. 
10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the patient has stopped study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Recurrent episodes, complications, or progression of the initial SAE must 
be reported as follow-up to the original episode within 24 hours of the investigator receiving 
the follow-up information. 
Screen failures: 
As patient is considered screen failure who is screened but is not treated or randomized SAEs 
occurring after the patient has provided informed consent until the time the patient is deemed a 
Screen Failure must be reported to Novartis. 
Randomized or treated patients: 
SAEs collected between time patient signs ICF until 30 days after the patient has discontinued 
or stopped study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification to inform all investigators 
involved in any study with the same study treatment 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 EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment. 


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10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to one year after the baby was due to be born 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 Novartis Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
10.1.5 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe. 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• note that hospitalizations for the following reasons should not be reported as serious 
adverse events :  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 


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emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.6 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring  
Not applicable 
10.2.1 
Data Monitoring Committee  
Not applicable 


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10.2.2 
Steering Committee  
The steering committee will be established comprising investigators, Novartis personnel 
participating in the trial and one patient, who is not participating in this trial. 
The steering committee will ensure transparent management of the study according to the 
protocol through recommending and approving modifications as circumstances require. The 
steering committee will review protocol amendments as appropriate. Together with the clinical 
trial team, the steering committee will also develop recommendations for publications of study 
results including authorship rules. The details of the role of the steering committee will be 
defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the assessment 
schedule and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Designated investigator staff will enter the data required by the protocol into the 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, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 


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Randomization codes and data about study treatment (ribociclib only) dispensed to the patient 
will be tracked using an IRT. The system will be supplied by a vendor, who will also manage 
the database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis to be accessed by 
programmer and statistician. Any changes to the database after that time can only be made after 
written agreement by Novartis- development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
/delegated CRO representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and 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. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/delegated CRO/CRA organization. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
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 on CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
12 
Data analysis and statistical methods 
It is planned that the data from all centers participating in the trial will be combined, so that an 
adequate number of patients are available for analysis. Novartis and/or a designated CRO will 
perform all analyses.  
Any data analysis carried out independently by any investigator should be submitted to Novartis 
before publication or presentation.  


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12.1 
Analysis sets 
12.1.1 
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 (ITT) principle, patients will be analyzed 
according to the treatment they have been assigned to during the randomization procedure. FAS 
will be the primary population for all efficacy analyses.  
12.1.2 
Safety Set 
The Safety Set (SS) includes all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized treatment was never received. 
12.1.3 
Per-protocol Set 
The Per-Protocol Set (PPS) is a subset of patients of the FAS who are compliant with 
requirements of the protocol. All protocol deviations or conditions leading to exclusion from 
the PPS will be detailed in the data handling plan and analysis plan. Sensitivity analyses of the 
primary endpoint may be performed using data from the PPS if the FAS and PPS differ and if 
the primary analysis is significant. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.  
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles (if appropriate), minimum, and maximum will be presented. 
The actual dose and duration of NSAI, goserelin, ribociclib and combination chemotherapy, as 
well as dose intensity (computed as the ratio of the dose intensity to planned dose received/ 
planned duration), will be listed and summarized using descriptive statistics. The total daily 
doses of NSAI, goserelin, ribociclib and combination chemotherapy for each patient will be 
summarized using descriptive statistics. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, for each treatment group.  


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Compliance to the study drug will be assessed by the number of dose reductions and dose 
interruptions. The duration of exposure will also be presented for the study treatment by arm.  
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data 
will be listed. 
12.4 
Analysis of the primary endpoint 
PFS will be summarized using Kaplan-Meier estimates. Median PFS with 95% confidence 
intervals will be provided by treatment group. Stratified Cox regression will be used to estimate 
the hazard ratio (HR) of PFS, along with 95% confidence intervals. 
12.4.1 
Definition of primary endpoint 
The primary endpoint of the study is PFS, defined as the time from the date of randomization 
to the date of the first documented progression or death due to any cause. PFS will be assessed 
via local review according to RECIST 1.1 (see Appendix 2 for further details).  
12.4.2 
Statistical model, hypothesis, and method of analysis  
Assuming proportional hazards for PFS, the following statistical hypotheses will be tested to 
address the primary efficacy objective:  
H01: 𝜃𝜃1  ≥1 𝑣𝑣𝑣𝑣. H𝐴𝐴1: 𝜃𝜃1  < 1 
where 𝜃𝜃1 is the PFS hazard ratio (ribociclib + NSAI + goserelin arm versus combination 
chemotherapy arm). The primary efficacy analysis to test these hypotheses and compare the 
two treatment groups will consist of a stratified log-rank test at an overall one-sided 10% level 
of significance. 
The primary efficacy variable, PFS, will be analyzed once 110 PFS events are observed. The 
PFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment 
group. The hazard ratio for PFS will be calculated, along with its 95% confidence interval, from 
a stratified Cox model. 
12.4.3 
Handling of missing values/censoring/discontinuations 
In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment 
if no PFS event is observed prior to the analysis cut-off date. 
If a PFS event is observed after two or more missing or non-adequate tumor assessments, then 
PFS will be censored at the last adequate tumor assessment before the PFS event. If a PFS event 
is observed after a single missing or non-adequate tumor assessment, the actual date of event 
will be used (see RECIST 1.1 in Appendix 2). PFS will be censored at the date of the last 
adequate tumor assessment before the start of new anticancer therapy if no PFS event is 
observed prior to and after the start of new antineoplastic therapy. 


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12.4.4 
Sensitivity and Supportive analyses 
As a sensitivity analysis, the distribution of PFS will be compared between the treatment groups 
using an un-stratified log-rank test and the hazard ratio along with the associated 95% 
confidence interval resulting from an un-stratified Cox model will be presented. 
Sensitivity analyses of the primary endpoint may be performed using data from the PPS if the 
FAS and PPS differ and if the primary analysis is significant. Other sensitivity analyses may be 
performed such as (1) including PFS events even if the events are recorded after two or more 
missed assessments, (2) backdating events occurring after missing tumor assessments. Patterns 
of censored data will be examined by the treatment groups using descriptive statistics (the 
numbers of censored patients and reasons for censoring) (3) including PFS events documented 
after initiation of new anti-neoplastic therapy and (4) using the primary analysis source on the 
FAS and considering treatment discontinuation due to ‘Disease Progression’ without 
documented progression as event. Sensitivity analyses considering COVID-19 impact will be 
included in the SAP. 
12.5 
Analysis of secondary endpoints 
The secondary objectives in this study are to compare the two treatment groups with respect to 
OS, to evaluate the ORR, CBR, TTR, TTF, 3-month TFR, safety and PROs for health related 
QoL. 
12.5.1 
Efficacy endpoints 
Overall survival (OS) is defined as the time from date of randomization to date of death due to 
any cause. If a patient is not known to have died, then OS will be censored at the latest date the 
patient was known to be alive. 
OS will be analyzed in the FAS population according to the randomized treatment group 
assigned at randomization. The OS distribution will be estimated using the Kaplan-Meier 
method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for OS will be calculated, along 
with its 95% confidence interval, using a stratified Cox model. 
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
(BOR) of CR or PR, as per local review and according to RECIST 1.1 (see Appendix 2 for 
details).  
ORR will be calculated based on the FAS population. ORR and its 95% confidence interval 
will be presented by treatment group. The Cochrane-Mantel-Haenszel chi-square test, stratified 
by the randomization stratification factor, will be used to compare ORR between the two 
treatment groups, at the one-sided 5% level of significance. 
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of CR, or PR or 
an overall response of SD, lasting for a duration of at least 24 weeks. CR, PR and SD are defined 
as per local review according to RECIST 1.1 (see Appendix 2 for details). 
CBR will be calculated based on the FAS and according to the intent-to-treat (ITT) principle. 
CBR and its 95% confidence interval will be presented by treatment group. The Cochrane-
Mantel-Haenszel chi-square test, stratified by the randomization stratification factor, will be 


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used to compare CBR between the two treatment groups, at the one-sided 5% level of 
significance. 
Time to Response (TTR) is defined as the time from the date of randomization to the first 
documented response of either CR or PR, which must be subsequently confirmed (although 
date of initial response is used, not date of confirmation). CR and PR are based on tumor 
response data as per local review and according to RECIST 1.1 (see Appendix 2 for details). 
All patients in the FAS will be included in TTR calculations. Patients without a confirmed CR 
or PR will be censored at the study-maximum follow-up time (i.e., LPLV-FPFV) for patients 
with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last 
adequate tumor assessment for patients without a PFS event. TTR will be listed and summarized 
by treatment group. Distribution of time to response will be estimated using Kaplan-Meier 
method if sufficient number of responses are recorded. 
Time to treatment failure (TTF) is defined as the time from the date of randomization to the 
earliest of date of progression (as per local review and according to RECIST 1.1), date of death 
due to any cause, change to other anti-cancer therapy, or date of discontinuation due to reasons 
other than protocol violation or administrative problems. All patients in the FAS will be 
included in TTF calculations. TTF will be listed and summarized by treatment group. 
Treatment failure rate (TFR) is defined as the proportion of patients who discontinued the study 
treatment due to death of any cause, progressive disease (as per local review and according to 
RECIST 1.1), change to other anti-cancer therapy, or change of treatment. All patients in the 
FAS will be included in 3-month TFR. 3-month TFR will be summarized by treatment group. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
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, which started or worsened during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment. 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
• on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
• post-treatment period: starting at Day 31 after last dose of study medication. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and patient. 


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The number (and proportion) of patients with AEs of special interest/related to identified and 
potential risks will be summarized by treatment. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the [Investigator’s Brochure].  
AESI include: Neutropenia including febrile neutropenia, QT prolongation, and hepatobiliary 
AEs. 
A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class. 
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of AE, relation to study treatment. 
Serious AEs, non-serious AEs and adverse events of special interest (AESI) during the on-
treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious AEs (including those from the pre and post-treatment periods) will 
be listed and those collected during the pre-treatment and post-treatment period will be flagged. 
Vital signs 
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 
12-lead ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each patient 
during the study. ECG data will be read and interpreted (locally).  
Categorical Analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced (by treatment group). 
All ECG data will be listed by treatment group, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. Shift tables using the low/normal/high/ (low and high) classification will be used 
to compare baseline to the worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version available at the time of analysis. 


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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 available at the time of analysis, 
results will be categorized as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
available at the time of analysis grades if applicable and the classifications relative to the 
laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE available at the time of analysis. 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE grades available at the time of analysis to compare baseline to 
the worst on-treatment value. 
• For laboratory tests where grades are not defined by CTCAE available at the time of analysis 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
12.5.3 
Patient reported outcomes 
 FACT-B questionnaire will be used to collect patient reported outcome data in this trial. Scores 
will be added to create subscale and overall scores.  
The FAS will be used for analyzing PRO data. Descriptive statistics will be used to summarize 
the subscale and overall scores at each scheduled assessment time point. Additionally, change 
from baseline at the time of each assessment will be summarized. Patients with an evaluable 
baseline score and at least one evaluable post baseline score during the treatment period will be 
included in the change from baseline analyses. Time to deterioration in the PRO scales will be 
performed and compared between the two treatment arms. 
 
 


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12.7 
Interim analyses 
No interim analysis is planned. 
12.8 
Sample size calculation 
The sample size calculation is based on the primary analysis of PFS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4.2. 
Based on available data, the median PFS in the control arm is expected to be approximately 
12 months. It is expected that treatment with ribociclib arm will result in a 33% reduction in the 
hazard rate for PFS, i.e., an expected hazard ratio of 0.667 (which corresponds to an increase in 
median PFS to 18 months under the exponential model assumption). 


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Then in order to ensure 80% power to test the null hypothesis: PFS hazard ratio = 1, versus the 
specific alternative hypothesis: PFS hazard ratio = 0.667, it is calculated that a total of 110 PFS 
events need to be observed. This calculation assumes analysis by a one-sided log-rank test at 
the overall 10% level of significance, patients randomized to the two treatment arms in a 1:1 
ratio. Considering that enrolment will continue for about 30 months, 3 patients for 0-6 months, 
10 patients for 7 -17 months and 6 patients thereafter, a total of 200 patients will be needed to 
observe the targeted 110 PFS events at about 4 months after the randomization date of the last 
patient. Assuming 10% drop-out, a total of 222 patients will be needed. The sample size of 
222 patients will be randomly assigned to each treatment arm in a 1:1 ratio (111 patients in the 
experimental arm, 111 patients in the control arm). These calculations were made using the 
software package East 6.4. 
13 
Ethical considerations and administrative procedures  
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, patient 
recruitment procedures (e.g., advertisements) and any other written information to be provided 
to patients. 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 Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 


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transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient 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 CRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the CRFs and all other required reports. Data reported on the CRF, that are 
derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. For electronic CRFs an audit trail will be maintained by the 
system. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
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. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (i.e., LPLV) and finalization of the 
study report the results of this trial will be submitted for publication and posted in a publicly 
accessible database of clinical trial results, such as the Novartis clinical trial results website and 
all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 


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


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15 
References 
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16 
Appendices  
16.1 
Appendix 1 – Concomitant medication 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or ribociclib. 
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on Novartis PK Sciences Memorandum, Drug-Drug Interaction and Co-Medication 
Considerations for Novartis Clinical Trials (, release date: Jan 2018), which was compiled from 
the 
Indiana 
University 
School 
of 
Medicine’s 
P450 
Drug 
Interaction 
Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm292362.pdf), and the University of Washington’s Drug Interaction Database 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(www.qtdrugs.org/). Please contact the medical monitor with any questions. 
The following medications (Table 16-1) are prohibited during combined ribociclib, NSAI, and 
goserelin treatment in this study. 
Table 16-1 
List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 
inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit 
juice, idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, voriconazole 
Strong CYP3A4/5 inducers 
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)2,3 
CYP3A4/5 substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, lomitapide5, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, simvastatin, sirolimus, 
tacrolimus 


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Category 
Drug Name 
Medications with a known 
risk for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
bepridil chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, 
cisapride, citalopram, clarithromycin, disopyramide, dofetilide, 
domperidone, donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacin, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, levomethadyl, mesoridazine methadone, moxifloxacin, 
ondansetron, oxaliplatin, papaverine HCl (intra-coronary), pentamidine, 
pimozide, probucol, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, terlipressin, 
terodiline, terfenadine, thioridazine, vandetanib 
Herbal preparations/ 
medications or dietary 
supplements 
Herbal preparations/medications known as strong inducers or inhibitors 
of CYP3A4/5 or those with a known risk of QT prolongation are 
prohibited throughout the study. These include, but are not limited to: St. 
John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, 
and ginseng. Patients should stop using these herbal medications or 
dietary supplements 7 days prior to first dose of study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on 
the study. Anticancer therapy (chemotherapy, hormonal therapy, 
including but not limited to all SERMS [including raloxifene], biologic or 
radiation therapy [except for palliative radiotherapy as outlined in the 
protocol], and surgery) other than the study treatments must not be 
given while the patient is on the study medication. If such agents are 
required, then the patient must discontinue the study drug. 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes) or drugs which have <2-fold difference in the minimum toxic concentrations and 
minimum effective concentrations in the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of December 2019.Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list.  
5 Drug has warning for risk of hepatotoxicity. As far as possible, avoid co-administration of QT 
prolonging drugs or any other drugs with the potential to increase the risk of drug-related QT 
prolongation (e.g., via a potential DDI that increases the exposure of ribociclib or the exposure of the 
QT prolonging drug). A definitive list of drugs with a known risk, possible risk, or conditional risk of QT 
prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana University 
“Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction Database, and FDA 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
The following medications (Table 16-2) should be used with caution during combined 
ribociclib, NSAI, and goserelin treatment in this study. 


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Table 16-2 
List of medications to be used with caution during study drug 
treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, Amprenavir, asafoetida resin (Ferula asafoetida), 
cimetidine, crizotinib, diltiazem, faldaprevir, imatinib, isavuconazole, 
netupitant, nilotinib, tofisopam, Schisandra sphenanthera (nan wu wei 
zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein, lopinavir5, 
modafinil, nafcillin, telotristat. 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine, apixaban, aprepitant, atorvastatin, avanafil, 
bosutinib, brotizolam, budesonide, buspirone, cannabinoids6, 
cannabidiol6,, cobimetinib, darifenacin, dasatininb, ebastine, eletriptan, 
eplerenone, everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, 
isavuconazole, ivabradine, ivacaftor, , lumefantrine, lurasidone, 
maraviroc, midazolam, midostaurin, naloxegol, neratinib, perospirone, 
quetiapine, ridaforolimus, rivaroxaban, sildenafil, simeprevir, ticagrelor, 
tilidine, tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, 
voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin, , bromocriptine, candesartan, clobetasol, 
clofaziminie, , dabigatran, dipyridamole, glyburide, grazoprevir, 
ledipasvir, mifepristone, pioglitazone, reserpine, rifamycin, simeprevir, 
telmisartan, timcodar, troglitazone, velpatasvir 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , 
asenapine, atazanavir, atomoxetine, bedaquiline, bendamustine, 
bortezomib, bosutinib, buprenorphine, cabozantinib, capecitabine, 
ceritinib, clomipramine, crizotinib, clozapine, cyamemazine 
(cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, 
epirubicin, eribulin mesylate, ezogabine (retigabine), famotidine, 
felbamate, fingolimod, flupentixol, gemifloxacin, granisetron, 
hydrocodone-ER, iloperidone, imipramine (melipramine), isradipine, 
ketanserin, lapatinib, lenvatinib, leuprolide, loperamide, lithium, 
melperone, midostaurin, mifepristone, mirabegron, mirtazapine, 
moexipril/HCTZ, necitumumab, nilotinib, norfloxacin, nusinersen, 
nortriptyline, ofloxacin, olanzapine, osimertinib, oxytocin, paliperidone, 
palonosetron, panabinostat, pasireotide, pazopanib, perflutren lipid 
microspheres, perphenazine, pilsicainide, pimavanserin, pipamperone, 
promethazine, prothipendyl, quetiapine, ranolazine, rilpivirine, 
risperidone, romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, 
telavancin, tetrabenazine, tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene, trimipramine, tropisetron, vardenafil, vemurafenib, 
venlafaxine, vorinostat, ziprasidone 
MATE1/2 substrates3  
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, 
glycopyrronium, metformin, pindolol, plisicainide, ranitidine, topotecan, 
varenicline  
OCT1/2 substrates4 
Amantadine, carboplatin, cisplatin, cephalexin, cephradine, 
ipratropium, lamivudine, linagliptin, metformin, oxaliplatin, oxybutynin, 
phenformin, picoplatin, pilsicainide, pindolol, ranitidine, sorafenib,  
tropisetron, trospium, umeclidinium, and zidovudine 


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


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16.2 
Appendix 2: Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1) 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.2: 11-Feb-2016 
Version 3.1: 29-Nov-2011 
Version 3:0: 19-Oct-2009 
Version 2:0: 18-Jan-2007 
Version 1:0: 13-Dec-2002 
Release date: 
11-Feb-2016 
Authors (Version 3.2): 
 
 
 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 
16.2.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 16.2.2 and the definition of best response in 
Section 16.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 16.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.4 of this 
guideline describes data handling and programming rules. This section is to be referred to in 
the Reporting and Analysis Plan (RAP) to provide further details needed for programming. 
16.2.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 


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16.2.3 
 
Definitions 
16.2.3.1 Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 16.3.2.9. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 
• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
16.2.3.2 Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 


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recommended that patients be excluded from trials where the main focus is on the ORR. 
Guidance on how patients with just non-measurable disease at baseline will be evaluated for 
response and also handled in the statistical analyses is given in Section 16.3.2.9. 
16.2.4 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow-up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• 
If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up assessments 
by CT will be needed to determine if there is truly progression occurring at that site. In all cases 
PD will be the date of confirmation of new disease by CT (or some other conventional technique 
such as MRI) rather than the date of the positive PET scan. If there is a positive PET scan 
without any confirmed progression at that site by CT, then a PD cannot be assigned. 


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• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.  
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, Lactate Dehydrogenase (LDH) and Beta-hCG for 
testicular cancer) can be integrated as non-target disease. If markers are initially above the 
upper normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and SD (an effusion may be a side effect of the 
treatment) or PD (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
16.2.5 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 


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lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.2.3.1. 
• Nodal target: See Section 16.2.3.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on Electronic Case Report Form (eCRF). 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
16.2.6 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-3) and non-target lesions (Table 16-4) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-5) as well as the presence or absence of new lesions. 
16.2.6.1 Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
16.2.6.1.1 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are patient to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 


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If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
16.2.6.1.2 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
16.2.6.2 Determination of target lesion response 
Table 16-3 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes 
on target lesion response and methodology change in Section 16.2.4.) 


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Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as PD 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-3 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 


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diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an stable disease (SD) target lesion response; 
however, this should be done with caution and conservatively as the response categories 
have well defined criteria. 
16.2.6.3 Determination of non-target lesion response 
Table 16-4 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2. 
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, PR 
or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer does 
prevail  
2 . It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details) 
Notes on non-target lesion response 
• The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 


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equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned. 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK) 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 16.2.6.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
16.2.6.4 New lesions 
The appearance of a new lesion is always associated with PD and has to be recorded as a new 
lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.2.7). 
A lymph node is considered as a “new lesion” and, therefore, indicative of PD if the short 
axis increases in size to ≥ 10 mm for the first time in the study plus 5 mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.2.4. 


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16.2.7 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 16-5. 
Table 16-5 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 16.2.6. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
16.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.3.2.9 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
16.3.1 
Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 


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withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• -For non-randomized trials where response is the primary endpoint, confirmation is 
needed. 
• -For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 
6 week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of ± 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment. 
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 


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at the next assessment (but not ≥20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.  
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 


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Early progression rate (EPR) is the proportion of patients with PD within 8 weeks of the start 
of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach). 
16.3.2 
Time to event variables 
The protocol should state which of the following variables is used in that study. 
16.3.2.1 Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, PFS is censored at the date of last adequate tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.  
16.3.2.2 Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
16.3.2.3 Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 


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a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
16.3.2.4 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
16.3.2.5 PFS2 
A recent EMA guidance (EMA, 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of re-sensitizing agents and 
where it is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments 
16.3.2.6 Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter DoR but where 
this probably primarily reflected selection bias which is explained as follows: It is postulated 
that there are two groups of patients: a good risk group and a poor risk group. Good risk patients 
tend to get into response readily (and relatively quickly) and tend to remain in response after 
they have a response. Poor risk patients tend to be difficult to achieve a response, may have a 
longer time to respond, and tend to relapse quickly when they do respond. Potent agents induce 
a response in both good risk and poor risk patients. Less potent agents induce a response mainly 
in good risk patients only. This is described in more detail by Morgan (1988) 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 


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responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if DoR is 
to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
16.3.2.7 Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the ORRs, since the same kind of selection bias may be introduced as 
described for DoR in Section 16.3.2.6. It is recommended that an analysis of all patients (both 
responders and non-responders) be performed whether or not a “responders only” descriptive 
analysis is presented. Where an inferential statistical comparison is required, then all patients 
should definitely be included in the analysis to ensure the statistical test is valid. For analysis 
including all patients, patients who did not achieve a response (which may have to be a 
confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 


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Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.3.2.8 Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start dates 
For all “time to event” variables, other than DoR, the randomization/ date of treatment start will 
be used as the start date. 
For the calculation of DoR the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.3.2.9). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 


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• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.3.2.9 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 16-6. 
Table 16-6 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 16.2.6. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 


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and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
16.3.2.10 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 16.3.2.8, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered: 


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Table 16-7 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in 
the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next scheduled 
assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or more 
missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim 
(1) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
As per above 
situations 
Progressed 
F 
New anticancer therapy given 
(1) Ignore the new anticancer therapy and 
follow situations above (ITT approach)  
(2) Date of last adequate assessment prior to 
new anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) Date of secondary anti-cancer therapy 
As per above 
situations 
Censored 
Censored 
Event 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP and 
duration of 
response) 
1.=Definitions can be found in Section 16.3.2.8 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 16.3.2.8. 
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 


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should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.  
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-7 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 


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16.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
16.4.1 
Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.4.2 
End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 15 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Patient/guardian decision 
• Death 
• Progressive disease 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
Treatment duration completed as per protocol (optional, to be used if only a fixed number of 
cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial.  
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation: 


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• Adjustments to study treatment due to toxicity that result in discontinuation. Please refer 
to Section 6.5.1 (for ribociclib treatment arm) and Section 6.5.3 (for combination 
chemotherapies arm). 
• Use of prohibited medication. Please refer to Section 6.2.2. 
16.4.3 
End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Patient/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.4.4 
Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 


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Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.4.5 
Programming rules 
The following should be used for programming of efficacy results: 
16.4.5.1 Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.4.5.2 Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.3.2.8). If all measurement dates have no 
day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.4.5.3 Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.4.5.4 Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.4.5.5 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.4.5.6 Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 


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• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 16-7) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 16.3.2.8. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
16.5 
References (available upon request) 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47. 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465. 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man. 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.  


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Zee DS (2001) application of a new multinomial phase II stopping rule using response and 
early progression, J Clin Oncol; 19: 785-791. 


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16.6 
Appendix 3 – Patient Reported Outcomes FACT-B 
 
 


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16.7 
Appendix 4 -Bone Marrow Reserve in Adults 
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol. 5, 255-258, 1961 
MARROW DISTRIBUTION OF THE ADULT 
SITE 
MARROW 
wt. (g) 
FRACTION 
RED MARROW 
AGE 40 
RED MARROW 
wt. (g) 
AGE 40 
% TOTAL RED 
MARROW 
CRANIUM AND 
MANDIBLE 
Head: 
Cranium 
Mandible 
165.8 
16.4 
0.75 
0.75 
136.6 
124.3 
12.3 
13.1 
13.1 
HUMERI, 
SCAPULAE, 
CLAVICLES 
Upper Limb Girdle : 
2 Humerus, head & 
neck 
2 Scapulae 
2 Clavicles 
26.5 
67.4 
21.6 
0.75 
0.75 
0.75 
86.7 
20.0 
50.5 
16.2 
8.3 
8.3 
STERNUM AND 
RIBS 
Sternum 
Ribs: 
1 pair 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
39.0 
10.2 
12.6 
16.0 
18.6 
23.8 
23.6 
25.0 
24.0 
21.2 
16.0 
11.2 
4.6 
0.6 
All 0.4 
23.4 
82.6 
4.1 
5.0 
6.4 
7.4 
9.5 
9.4 
10.0 
9.6 
8.5 
6.4 
4.5 
1.8 
2.3 
7.9 
10.2 
PELVIC BONES Sacrum 
2 os coxae 
194.0 
310.6 
0.75 
0.75 
145.6 
233.0 
13.9 
22.3 
36.2 
FEMUR 
2 Femoral head 
and neck 
53.0 
0.75 
40.0 
3.8 
 
 

SAP_001.pdf: 
Clinical Development 
LEE011/Ribociclib/Kisqali® 
CLEE011A3201C (RIGHT CHOICE) / NCT03839823
A phase II randomized study of the combination of 
Ribociclib plus Goserelin acetate with Hormonal Therapy 
versus physician choice chemotherapy in premenopausal 
or perimenopausal patients with hormone receptor-
positive/HER2-negative inoperable locally advanced or 
metastatic breast cancer – RIGHT Choice Study 
Statistical Analysis Plan (SAP) 
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
23-Jun-2022
Number of pages: 
49 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
26-
Feb-
2019 
Prior 
to 
FPFV 
Creation of 
final 
version 
N/A - First version 
NA 
28-
Jan-
2021 
After 
Protocol 
amendment 
1 
Creation of 
amendment 
Secondary objectives updated and 
included 
comparing 
3-month 
treatment failure rate between two 
arms.
 
 
Definition of last date of exposure 
was updated. 
Dose calculation was updated and 
clarified. 
Censoring for new anti cancer 
therapy before PFS events was 
updated and clarified. 
Section 1.1 
 
 
 
 
Section 2.1.1 
 
Section 2.4.1 
 
Section 2.5.1 
 
 
 
Definitions and method of analysis 
were updated to include 3-month 
treatment failure rate as secondary 
endpoint. 
Section 2.7 
 
 
 
PRO analysis updated. 
Section 2.10 
18-
Feb-
2022 
After 
protocol 
amendment 
2 
Creation of 
amendment 
Study 
design 
description 
were 
updated to align with protocol 
amendment. 
Interim analysis was removed as per 
protocol amendment.  
Last contact date data sources 
updated in Table 2-5 
Exclusion criteria for PPS was 
udpated. 
Last date of exposure definition 
updated 
for 
chemotherapy. 
Leuprorelin was added in definition. 
Section 1.1 
 
Section 
1.1, 
2.1, 2.13 
Section 2.1.1 
 
Section 2.2 
 
Section 
2.1, 
2.4 
 


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CLEE011A3201C 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
DFI defitinition was updated for 
clarifications and calculations based 
on CRF. 
Protocol deviation related to COVID-
19 pandemic were added. 
Significance 
level 
and 
required 
number of events were updated in 
primary anlaysis. Sensitivity anlaysis 
considering COVID-19 impact was 
added. 
Study 
follow-up 
summary 
was 
added. 
Notable ECG list was updated. 
PRO analysis was updated for 
clarification. Time to deteriation 
anlaysis was added. 
Sample size calcuation updated with 
significance 
level 
and 
required 
number of events. 
Section 2.3 
 
 
Section 2.5 
 
 
 
Section 2.7 
 
Section 2.8  
Section 2.10 
 
 
Section 2.13 
23-
Jun-
2022 
Prior 
to 
DBL 
Creation of 
amendment 
Time 
window 
for 
multiple 
assessments was updated. 
Section 2.1 
 
 
 
Withdraw of informed consent was 
updated. 
Section 2.2 
 
 
 
Subgroup of interes was updated. 
Section 2.2.1 
 
 
 
ORR and CBR definitions were 
updated to clarify confirmed and 
unconfirmed responses. 
Section 2.7.1 
 
 
 
Gap time calculation was added. 
Section 2.7.2 
 
 
 
Sodium and Phosphorus will be 
excluded 
from 
laboratory 
data 
summary due to protocol amendment 
and CRF updates. 
Section 2.8.3 
 
 
 
Baseline for PRO was updated. 
Section 2.10 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 6 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 18 
2.2.1 
Subgroup of interest .............................................................................. 19 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 21 
2.3.1 
Patient disposition ................................................................................. 22 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 23 
2.4.1 
Study treatment / compliance ................................................................ 23 
2.4.2 
Prior, concomitant and post therapies ................................................... 27 
2.5 
Analysis of the primary objective .......................................................................... 28 
2.5.1 
Primary endpoint ................................................................................... 28 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 29 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 29 
2.5.4 
Supportive analyses ............................................................................... 30 
2.6 
Analysis of the key secondary objective ............................................................... 32 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 33 
2.7.1 
Secondary endpoints ............................................................................. 33 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 34 
2.8 
Safety analyses....................................................................................................... 36 
2.8.1 
Adverse events (AEs) ............................................................................ 36 
2.8.2 
Deaths .................................................................................................... 37 
2.8.3 
Laboratory data ..................................................................................... 37 
2.8.4 
Other safety data ................................................................................... 39 
2.9 
Pharmacokinetic endpoints .................................................................................... 40 
2.10 
Patient-reported outcomes ..................................................................................... 40 
 
42 
 
 42 
2.13 
Interim analysis ...................................................................................................... 42 
3 
Sample size calculation ..................................................................................................... 42 


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3.1 
Primary analysis .................................................................................................... 42 
3.2 
Power for analysis of key secondary variables ...................................................... 43 
4 
Change to protocol specified analyses .............................................................................. 43 
5 
Appendix ........................................................................................................................... 43 
5.1 
Imputation rules ..................................................................................................... 43 
5.1.1 
Study drug ............................................................................................. 43 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 44 
5.2 
AEs coding/grading ............................................................................................... 45 
5.3 
Laboratory parameters derivations ........................................................................ 46 
5.4 
Statistical models ................................................................................................... 47 
5.4.1 
Primary analysis .................................................................................... 47 
5.4.2 
Key secondary analysis ......................................................................... 48 
5.4.3 
Audit-based BIRC assessment of PFS .................................................. 48 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 48 
6 
Reference ........................................................................................................................... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of tables 
Table 1-1 
Study objectives and endpoints ............................................................. 10 
Table 2-1 
Time window for ECOG PS, ECG, vital signs and Laboratory 
assessments (LEE011 arm only) ........................................................... 15 
Table 2-2 
Time window for ECOG PS, ECG, vital signs and Laboratory 
assessments (Chemotherapy arm only) ................................................. 15 
Table 2-3 
Time window for PRO assessments (LEE011 arm only) ..................... 16 
Table 2-4 
Time window for PRO assessments (Chemotherapy arm only) ........... 16 
Table 2-5 
Last contact date data sources ............................................................... 17 
Table 2-6 
Subject classification based on protocol deviations and non-PD 
criteria ................................................................................................... 19 
Table 2-7 
Planned dose intensity ........................................................................... 25 
Table 2-8 
Outcome and event/censor dates for PFS analysis ................................ 30 
Table 2-9 
ECOG Performance Scale ..................................................................... 35 
Table 2-10 
Clinically notable changes in vital signs ............................................... 40 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 44 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 45 
 
 


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List of abbreviations 
 
AE 
Adverse event 
AESI 
Adverse event os special interest 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ALP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GPT 
ATC 
Anatomical Therapeutic Classification 
BOR 
Best Overall Response 
BMI 
Body Mass Index 
CBR 
Clinical Benefit Rate 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Dosage Administration eCRF pages 
DFS 
Disease Free Interval 
DI 
Dose Intensity 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
FACT-B 
Functional Assessment of Cancer Therapy - Breast 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
HER2 
Human Epidermal Growth Factor Receptors 
HLGTs 
High Level Group Terms 
HLT 
High Level Term 
HR+ 
Hormone Receptor Positive 
IA 
Interim Analysis 
IRT 
Interactive Response Technology 
IV 
Intravenous 
LPFV 
Last Patient First Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NMQ 
Novartis MedDRA queries 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PDI 
Planned Dose Intensity 
PFS 
Progression-Free Survival 


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PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
PS 
Performance Status 
PT 
Preferred Term 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TA 
Tumor Assessment 
TTF 
Time to Treatment Failure 
TTR 
Time to Response 
TTP 
Time to Progression 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes the detailed statistical methodology to be used for 
the Clinical Study Report (CSR) for the analysis of study CLEE011A3201C, a phase II 
randomized study of the combination of Ribociclib plus goserelin acetate with hormonal 
therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients 
with hormone receptor-positive/HER2-negative inoperable locally advanced or metastatic 
breast cancer.  
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
will be described in Tables Figures and Listings (TFL) shells and Programming Datasets 
Specifications (PDS) documents, respectively. 
The content of this SAP is based on protocol CLEE011A3201C version 02. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data. 
1.1 
Study design 
This is a randomized, phase II, open label, multi-center trial comparing the combination of 
NSAI (letrozole or anastrozole) + goserelin + ribociclib versus combination chemotherapy 
(either of docetaxel+capecitabine, paclitaxel+gemcitabine or capecitabine+vinorelbine). 
Premenopausal or perimenopausal women with HR+, HER2-negative, advanced breast cancer 
with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and fulfill at 
least one of the following criteria will be considered for this study: symptomatic visceral 
metastases, or rapid progression of disease or impending visceral compromise, or markedly 
symptomatic non-visceral disease. 
Approximately, 222 eligible women patients will be competitively enrolled and randomly 
assigned to one of the below treatment arms in 1:1 ratio: 
 Ribociclib arm: NSAI + goserelin + ribociclib (N = 111)  
 Combination chemotherapy arm: Either of docetaxel+capecitabine, 
paclitaxel+gemcitabine or capecitabine+vinorelbine based chemotherapy treatment (N = 
111). The choice of which chemotherapy combination will be used on study will be 
decided by the study investigator; once patients initiate the treatments, switching to 
another combination chemotherapies will not be allowed. 
Randomization will be stratified by the presence of liver metastases (present or absent), and 
Disease free interval (DFI) < 2 years (yes or no, de novo stage 4 is defined as DFI >2 years).  
Progression free survival (PFS) as assessed by local investigator review of tumor assessments 
and using RECIST 1.1 criteria is the primary endpoint in this study. Secondary efficacy 
endpoints include overall survival (OS), time to treatment failure (TTF), overall response rate 
(ORR), clinical benefit rate (CBR), time to response (TTR), and 3-month treatment failure rate. 
   
 


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Table 1-1 
Study objectives and endpoints 
Primary Objective:  
Primary Endpoint: 
 
To determine whether treatment with NSAI 
+ goserelin+ ribociclib prolongs PFS 
compared to treatment with combination 
chemotherapy in premenopausal or 
perimenopausal women with HR+, HER2 
negative locally advanced or metastatic 
breast cancer. 
 
Progression-free survival is defined as the time from 
the date of randomization to the date of the first 
documented progression as per local review and 
according to RECIST 1.1 or death due to any cause. 
Secondary Objectives:  
Secondary Endpoints:  
To compare time to treatment failure (TTF) 
between the two treatment arms. 
Time to treatment failure is defined as the time from 
the date of randomization to the earliest of date of 
progression, date of death due to any cause, change 
to other anti-cancer therapy, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or 
‘Administrative problems’. 
To compare 3-month treatment failure rate 
between two treatment arms 
Treatment failure rate is defined as the proportion of 
patients who discontinued the study treatment by 3 
months due to progression disease, death due to any 
cause, change to other anti-cancer therapy, or 
discontinuation due to reasons other than protocol 
violation or administrative problems. 
To determine whether treatment with NSAI 
+ goserelin + ribociclib increases overall 
response rate (ORR), clinical benefit rate 
(CBR), and Time to response (TTR) 
compared to treatment with combination 
chemotherapy. 
 
 
Overall response rate (ORR) is defined as the 
proportion of patients whose best overall 
response is either CR or PR, as per local review 
and according to RECIST 1.1. 
 
Clinical benefit rate is defined as the proportion of 
patients with a best overall response of complete 
response (CR), or partial response (PR) or stable 
disease, lasting for a duration of at least 24 
weeks, as defined by RECIST 1.1. 
 
Time to response is defined as the time from the 
date of randomization to the first documented 
response of either CR or PR, which must be 
subsequently confirmed, as defined by RECIST 
1.1. 
To compare the overall survival (OS) 
between two treatment arms. 
 
Overall survival is defined as the time from the date of 
randomization to the date of death due to any cause. 
To evaluate the safety of ribociclib in 
combination with NSAI and goserelin, and 
combination chemotherapies 
 
Frequency/severity of adverse events, lab 
abnormalities. 
To compare patient reported outcomes for 
health-related quality of life in the two 
treatment arms 
 
 
 
Change from baseline in the global health status/QOL 
scale score by using FACT-B questionnaires. 


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2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings. Analysis using RShiny apps might also be used as needed. 
Data included in the analysis 
There is one primary analysis planned for the primary efficacy endpoint and one final anlaysis 
planned for overall survival. An unique cut-off date will be established after the targeted 
number of events for the planned primary and final analyses has been documented. For each 
of the analyses, all statistical analyses will be performed using all data collected in the database 
up to the data cut-off date. All data with an assessment date or event start date (e.g. vital sign 
assessment date or start date of an adverse event) prior to or on the cut-off date will be 
included in the analysis. Any data collected beyond the cut-off date will not be included in the 
analysis and will not be used for any derivations. 
The analysis cut-off date for the primary analysis of study data will be established after 110 
targetted PFS events have been documented. All statistical analyses will be performed using 
all data collected in the database up to the data cutoff date. All data with an assessment date or 
event start date (e.g. vital sign assessment date or start date of an adverse event) prior to or on 
the cut-off date will be included in the analysis. Any data collected beyond the cut-off date 
will not be included in the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings. 
The analysis cutoff date for the final analysis of study data will be established at the end of the 
study (after 46 months from FPFV) or when OS events have been reached (80% of 222 patients 
have died), whichever occurs first. 
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.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 


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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 
Study (Investigational) drug  is defined as LEE011 (ribociclib).  
Study treatment is defined as LEE011 (ribociclib) + NSAI ( Letrozole, Anastrozole) + 
goserelin (or leuprorelin), and combination chemotherapy is defined as docetaxel+capecitabine, 
paclitaxel+gemcitabine or capecitabine+vinorelbine based chemotherapy 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) Electronic Case Report Form (eCRF). The date of first administration of study 
drug will also be referred as start of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on the 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 is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the Dosage Administration 
(e)CRF. (Example: if 1st dose of LEE011 is administered on 15-Mar-2019, and 1st dose of 
combination partner is administered on 12-Mar-2019, then the date of first administration of 
study treatment is on 12-Mar-2019).  
Date of last administration of study treatment  
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per Dose Administration (e)CRF. 
(Example: if the last LEE011 dose is administered on 24-Oct-2019, and the last dose of a 
combination partner is administered on 26-Oct-2019, then the date of last administration of 
study treatment is on 26-Oct-2019).  


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Last date of exposure to study drug/treatment  
The last date of exposure to study treatment is derived to be the latest date of the last date of 
exposure to ribociclib, letrozole, anastrozole,  goserelin (or leuprorelin), and chemotherapy drug 
(docetaxel, capecitabine, paclitaxel, gemcitabine, vinorelbine). The last date of exposure will 
be derived as follows:  
For ribociclib, letrozole, and anatrazole, the last date for exposure is defined as the date 
of last administration of the corresponding medication. 
For goserelin and leuprorelin, the last date of exposure is defined as the date of last 
administration of goserelin + 27 days. If a patient died or was lost to follow-up within date of 
last administration +27 days, then the last date of exposure is the date of death or last contact 
date, respectively. 
For docetaxel and paclitaxel (175mg/m2), the last date of exposure is defined as the date of last 
administration of the chemotherapy + 20 days. If a patient died or was lost to follow-up within 
date of last administration +20 days, then the last date of exposure is the date of death or last 
contact date, respectively. 
For capecitabine, the last date of exposure is defined as the date of last administration of the 
chemotherapy + 7 days. If a patient died or was lost to follow-up within date of last 
administration +7 days, then the last date of exposure is the date of death or last contact date, 
respectively. 
For gemcitabine, paclitaxel (80-90mg/m2), and vinorelbine, the last date of exposure is defined 
as the date of last administration of the chemotherapy + 13 days. If a patient died or was lost to 
follow-up within date of last administration +13 days, then the last date of exposure is the date 
of death or last contact date, respectively.  
The last date of exposure to study treatment is defined as the latest date among the last date of 
exposure to ribociclib, letrozole, anastrozole,  goserelin, and chemotherapy drugs (docetaxel, 
capecitabine, paclitaxel, gemcitabine, vinorelbine).  
If the derived last date of exposure to study drug/study treatment goes beyond the data cutoff 
date, it should be truncated to the date of data cutoff . 
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.  


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The reference start date for all other, non-safety assessments (i.e., tumor assessment, survival 
time, disease progression, tumor response, ECOG performance status, and patient reported 
outcomes (PRO)) is the date of randomization.  
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. 
‘Death’ is an efficacy endpoint (for OS), but it can also be included in the safety analysis.  For 
safety, the ‘study day’ will be calculated relative to start of study treatment, while for efficacy 
overall survival will be derived relative to randomization date.  
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 ECOG 
performance status. For RECIST-based endpoints (e.g. PFS, best overall response), a window 
of +/-7 days for the start of study treatment will be allowed, i.e. the baseline will be considered 
valid if it occurs within 7 days of the treatment start date.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘baseline’ assessment.  
In case time of assessment and time of treatment start is captured , the last available assessment 
before the treatment start date/time is used for baseline.   
For demographic and baseline summary (vital signs, ECG, etc.), the assessment on or prior to 
the date of randomization is taken as “baseline”. 
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:  
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 31 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 


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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).  
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. 
Windows for multiple assessments  
In order to summarize performance status (ECOG), PRO measures, laboratory, ECG, and vital 
signs collected over time (including unscheduled visits), the assessments will be time slotted. 
The following general rule will be applied in creating the assessment windows: If more than 
one assessment is done within the same time window, the assessment performed closest to the 
target date will be used. If 2 assessments within a time window are equidistant from the target 
date, then the earlier of the 2  assessments will be used. If multiple assessments on the same 
date then the worst case will be used. Data from all assessments (scheduled and unscheduled), 
including multiple assessments, will be listed. 
The following provides an example how to define the time windows for ECOG performance 
status (PS). 
Table 2-1 
Time window for ECOG PS, ECG, vital signs and Laboratory 
assessments (LEE011 arm only) 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
≤ Day 1 
Cycle 1 Day 15 
15 
Day 2 to day 21 
Cycle 2 Day 1 
29 
Day 22 to day 35 
Cycle 2 Day 15 
43 
Day 36 to day 49 
Cycle 3 Day 1 
57 
Day 50 to day 70 
Cycle k Day 1 (4≤k≤11) 
d=(k-1)*28+1 
Day d-14 to day d+13 
Cycle 12 Day 1 
309 
Day 295 to day 350 
Cycle 15 Day 1 
393 
Day 351 to day 434 
Cycle k Day 1 (k=18, 21,.....) 
d=(k-1)*28+1 
Day d-42 to day d+41 
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
Table 2-2 
Time window for ECOG PS, ECG, vital signs and Laboratory 
assessments (Chemotherapy arm only) 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
≤ Day 1 
Cycle 1 Day 15 
15 
Day 2 to day 18 
Cycle 2 Day 1 
22 
Day 19 to day 28 
Cycle 2 Day 15 
36 
Day 29 to day 39 
Cycle 3 Day 1 
43 
Day 40 to day 53 
Cycle k Day 1 (4≤k≤11) 
d=(k-1)*21+1 
Day d-10 to day d+10 
Cycle 12 Day 1 
232 
Day 222 to day 263 


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Assessment 
Target day of assessment 
Time Interval 
Cycle 15 Day 1 
295 
Day 264 to day 326 
Cycle k Day 1 (k=18, 21,.....) 
d=(k-1)*21+1 
Day d-31 to day d+31 
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
 
Time windows will be defined for descriptive summary of PRO data by visit and longitudinal 
data analysis. If more than one assessment is available in the same time window, the assessment 
closest to the planned date will be considered. If two assessments are obtained with the same 
time difference compared to the scheduled visit day, the assessment obtained prior to visit will 
be considered. Data obtained at the end of treatment will be classified as other assessment in 
the corresponding time window. Note that only data collected under treatment (i.e. while the 
patient is treated) will be included in the time to definitive deterioration or longitudinal model 
analysis. Post-treatment data will be summarized separately. The end of treatment assessment 
will be included if collected within 30 days of the last dose intake.   
Table 2-3 
Time window for PRO assessments (LEE011 arm only) 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
≤ Day 1 
Cycle 2 Day 15 
43 
Study days 2 – 64 
Cycle 4 Day 1 
85 
Study days 65 – 112 
Cycle 6 Day 1 
141 
Study days 113 – 168 
Cycle 8 Day 1 
197 
Study days 169 – 224 
Cycle 10 Day 1 
253 
Study days 225 – 280 
Cycle 12 Day 1 
309 
Study days 281 – 350 
Cycle 15 Day 1 
393 
Study days 351 – 434 
Cycle k Day 1 (k=18, 21, 24,....) 
d=(k-1)*28+1 
Day d-42 to day d+41  
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
30-day safety follow-up 
Post treatment study day 30 
Post treatment study day 27 
- 33 
Table 2-4 
Time window for PRO assessments (Chemotherapy arm only) 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
≤ Day 1 
Cycle 3 Day 1 
43 
Study days 2 – 64 
Cycle 5 Day 1 
85 
Study days 65 – 112 
Cycle 7 Day 15 
141 
Study days 113 – 168 
Cycle 10 Day 8 
197 
Study days 169 – 224 
Cycle 13 Day 1 
253 
Study days 225 – 280 
Cycle 15 Day 15 
309 
Study days 281 – 350 
Cycle 19 Day 15 
393 
Study days 351 – 434 
Cycle k Day xx (k=21, 24,....) 
d=(3k-1)*7+1 
Day d-42 to day d+41  


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Assessment 
Target day of assessment 
Time Interval 
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
30-day safety follow-up 
Post treatment study day 30 
Post treatment study day 27 
- 33 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 
 
Table 2-5 
Last contact date data sources  
Source data 
Conditions 
Date of Randomization  
 
No Condition 
Last contact date/last date patient was known to be 
alive from Survival Follow-up page  
Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic therapy 
Non-missing medication/procedure term. 
Start/End dates from drug administration record  
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
No condition. 
Tumor (RECIST) assessment date 
Evaluation is marked as ‘done’. 
Laboratory 
Sample collection marked as ‘done’.  
Vital signs date 
At least one non-missing parameter value 
Performance Status date 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
Concomitant medication date 
Non-missing medication 
Date of ECG assessment 
At least one non-missing parameter value 
Date of PRO assessment 
At least one non-missing parameter value 
Cardiac imaging date 
Non-missing LVEF or overall interpretation 
Start/End dates from antineoplastic therapy after 
study treatment 
Non-missing medication/procedure term 
Date of withdraw informed consent 
No condition 
 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date . The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 


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2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat (ITT) principle, subjects will be analyzed 
according to the treatment they have been assigned to during the randomization procedure 
regardless of whether or not treatment was administered. This population will be the primary 
population for all efficacy analyses.  
Per protocol set (PPS)  
 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. 
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set: 
 Patient is less than 18 or greater than or equal to 60 years old at the time of informed 
consent (INCL01a) 
 Patient did not provide informed consent (INCL01b) 
 Patient does not have histologically and/or cytologically confirmed diagnosis of ER 
and/or PR postitive breast cancer by local laboratory (INCL02a)  
 Patient does not have HER2 negative breast cancer defined as a negative in situ 
hybridization test or IHC status of 0, 1 or 2 (INCL03) 
 Allred (Estrogen receptor ) score should be greater than... or equal to 5 when ER 
status is positive and percentage is not provided by local laboratory testing 
(INCL04d) 
 Estrogen Receptor (ER) percentage should be greater than 10 when ER status is  
positive and Allred score is not provided by local laboratory testing (INCL04e) 
 Both Allred score and Estrogen receptor percentage present but Protocol inclusion 
criteria not met (INCL04f) 
 Patient does not have at least one measurable lesion as per RECIST 1.1 criteria 
(INCL06d)   
 Patient has received prior systemic anti-cancer therapy (including hormonal therapy 
and chemotherapy, or any CDK4/6 inhibitor for advanced breast cancer) (EXCL01) 
 Patient is post menopausal (EXCL05) 
 Patient is concurrently using hormone replacement therapy (EXCL14) 
 Patient was switched from one combination chemotherapy to another combination 
chemotherapy (TRT18)Patient on combination chemotherapy treatment, without 
disease progression and any related toxicity, switched to endocrine treatment 
(TRT19) 
 Patient received other investigational therapy, other antineoplastic therapy while on 
study drug (COMD05) 
 Patient received megestrol acetate while on study drug (COMD08) > 7 days 


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 Patient received medroxyprogesterone while on study drug (COMD09) > 7 days 
A sensitivity analysis of the primary endpoint (i.e., PFS) will be performed using PPS if the 
primary efficacy analysis is significant and the FAS and PPS differ. 
Safety 
The Safety set includes all subjects who received any study treatment (i.e. at least one dose of 
any component of the study treatment). 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 
2-6.  
Table 2-6 
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  
Per-protocol set 
Any major protocol deviation as 
listed in definition of per protocol 
set 
No dose of study treatment 
Withdraw of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a patient 
withdraws full consent is recorded in the eCRF.   
Analysis of biological sample(s) after a subject withdrew consent from the study is not allowed. 
Data containing confirmed cases of biological sample analysis after withdrawal of consent 
should not be transferred by the vendor to Novartis. 
Patient from Malaysian and withdraw consent from study will be excluded in the analysis as 
per local regulation. 
2.2.1 
Subgroup of interest 
Subgroup analyses will be performed for safety and efficacy. Subgroups will be formed using 
CRF data. This includes variables related to stratification factors i.e. CRF data will be used to 


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define these subgroups. Efficacy and safety subgroup analyses will be based on following 
subgroups: 
 Visceral crisis status (Yes vs No) 
 Disease free interval (<  2 years vs ≥ 2 years) (based on CRFdata ) 
 De novo (Yes vs No) 
 Presence of liver metastasis (Yes vs No) (based on CRF data) 
 Age (< 40 years and ≥ 40 years) 
 Recurrence during or within one year of completion of adjuvant hormonal therapy 
(Yes vs No) 
 Baseline ECOG performance status (0 vs ≥1) 
 History of adjuvant endorine therapy (Yes vs No) 
 History of adjubant chemotherapy (Yes vs No) 
 Presence of lung and/or liver metastasis (Yes vs No)Patients eligible for inclusion 
criteria 4c (Yes vs No) 
Efficacy 
The primary efficacy endpoint will be summarized by the above mentioned subgroups to 
examine the homogeneity of treatment effect provided that the primary efficacy analysis based 
on the FAS is statistically significant. 
For each of the subgroups, the following analyses will be performed: 
 Kaplan-Meier estimates of the survival distribution of PFS 
 Hazard ratio with 95% CI using stratified Cox proportional hazards model. For 
subgroups based on DFI, and presence of liver metastasis, unstratified analyses 
will be performed to avoid estimation issues, since these variables are related to 
the stratification factors. 
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95%-confidence intervals will be provided.  
Safety 
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses will be repeated on safety set in the above mentioned subgroups. 
The main safety analyses include: 
 AEs, irrespective of causality, by primary system organ class, preferred term and 
maximum grade 
 AEs with suspected relationship to study treatment by primary system organ class, 
preferred term and maximum grade 
 All deaths, by primary system organ class and preferred term 
 Serious AEs, irrespective of causality, by primary system organ class and preferred 
term – overall and grade 3 or 4 


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The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to a subgroup of patients, or safety issues that are more commonly bserved 
in a subgroup of patients. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The FAS will be used for all baseline (including disease characteristics) 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: <40 and ≥ 40 years, race, ethnicity, 
etc...) 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, 
minimum and maximum). Body Mass Index (BMI) (kg/m2) will be calculated as weight[kg] / 
(height[m]2) using weight at Baseline.  
Baseline stratification factors 
The number (%) of patients in each stratum (presence of liver metastases (present or absent), 
and DFI < 2 years (yes or no)) based on data obtained from the IRT system will be summarized 
overall and by treatment arm for the FAS. 
DFI  is defined as duration between the date of patient received curative surgery for primary 
breast cancer lesion to the date of most recent relapse documented < 2 years (yes or no) , de 
novo stage 4 disease is defined as DFI >2 years.  
The date of curative surgery will be based on Prior Antineoplastic Therapy -  Surgery CRF data 
and the date of most recent replase will be based on Diagnosis and Extent of Cancer CRF. For 
patients with missing surgery date, start date of prior antineoplastic therapy in adjuvant setting 
will be used, or data of initial diagnosis will be used if the start date of prior adjuvant therapy 
is missing. 
Discordances between the stratum recorded in IRT at the time of randomization and the actual 
stratum recorded in the clinical database through the data collected on eCRF will be cross-
tabulated and listed. 
Diagnosis and extent of cancer  
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, current disease status, histological grade, 
predominant histology/cytology,  time since initial diagnosis, time from initial diagnosis to first 
recurrence/progression (in months), time since most recent relapse/progression to 
randomization (in months), stage at time of study entry, presence/absence of target and non-
target lesions, number and type of metastatic sites involved, HER-2/estrogen/progesterone 


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receptor status, estrogen/progesterone receptor percentage, estrogen/progesterone allred score, 
criteria met for entering the study, visceral crisis status. Note: Presence/absence of target and 
non-target lesions will be based on the data collected on RECIST target/non-target lesion 
assessment eCRF pages. Metastatic sites will be based on diagnosis page. 
Time since initial diagnosis, time since most recent relapse/progression to randomization will 
be summarized in months. A month is defined as 365.25/12=30.4375 days. 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be summarized and listed by treatment arm. Separate summaries will 
be presented for ongoing and historical medical conditions.  The summaries will be presented 
by primary SOC, PT and treatment arm. Medical history and current medical conditions will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
Other 
All data collected at baseline such as source of patient referral will be listed. 
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 screened and not-randomized 
patients will also be displayed. 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  
 Number (%) of patients who were randomized but not treated (based on ‘DAR’ 
eCRF page not completed for any study treatment component) 
 Number (%) of patients who were treated (based on ‘DAR’ 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) 
 Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘End of Treatment Phase’ page); 
 Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on the End of Post-treatment follow-up  page); 


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 Reasons for discontinuation from the post-treatment follow-up (based on End of 
Post-treatment follow-up page); 
 Number (%) of patients who have entered the survival follow-up (based on the 
‘End of Treatment Phase’ or ‘End of Post-treatment follow-up’ 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. 
In addition to the pre-defined standard PD terms, the following protocol deviations related to 
the COVID-19 pandemic were added and will be summarized. 
 Extended screening period due to COVID-19 outbreak 
 Extended period between safety or efficacy assessments due to COVID-19 outbreak 
 Failure to follow drugs administration scheme due to restrictions imposed for hospital 
visits due to COVID-19 outbreak 
 Missed patient visit due to COVID-19 
 Visit done outside of study site due to COVID-19 
 Assessment/procedure changed due to COVID-19 
 Drug supply method changed due to COVID-19 
 Discontinuation due to COVID-19 
 Treatment not given due to COVID-19 
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) 
The Safety set will be used for the analysis below unless otherwise specified. Categorical data 
will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, 25th and 75th percentiles, minimum and maximum will be presented. 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, average daily dose, dose intensity (DI) and 
relative dose intensity (RDI) will be summarized by treatment arm, separately for each 
component of study treatment. The duration of treatment will also be presented for each 
combination 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. The number 
(%) of subjects who have dose reductions or interruptions, and the reasons, will be summarized 
by treatment arm.  


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Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control, and any combination partner: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug or control, and any combination partner. 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries (<3 months; 3 to <6 months, 6 to <9 months, 9 to <12 months, etc) and 
continuous summaries (i.e. mean, standard deviation etc.) using appropriate units of time. 
Duration of exposure to LEE011, combination partner and chemotherapy  
Duration of exposure to any single component of study treatment will be calculated as 
Duration of exposure (days) = (last date of exposure to study treatment component) – (date of 
first administration to study treatment component) + 1.  
The duration includes the periods of temporary interruption. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. The planned 
cumulative dose is not summarized/listed. It is used for relative dose intensity calculations.  
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
For ribociclib and letrozole, anastrozole, goserelin and leuprorelin, the cumulative dose in mg 
is the sum of “dose administered” from the eCRF of all cycles during the exposure of ribociclib 
and letrozole, anastrozole, goserelin respectively. 
For docetaxel (IV infusion) and paclitaxel (IV infusion), the dose is collected in mg/m2 at cycle 
N and it should be obtained by the investigator as the dose administered (mg) at cycle N divided 
by the body surface area (BSA) at the beginning of the cycle N using the weight measured 
before the infusion.  
For gemcitabine (IV infusion), paclitaxel (IV infusion), and vinorelbine, the dose in mg/m2 at 
cycle N will be the sum of the 2 doses planned to be received at day 1 and  day 8 of cycle N 
when applicable. 


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Dose intensity and relative dose intensity 
Dose intensity (DI) is defined for subjects with non-zero duration of exposure. For subjects who 
did not take the drug, the DI is by definition equal to zero. 
DI (dosing unit/unit of time) = cumulative dose (dosing unit) / duration of exposure (unit of 
time) 
Planned dose intensity (PDI) is defined as the assigned dose by unit of time planned to be given 
to patients as per protocol. The PDI for each study treatment component is displayed in Table 
2-7. Note that DI will also be calculated and reported in the units displayed in Table 2-7, 
whereas duration of exposure itself will be summarized in months. 
Table 2-7 
Planned dose intensity 
Medication 
PDI (dose unit/unit of time) 
Ribociclib/placebo 
600 mg/day 
Letrozole 
2.5 mg/day 
Anastrozole 
1 mg/day 
Goserelin 
3.6 mg/28 days 
Leuprorelin 
3.75 mg/28 days 
Docetaxel 
60 – 75 mg/m2 
Capecitabine 
Paclitaxel 
Gemcitabine 
Vinorelbine 
1600 – 2500 mg/m2 
175 mg/m2 or 80-90 mg/m2 
1000 – 1250 mg/m2 or 800-1250 mg/m2 
60 – 80 mg/m2 or 25-30 mg/m2 
Relative dose intensity (RDI) is defined as: 
RDI = DI (dosing unit / unit of time)  / PDI (dosing unit / unit of time).   
DI will be summarized separately for each of the study treatment components but using the 
duration of exposure of each of the components. RDI will summarized for ribociclib, goserelin, 
leuprorelin, letrozole and anatrozole. 
DI and relative dose intensity (RDI) are defined as follows : 
For letrozole and anastrozole, DI is defined as  
DI (mg/day) = Cumulative dose (mg) / duration of exposure to study treatment component (days) 
RDI = DI (mg/day)  / PDI (mg/day).   
For goserelin, DI is defined as  
DI (mg/28 days) = Cumulative dose (mg) / {[(date of last administration of goserelin + 27) – 
(date of first administration of goserelin)+1] / 28}, 
RDI = DI (mg/28days) / PDI (mg/28days). 
For ribociclib, DI is defined as 
DI (mg/day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib/placebo 
(days), 


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RDI = DI (mg/day)  / PDI (mg/day) 
where adjusted duration of exposure (days) to ribociclib represents the number of ribociclib 
dosing days a patient would be expected to have received per protocol, given their duration of 
exposure to ribociclib. Since ribociclib follows a 3 weeks on, 1 week off schedule, the adjusted 
duration of exposure to ribociclib is the duration of exposure to ribociclib minus the planned 
off days. The adjusted duration of exposure to ribociclib is therefore 21 x (# completed 28 day 
cycles) + min(21, duration of last incomplete cycle). 
For example, if the duration of exposure to ribociclib is 66 (corresponding to two cycles and 10 
days), then the adjusted duration of exposure to ribociclib is 21*2+10=52. If the duration of 
exposure to ribociclib is 108 days (corresponding to three cycles and 24 days), then the adjusted 
duration of exposure is 21*3+21=84 days. 
Specifically, let D1 represent the duration of exposure to ribociclib. Then the adjusted duration 
of exposure is defined as  
D=21*[D1/28]+min(21,D1-28*[D1/28]) days,  
where [x] stands for the integer part of x. In this equation [D1/28] is the number of completed 
cycles, and D1-28*[D1/28] is the additional number of days in the last, incomplete cycle (if 
any). For example, if D1=30 then [D1/28]=1, D1-28*[D1/28]=2, and D=23. If D1=7 then D=7; 
if D1=22 then D=21; if D1=28 then D=21, etc. 
DI for chemotherapy 
For capecitabine,  
DI (mg/ cycle) = [cumulative dose (mg/ m2) / adjusted duration of exposure to capecitabine 
(days), 
Where adjusted duration of expousre (days) is 14 x (# completed 21 day cycles) + min(14, 
duration of last incomplete cycle). 
For other chemotherapy : 
DI (mg/cycle) = [cumulative dose (mg/m2) / duration of exposure (days)]*21 
 
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.  
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
Dose interruptions are captured in the eCRF following the Oncology Data standard Reference 
manual and CRF Completions Guidelines. Depending on the dosing administration schedule 
(e.g. continuous dosing, interval dosing), data would be collected in different fashion. For 


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instance, for continuous dosing an interruption is defined as a dose of zero in a unit of time 
between two non-zero dosing records. In general any rest period as part of the regimen/schedule 
is not considered as an interruption.  
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically based on the dose change and the  direction of the 
change. 
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery, or other therapies not defined 
by the previous categories, will be summarized by treatment arm. Prior anti-neoplastic 
medications will be summarized by therapy type (e.g. chemotherapy, hormonal therapy, 
immunotherapy etc.), setting (e.g. adjuvant, neoadjuvant etc.) and also by lowest Anatomical 
Therapeutic Classification (ATC) class, preferred term and treatment.  
Number of lines of prior medication therapy, prior chemotherapy, and prior hormonal therapy 
will be summarized by treatment arm in any setting and in the metastatic setting. In addition, 
number of lines of prior chemotherapy in the neo-/adjuvant setting will also be summarized by 
treatment group. 
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.  
Anti-neoplastic medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO-DD); anti-neoplastic surgery will be coded using MedDRA. Details 
regarding MedDRA and WHO-DD version will be included in the footnote in the 
tables/listings.  
The above analyses will be performed using the FAS. 
Post treatment anti-cancer therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, PT, overall and by treatment group by means of frequency counts and 
percentages using FAS. 


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Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and PT using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and PT. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study  treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing.  
2.5 
Analysis of the primary objective 
The primary objective of the study is to determine whether treatment with LEE011 + NSAI + 
goserelin prolongs PFS compared to treatment with combination chemotherapy in 
premenopausal or perimenopausal women with HR+, HER2  negative locally advanced or 
metastatic breast cancer. 
2.5.1 
Primary endpoint 
The primary endpoint of the study is PFS, defined as the time from the date of randomization 
to the date of the first documented progression or death due to any cause. For the primary 
efficacy analysis, PFS will be based on local investigators review of tumor assessments and 
using RECIST 1.1 criteria (see Appendix 2 of the study protocol). The primary analysis will be 
based on FAS and will include all data observed up-to the cut-off date. 
If a patient has not progressed or died  at the analysis cut-off date, PFS will be censored at the 
date of the last adequate tumor evaluation date before the cut-off date. PFS events documented 
after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. documented disease 
progression or death) will be censored for the primary analysis. (See Section 2.5.3 for additional 
details regarding censoring rules and determination of date of last adequate tumor assessment).  
Discontinuation due to disease progression (collected on the ‘End of treatment’ and ‘End of 
post treatment follow up’ disposition pages without supporting objective evidence satisfying 
progression criteria per RECIST 1.1) will not be considered disease progression for PFS 
derivation. Clinical deterioration will not be considered as a qualifying event for progression 
for the primary analysis. 


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2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy analysis will be the comparison of the distribution of PFS between the 
two treatment groups. Assuming proportional hazards for PFS, the following statistical 
hypothesis will be tested to address the primary efficacy objective: 
H଴ଵ: θଵ ൒1   vs.   H୅ଵ: θଵ൏1 
where θଵ is the PFS hazard ratio (ribociclib + NSAI + goserelin arm vs combination 
chemotherapy arm). The analysis to test this hypothesis will consist of a stratified log-rank test 
at an overall one-sided 10% level of significance. Stratification will be based on the 
randomization stratification factors: presence of liver metastases (present or absent), and DFI < 
2 years (yes or no, de novo stage 4 is defined as DFI < 2 years).  
The primary efficacy variable, PFS will be analyzed once 110 PFS events are observed. The 
survival distribution of  PFS will be estimated using the Kaplan-Meier method. The results will 
be plotted graphically by treatment arm. The median, 25th and 75th percentiles of PFS along 
with 95% confidence intervals will be presented by treatment group. The survival probabilities 
at 2-month intervals, and the associated 95% confidence intervals will be summarized by 
treatment arm. Kaplan-Meier estimates will be obtained using PROC LIFETEST with 
method=KM option in SAS. The loglog option available within PROC LIFETEST will be used 
to compute the confidence intervals.  
A stratified Cox regression will be used to estimate the hazard ratio (HR) of PFS, along with 
95% confidence interval using the same strata information as the primary efficacy comparison. 
SAS PHREG procedure with ties=EXACT option will be used to carry out this analysis in 
which the model statement will include treatment arm variable as the only covariate and the 
STRATA statement will include the stratum information as obtained via IRT. 
2.5.3 
Handling of missing values/censoring/discontinuations 
This is an event-driven trial and the final analysis for PFS will be performed after approximately 
110 PFS events have been documented based on local investigators review of tumor 
assessments.  
In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment 
if no PFS event is observed prior to the analysis cut-off date. 
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. 
documented disease progression or death) will be censored on the date of the last adequate 
tumor assessment before the start of new anticancer therapy if no PFS event is observed prior 
to the start of new antineoplastic therapy. 
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or stable disease (SD) or non-CR/non-PD before an event or a 
censoring reason occurred. In this case the last tumor evaluation date at that assessment will be 
used. If no post-baseline assessments are available (before an event or a censoring reason 
occurred) then  the date of randomization will be used. 
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after two or more missing tumor assessments. The 


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term “missing adequate tumor assessment” is defined as a tumor assessment (TA) not 
performed or tumor assessment with overall lesion response of “UNK”. The rule to determine 
number of missing TAs is based on the time interval between the date of last adequate tumor 
assessment and the date of an event. If the interval is greater than  twice the protocol-specified 
interval between the TAs and 2 times the protocol-allowed time window around assessments, 
then the number of missing assessments will be 2 or more. 
Refer to Table 2-8 for censoring and event date options and outcomes for PFS. 
Table 2-8 
Outcome and event/censor dates for PFS analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Date of randomization  
Censored 
Progression or death at or 
before next scheduled 
Assessment 
Date of progression (or 
death) 
Progressed 
 
Progression or death after 
exactly one missing assessment 
Date of progression (or 
death) 
Progressed 
 
Progression or death after two or 
more missing assessments 
Date of last adequate 
assessment prior to 
missed assessment  
Censored 
 
No progression (or death) 
Date of last adequate 
assessment  
Censored 
 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
Date of last adequate 
assessment  
  
 
Censored 
 
New anticancer therapy given 
prior to protocol defined 
progression  
Date of last adequate 
assessment prior to new 
anticancer therapy   
Censored 
Death before first PD 
assessment 
Date of death 
Progressed 
2.5.4 
Supportive analyses 
As a sensitivity analysis to assess the impact of stratification, the two treatment groups will be 
compared using the unstratified log-rank test. The HR together with the associated 95% 
confidence interval obtained using the unstratified Cox regression model will also be presented. 
The primary analysis will be repeated using the PPS if the primary efficacy analysis is 
statistically significant and if the number of patients in the FAS and PPS differ by more than 10 
percent. 
 
The following will be provided:  
Kaplan-Meier estimates, estimate of the median PFS along with 95% confidence interval, and 
hazard ratio obtained using the Cox proportional hazards model. 
 


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 using the primary analysis source (i.e., investigator assessment) on the FAS and including 
events whenever it occurs, even after two or more missing tumor assessments. In the 
summary tables, this approach is referred as ‘actual event PFS sensitivity analyses. 
 using the primary analysis source (i.e., investigator assessment)  on the FAS and 
backdating of events occurring after missing one or more tumor assessments. In the 
summary tables, this approach is referred as ‘backdating PFS sensitivity analysis’. 
 using the primary analysis source (i.e., investigator assessment)  on the FAS and including 
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 
1.1. documented disease progression or death) for the primary analysis provided tumor 
assessments continue after initiation of new cancer therapy.  . In the summary tables, this 
approach is referred to as ‘new anticancer therapy PFS sensitivity analysis’.  
 using the primary analysis source (i.e., investigator assessment) on the FAS and 
considering treatment discontinuation due to ‘Disease progression’ without documented 
progression as event. In the summary tables, this approach is referred to as ‘clinical PD 
sensitivity analysis’. 
 using the primary anlaysis source (i.e., investigator assessment) on the FAS and 
considering impact of COVID-19 pandemic. For patients who discontinued due to 
COVID-19 pandemic reasons, PFS will be censored at the date of last adequate 
assessment prior to discontinuation of treatment due to COVID-19 pandemic. For death 
due to COVID-19, PFS will be censored at the date of the last adequate assessment prior 
to death due to COVID-19. In the summary tables, this approach is referred to as 
‘COVID-19 sensitivity analysis’.  
 
Further supportive analyses will include: 
 
 Number of patients and number of events by treatment arm within each stratum will be 
presented along with the hazard ratio for treatment effect obtained using the Cox 
proportional hazards regression with corresponding confidence intervals. No p-values will 
be presented for this analysis. Kaplan-Meier plots of survival distributions will be 
presented by stratum. 
Subgroup analyses for the primary endpoint  
If the primary efficacy analysis is statistically significant, the primary endpoint of PFS  will be 
summarized for the subgroups specified in Section 2.2.1 and using the same conventions as for 
the primary analysis.  
 
For each of the subgroups, the following analyses will be performed: 
 
 Kaplan-Meier estimates of the survival distribution of PFS 
 Hazard ratio with 95% CI using stratified Cox proportional hazards model. 
 
Efficacy analyses in subgroups are intended to explore the consistency (homogeneity) of 
treatment effect. Forest plot (including sample size/number of events and HR with 95% CI) will 


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be produced to graphically depict the treatment effect estimates in different subgroups. No 
inferential statistics (p-values) will be produced for the subgroups. 
Censoring pattern of PFS 
Number of patients with a PFS event and number of patients censored for the PFS analysis will 
be summarized. In addition, a summary of reasons for PFS censoring will be provided by 
treatment arm based on the following reasons: 
 
1: Ongoing without event 
2: Lost to follow-up 
3: Withdrew consent 
4: Adequate assessment no longer available 
5: Initiation of new cancer therapy prior to progression 
6: Event after >=2 missing tumor assessments 
The PFS censoring reasons are defined in the following way.  
If the time interval between the last adequate TA date and the earliest of the following dates is 
smaller or equal to interval of 2 missing tumor assessments: 
1. Analysis cut-off date,  
2. Start date of further anti-neoplastic therapy, 
3. Date of consent withdrawal, 
4. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up. 
Then the PFS censoring reason will be: 
1. ‘Ongoing’,  
2. ‘New cancer therapy added’,  
3. ‘Withdrew consent’,  
4. ‘Lost to follow-up’,   
If the time interval is larger than the interval of 2 missing tumor assessments with no event 
observed then the PFS censoring reason will always default to ‘Adequate assessment no longer 
available’.  If the time interval between the last adequate tumor assessment date and the PFS 
event date is larger than the interval of 2 missing tumor assessments then the patient will be 
censored and the censoring reason will be 'Event documented after two or more missing tumor 
assessments'. 
These summaries on censoring reasons will be produced for PFS by investigator assessment. 
The censoring patterns will be compared between treatment arms. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective in the study. 


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2.7 
Analysis of secondary efficacy objective(s) 
The secondary efficacy objectives are to:  
 compare the two treatment arms with respect to overall survival ( OS)  
 compare 3-month treatment failure rate between the two treatment arms 
 evaluate the two treatment arms with respect to overall response rate( ORR) and 
clinical benefit rate (CBR) 
 describe time to response (TTR) and time to treatment failure (TTF) in each 
treatment arm 
2.7.1 
Secondary endpoints 
For detailed information on guidelines of the below secondary efficacy endpoints, please refer 
to protocol Section 16.2.   
Overall survival (OS) 
OS is defined as the time from date of randomization to date of death due to any cause. A cut-
off date will be established for analysis of OS. All deaths occurring on or before the cut-off date 
in the FAS will be used in the OS analysis. 
If a patient is not known to have died at the time of analysis cut-off, then OS will be censored 
at the last contact date.  
Overall response rate (ORR) 
ORR with confirmation is defined as proportion of patients with best overall response (BOR) 
of confirmed CR or confirmed PR according to RECIST 1.1. ORR without confirmation is the 
proportion of patients with best overall response (BOR) of CR or PR without confirmation 
according to RECIST 1.1. Both ORR with confirmation and without confirmation will be 
calculated based on the FAS using investigators’ review of tumor assessment data. Patients with 
only non-measurable disease at baseline will be part of the analysis and will be included in the 
numerator only if a complete response was observed.   
Clinical benefit rate (CBR)  
CBR with confirmation is defined as the proportion of patients with a BOR of confirmed CR or 
PR, or SD lasting 24 weeks or longer, according to RECIST 1.1 criteria. CBR without 
confirmation is defined as the proportion of patients with a BOR of CR or PR without 
confirmation, or SD lasting 24 weeks or longer, according to RECIST 1.1 criteria. A patient 
will be considered to have SD for 24 weeks or longer if a SD response is recorded at 24-1=23 
weeks or later from randomization, allowing for the ±1 week visit window for tumor 
assessments. Patients with only non-measurable disease at baseline will be part of the analysis 
and will be included in the numerator only if they achieve a complete response or have a ‘Non-
CR/Non-PD’ response at 23 weeks or more after randomization. CBR  will be calculated using 
the FAS based on the investigators’ tumor assessments.  
 


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Time to response (TTR) 
Time to response (CR or PR) is the time from date of randomization to first documented 
response of CR or PR (which must be confirmed subsequently) using local investigator’s review 
of tumor assessment data and according to RECIST 1.1. All patients in the FAS will be included 
in the time to response calculation. Patients who did not achieve a confirmed PR or CR will be 
censored at: 
 the maximum follow-up time (i.e. LPLV -  FPFV used for the analysis) for patients 
who had a PFS event (i.e. either progressed or died due to any cause); 
 the last adequate tumor assessment date for all other patients. 
Time to treatment failure (TTF) 
Time to treatment failure (TTF) is defined as the time from the date of randomization to the 
earliest of date of progression, date of death due to any cause, or date of discontinuation due to 
reasons other than ‘protocol violation’ or ‘administrative problems’. 
The following discontinuation reasons will be considered as events for TTF: Adverse event, 
Death due to any reasons, Lost to follow-up, Physician decision, Pregnancy, Progressive disease, 
Subject decision and New therapy for study indication. 
Treatment failure rate (TFR) 
TFR is defined as the proportion of patients who discontinued the study treatment by 3 months 
due to progression disease, death due to any cause, change to other anti-cancer therapy, or 
discontinuation due to reasons other than ‘protocol violation’ or ‘administrative problems’. All 
patients in the FAS will be included in 3-month TFR. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Overall Survival 
The analysis of OS will be based on FAS population according to the randomized treatment 
group assigned at randomization. The survival distribution of OS distribution will be estimated 
using the Kaplan-Meier method, and Kaplan-Meier curves, medians  and 95% confidence 
intervals [Brookmeyer and Crowley 1982] of the medians intervals will be presented for each 
treatment group. The hazard ratio for OS will be calculated, along with its 95% confidence 
interval, using a stratified Cox model. 
Study follow-up will be summarized using the following methods: 
Summary of duration between randomization and cut-off date, and follow-up times for PFS/OS, 
which are defined as follows: 
 Randomization (recruitment) period = (Date of last patient randomized - Date of first 
patient randomized + 1) / 30.4375 (months) 
 Duration between randomization and data cut-off date = (Cut-off date – Date of 
randomization + 1) / 30.4375 (months).. 
 Follow-up time = (Date of event or censoring – Date of randomization + 1) / 30.4375 
(months) regardless of censoring. Date of censoring is defined as the last adequate 
tumor assessment date for PFS or last contact date for OS. 


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All summaries will be reported in months. The calculations for PFS will be based on local 
assessment. Date of censoring is the same as defined for the PFS and OS analysis. 
The time from PFS and OS censoring date to data cut-off date will be summarized by time 
intervals in months: <3, 3 - < 6, 6 - < 12, 12 - < 18, 18 - <24 and by 12 month intervals thereafter 
if necessary. The gap time is calculated as (analysis cut-off date – censoring date +1)/30.4375. 
Treatment failure rate (TFR) 
3-month TFR will be compared between two treatment. The stratification will be based on the 
randomization stratification factors: presence of liver metastases (present or absent), and DFI < 
2 years (yes or no, de novo stage 4 is defined as DFI < 2 years). 
3-month TFR will be summarized using descriptive statistics by treatment arm along with 
standard Wald asymptotic (i.e. normal approximation) 95% confidence intervals. 
Overall response rate 
ORR will be compared between two treatment arms. The stratification will be based on the 
randomization stratification factors: presence of liver metastases (present or absent), and DFI < 
2 years (yes or no, de novo stage 4 is defined as DFI < 2 years). 
ORR will be summarized using descriptive statistics by treatment arm along with standard Wald 
asymptotic (i.e. normal approximation) 95% confidence intervals.  
Clinical benefit rate 
CBR will be compared between two treatment. The stratification will be based on the 
randomization stratification factors: presence of liver metastases (present or absent), and DFI < 
2 years (yes or no, de novo stage 4 is defined as DFI < 2 years). 
ORR will be summarized using descriptive statistics by treatment arm along with standard Wald 
asymptotic (i.e. normal approximation) 95% confidence intervals.  
Time to response and Time to treatment failure 
TTR and TTF data will be listed and summarized by treatment arm. The distribution of TTR 
and TTF will be estimated using the Kaplan-Meier method and the median time to 
response/failure will be presented along with 95% confidence interval. No inferential analysis 
that compares the two treatment arms will be performed. 
ECOG performance status 
The ECOG PS scale (Table 2-9) will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active): 
Table 2-9 
ECOG Performance Scale 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 


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Score 
Description 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point based on the windows defined in Section 2.1. 
2.8 
Safety analyses 
The assessment of safety will be based mainly on the frequency of AE and on the number of 
laboratory/ECG values that fall outside of pre-determined ranges. Other safety data (e.g. vital 
signs and special tests) will be considered as appropriate. 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. Safety summary tables will include only ‘on-treatment’ events/assessments. 
The AEs started before the first dose but worsening during the treatment period are also 
considered as ‘on-treatment’ events. All safety events/assessments will be listed and those 
collected outside of the on-treatment window will be flagged. 
If dates are incomplete in a way that clear assignment to pre-, on-, or post-treatment period 
cannot be made, then the respecctive data will be assigned to the on-treatment period.  
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on treatment period. Additional sumaries 
will be displayed to report all AEs, AEs related to study treatment, all SAEs. All AEs collected 
in the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
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 SOC and for each (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 Common Terminology Criteria for Adverse Events (CTCAE) grades for 
the same PT 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 SOC will be presented alphabetically and the PT will be sorted 
within primary SOC in descending frequency. The sort order for the PT will be based on their 
frequency in the investigational arm. 
The following AE summaries will be produced by treatment arm: overview of AE and deaths 
(number and % of subjects who died, with any AE, any SAE, any dose reductions/interruptions, 
leading to treatment discontinuation), AEs by SOC and PT, summarized by relationship (all 
AEs and AEs related to study treatment), seriousness (SAEs and non-SAEs), leading to 


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treatment discontinuation, leading to dose interruption/adjustment, requiring additional therapy 
and leading to fatal outcome. In addition, a summary of  serious adverse events with number of 
occurrences will be produced (an occurrence is defined as >1 day between start and prior end 
date of record of same preferred term).  
For clinicaltrials.gov and EudraCT site reporting, tables on on-treatment AE which are not 
serious with an incidence greater than and equal to 5%; on-treatment serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and PT 
on the safety set. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Adverse events of special interest (AESI) during the on-treatment period will be tabulated.  
A Case Retrieval Sheet (CRS; an Excel file) with the exact composition of the AE groupings is 
to be used to map reported AE to the AESIs groupings (termed Specific Event Categories (SECs) 
in the CRS). This file may be updated (i.e. it is a living document) based on review of 
accumulating trial data.   
Data analysis of AESIs 
An AESI interest is a grouping of AE that are of scientific and medical concern specific to 
ribociclib. These groupings are defined using MedDRA terms, SMQs (standardized MedDRA 
queries), HGLTs (high level group terms), HLTs (high level terms) and PTs (preferred terms). 
Customized SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a 
customized group of search terms which defines a medical concept for which there is no official 
SMQ available or the available SMQ does not completely fit the need. It may include a 
combination of single terms and/or an existing SMQ, narrow or broad. For each specified AESI, 
number and percentage of patients with at least one event of the AESI occurring during on 
treatment period will be summarized.  
Summaries of these AESIs will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
hospitalization, death etc.).  
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths will be produced by treatment arm, SOC 
and PT.  
All deaths  will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects. 
2.8.3 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) CTCAE v4.03. The calculation of CTCAE grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account. 


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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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
On analyzing laboratory, data from all sources 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). 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 
 Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
 Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
 For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment  value. 
The following listings will be produced for the laboratory data: 
 Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.   
 Listing of all CTC grade 3 or 4 laboratory toxicities 
Sodium and Phosphorus will be excluded from laboratory data summary. Sodium and 
Phosphorus were removed in Protocol amendment 1 and therefore the data is incomplete; data 
fields are hidden due to CRF updates.  
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (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 > 2xULN 
 TBL > 3xULN 
 ALT or AST > 3xULN & TBL > 2xULN 


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 ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law)    
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN  in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as, liver metastates, liver function at baseline etc. 
2.8.4 
Other safety data 
2.8.4.1 
ECG data 
Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these subjects will be produced by treatment group. 
Data handling 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses. 
Data analysis 
12-lead ECGs including QTcF and intervals will be obtained for each subject during the study. 
ECG data will be read and interpreted locally.  
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 
 PR 
- 
New PR > 200 ms 
- 
Increase > 25% and PR > 200 ms 
 QRS 
- 
New QRS >110  ms 
- 
Increase QRS > 25% and QRS >110 ms 
 HR 
- 
Increase from baseline >25% and HR > 100 bpm 
- 
Decrease from baseline > 25% and HR < 50 bpm 
 
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. 


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2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse 
rate (beats per minute), systolic and diastolic blood pressure (mmHg), and body surface area. 
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 2-10 
below. 
Table 2-10 
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  
- 
The number and percentage of subjects with notable vital sign values (high/low) 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.  
2.9 
Pharmacokinetic endpoints   
Not applicable. 
2.10 
Patient-reported outcomes 
The FAS will be used for analyzing PRO data unless specified differently. The PRO Analysis 
Set will be used for analyzing PRO data unless specified differently. The FACT-Breast (FACT-
B) quality of life questionnaire (see Appendix 2 of the protocol) will be used to explore patient-


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reported outcome measures of health-related quality-of-life, functioning, disease symptoms and 
treatment-related side effects.  
The baseline is defined as the last PRO assessment on or prior randomization. Collection of 
FACT-B PRO have a ±3 days window unless otherwise indicated. 
No formal statistical tests will be performed for PRO data and hence no multiplicity adjustment 
will be applied. Descriptive statistics will be used to summarize the subscale and overall scores 
at each scheduled assessment time point as given in Table 8-1 of the protocol. 
Scores from the FACT-B will be displayed as mean profiles, presented over time using time 
windows as described in Section 2.1. Change from baseline in the scores at the time of each 
assessment will also be summarized for overall FACT-B scores, physical well-being, 
social/family well-being, emotional well-being, functional well-being, and additional concerns. 
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. 
Compliance to the schedule of administration of PRO will be summarized, for baseline and 
post-baseline on treatment scheduled assessments (the number of ongoing patients will be used 
as denominator). The following categories, as collected on the eCRF, will be used to describe 
whether the questionnaire was completed at a specific time point: 
1. yes, fully completed 
2. yes, partly completed 
3. no. 
If more than 50% of the items are missing in a scale or subscale, the score for this scale or 
subscale will be considered missing for this assessment. Otherwise, the average of the non-
missing items in the scale or subscale will be used to impute for the missing items when 
calculate the score for the scale or subscale. 
The following time to event analyses will be summarized for FACT-B total scores: 
 Time to first occurrence of a clinically relevant deterioration, defined as a ≥ 5 points 
decrease in FACT-B total scores with no subsequent observation of a <5 points 
decrease 
 Time to first occurrence of a clinically relevant deterioration, defined as a ≥ 7 points 
decrease in FACT-B total scores with no subsequent observation of a <7 points 
decrease 
 Time to first occurrence of a clinically relevant deterioration, defined as a ≥ 10% 
decrease in FACT-B total scores with no subsequent observation of a <10% decrease 
The following symptoms will be summarized:  
 Pain (Question GP4: I have pain), time to first occurrence of a clinically relevant 
deterioration, defined as a ≥ 10% decrease with no subsequent observation of a <10% 
decrease 
 Nausea (Question GP2: I have nausea), time to first occurrence of a clinically relevant 
deterioration, defined as a ≥ 10% decrease with no subsequent observation of a <10% 
decrease 


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Time to deterioration is the number of days between the date of randomization and the date of 
the assessment at which deterioration is seen. If a patient has not had an event prior to analysis 
cut-off, end of treatment, start of new anti-neoplastic therapy, lost to follow-up, or withdrawal 
of consent, the time to deterioration will be censored at the date of the last evaluation on or 
before the earliest of these times. Only assessments collected while the patient is on treatment 
and on or before the end of treatment visit will be included in the PRO time to deterioration 
analysis. 
If deterioration is observed after two or more missing assessments, time to deterioration will be 
censored at the date of the last assessment prior to the deterioration.  
Time to deterioration in the PRO scales will be compared between the two treatment arms using 
a stratified logrank test (strata based on IRT data) at one-sided 5% level of significance. The 
survival distributions will be presented descriptively using Kaplan-Meier curves. Summary 
statistics from the Kaplan-Meier distributions will be determined, including the median time to 
10% deterioration. Both point estimates and 95% CIs will be presented.  
 
 
 
 
 
2.13 
Interim analysis 
Not interim analysis is planned.  
3 
Sample size calculation 
3.1 
Primary analysis 
The sample size calculation is based on the primary analysis of PFS.  


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Based on published available data (O’Shaughnessy et al 2002, Albain et al 2008, Jassem et al 
2001), the median PFS in the combination chemotherapy arm is expected to be approximately 
8 months. It is expected that treatment with ribociclib arm will result in a 33% reduction in the 
hazard rate for PFS, i.e., an expected hazard ratio of 0.667 (which corresponds to an increase in 
median PFS to 12 months under the exponential model assumption). 
Then in order to ensure 80% power to test the null hypothesis: PFS hazard ratio = 1, versus the 
specific alternative hypothesis: PFS hazard ratio = 0.667, it is calculated that a total of 110 PFS 
events need to be observed. This calculation assumes analysis by a one-sided log-rank test at 
the overall 10% level of significance, patients randomized to the two treatment arms in a 1:1 
ratio. Considering that enrolment will continue for about 30 months, 3 patients for 0-6 months, 
10 patients for 7-17 months and 6 patients thereafter, a total of 200 patients will be needed to 
observe the targeted 110 PFS events at about 4 months after the randomization date of the last 
patient. Assuming 10% drop-out, a total of 222 patients will be needed. The sample size of 
222 patients will be randomly assigned to each treatment arm in a 1:1 ratio (111 patients in the 
experimental arm, 111 patients in the control arm). These calculations were made using the 
software package East 6.4. 
3.2 
Power for analysis of key secondary variables 
Not applicable. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
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 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.   
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 


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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. 
 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of 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 
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 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawl of consent date)) 
day, month, 
and year 
 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
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.  
5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 
a previous and following assessment is not available, this assessment will not be used for any 
calculation. 
Applying the cut-off to tumor assessment 
For tumor related assessments, if an evaluation has some assessments done prior to  cut-off date 
and  others after the cut-off date , then the evaluation is considered post-cut-off date and will 
be excluded from analysis. 
5.2 
AEs coding/grading 
AEs are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 


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AEs will be assessed according to the 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).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI CTCAE 
version 4.03. The calculation of CTCAE grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account. 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 v4.03, results 
will be graded by the low/normal/high (or other project-specific ranges, if more suitable) 
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. 
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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5.4 
Statistical models 
5.4.1 
Primary analysis 
Analysis of time to events Data 
Hypothesis and test statistic 
The null hypothesis stating that PFS survival distributions of the two treatment groups are 
equivalent will be tested against one-sided alternative.  
Assuming proportional hazards for PFS, the following statistical hypotheses will be tested: 
H଴ଵ: θଵ ൒1   vs.   H୅ଵ: θଵ൏1 
where 𝜃ଵ is the PFS hazard ratio (ribociclib arm vs  combination chemotherapy arm). 
Stratified log-rank test adjusting for the strata used in the randomization will be implemented 
as follows: In each of the K strata separately, the LIFETEST procedure with STRATA 
statement including only the treatment group variable and with the TIME statement will be used 
to obtain the rank statistic 𝑆௞ and variance var(𝑆௞) where k=1, 2, …, K. The final test statistics 
will then be reconstructed as follows: 
Z=[S1 +…+ SK]/√ [var(S1) +…+ var(Sk)]. 
 
Kaplan-Meier estimates 
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM 
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG. 
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence 
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994]. 
 
 
Hazard ratio 
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS  
procedure PHREG (with TIES=EXACT option in the MODEL statement).  
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the treatment 
group variable as the only covariate and the STRATA statement will include stratification 
variable(s). 
Hazard ratio with two-sided 95% confidence interval will be based on Wald test. 
 
Treatment of ties 


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The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model. 
 
Checking proportionality of hazard assumption 
Plots (SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS will 
be used to provide visual checks of the proportional hazard assumption.  
 SURVIVAL plots estimated survivor functions.  The shape of the curves should be 
basically the same if hazards are proportional. 
 LOGSURV plots the cumulative hazard functions The larger cumulative hazard 
should be a multiple of smaller if hazards are proportional 
 LOGLOGS plots log (cumulative hazard). The LOGLOG plot will show parallel 
curves if hazards are proportional.  
Analysis of Binary Data 
Confidence interval for response rate 
Responses will be summarized in terms of percentage rates with 100(1 − α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement for one-way table [Clopper and Pearson 1934]. 
 
5.4.2 
Key secondary analysis 
Not applicable. 
5.4.3 
Audit-based BIRC assessment of PFS  
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
Not applicable. 
6 
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