Conditions: Breast Cancer
Keywords: Breast Cancer (BC) hormone receptor (HR) HR-positive human epidermal growth factor receptor 2 (HER2) HER2-negative ER-positive advanced breast cancer (aBC) ribociclib (LEE011) premenopausal postmenopausal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 376
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the safety and efficacy of a reduced ribociclib starting dose of 400 mg in combination with a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have received no prior therapy for advanced disease. Premenopausal women were required to receive goserelin in both treatment arms.

Detailed description:
Patients were assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a ratio of 1:1:

* Experimental arm: Ribociclib 400 mg (2 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  • For postmenopausal women:
  * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously

    • For premenopausal women:
  * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.
* Control arm: Ribociclib 600 mg (3 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  * For postmenopausal women:

    \~ Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously.
  * For premenopausal women:

    * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.

Participants received study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

For participants who discontinued treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments continued to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).

Arms:
arm 1: Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) arm 2: Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women)

Interventions: intervention 1: Ribociclib intervention 2: Anastrozole intervention 3: Letrozole intervention 4: Goserelin
Intervention descriptions: intervention 1: Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib was supplied as 200 mg tablets as individual patient supply packaged bottles. intervention 2: Anastrozole 1 mg tablets for oral use QD continuously intervention 3: Letrozole 2.5 mg tablets for oral use QD continuously intervention 4: Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
LEE011
Clinical Trial Protocol CLEE011A22071&7
A phase II, multicenter, randomized, open-label study to 
evaluate the safety and efficacy of 400 mg of ribociclib in 
combination with non-steroidal aromatase inhibitors for the 
treatment of pre-and postmenopausal women with 
hormone receptor-positive, HER2-negative advanced 
breast cancer who received no prior therapy for advanced 
disease
Document type:
Amended Protocol Version
EUDRACT number:
2018-004234-15
Version number:
01 (clean)
Clinical Trial Phase:
II
Release date:
24-Jan-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 1 (24-Jan-2020).............................................................................................13
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.1.1
Breast cancer epidemiology and current treatment landscape ..............21
1.1.2
Role of the CDK4/6 pathway in BC .....................................................21
1.1.3
Overview of Investigational Treatment and Other Trial Treatments....22
1.2
Purpose ..................................................................................................................26
2
Objectives and endpoints...................................................................................................27
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................28
4.1
Rationale for study design .....................................................................................28
4.2
Rationale for dose/regimen and duration of treatment ..........................................28
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................31
4.4
Purpose and timing of interim analyses/design adaptations..................................31
4.5
Risks and benefits..................................................................................................31
5
Population..........................................................................................................................32
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria...................................................................................................34
6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Investigational and control drugs..........................................................37
6.1.2
Additional study treatments ..................................................................37
6.1.3
Treatment arms/group ...........................................................................37
6.1.4
Guidelines for continuation of treatment ..............................................39
6.1.5
Treatment duration................................................................................40
6.2
Other treatment(s)..................................................................................................40
6.2.1
Concomitant therapy.............................................................................40
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6.2.2
Prohibited medications..........................................................................42
6.2.3
Drug with QT prolongation...................................................................43
6.3
Subject numbering, treatment assignment, randomization....................................43
6.3.1
Subject numbering ................................................................................43
6.3.2
Treatment assignment, randomization ..................................................43
6.4
Treatment blinding.................................................................................................44
6.5
Dose modification..................................................................................................44
6.5.1
Dose modifications................................................................................44
6.5.2
Follow-up for toxicities.........................................................................50
6.6
Additional treatment guidance...............................................................................51
6.6.1
Treatment compliance...........................................................................51
6.6.2
Emergency breaking of assigned treatment code..................................51
6.7
Preparation and dispensation.................................................................................51
6.7.1
Handling of study treatment and additional treatment..........................52
7
Informed consent procedures ............................................................................................52
8
Visit schedule and assessments .........................................................................................53
8.1
Screening ...............................................................................................................58
8.1.1
Eligibility screening ..............................................................................58
8.1.2
Information to be collected on screening failures.................................58
8.2
Subject demographics/other baseline characteristics.............................................58
8.3
Efficacy..................................................................................................................59
8.3.1
Imaging tumor assessments...................................................................59
8.3.2
Appropriateness of efficacy assessments..............................................65
8.4
Safety and tolerability............................................................................................65
8.4.1
Laboratory evaluations..........................................................................66
8.4.2
Electrocardiogram (ECG) .....................................................................67
8.4.3
Pregnancy and assessments of fertility .................................................69
8.5
Additional assessments..........................................................................................69
8.5.1
Pharmacokinetics ..................................................................................69
9
Study discontinuation and completion ..............................................................................71
9.1
Discontinuation......................................................................................................71
9.1.1
Discontinuation of study treatment .......................................................71
9.1.2
Safety evaluations follow-up.................................................................72
9.1.3
Efficacy follow-up ................................................................................73
9.1.4
Withdrawal of informed consent...........................................................73
9.1.5
Lost to follow-up...................................................................................73
9.1.6
Early study termination by the sponsor.................................................74
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9.2
Study completion and post-study treatment ..........................................................74
10 Safety monitoring and reporting........................................................................................75
10.1
Definition of adverse events and reporting requirements......................................75
10.1.1
Adverse events ......................................................................................75
10.1.2
Serious adverse events ..........................................................................76
10.1.3
SAE reporting........................................................................................77
10.1.4
Pregnancy reporting ..............................................................................78
10.1.5
Reporting of study treatment errors including misuse/abuse................79
10.2
Additional Safety Monitoring................................................................................79
10.2.1
Steering Committee...............................................................................79
11 Data Collection and Database management......................................................................79
11.1
Data collection.......................................................................................................79
11.2
Database management and quality control............................................................80
11.3
Site monitoring ......................................................................................................81
12 Data analysis and statistical methods ................................................................................81
12.1
Analysis sets ..........................................................................................................81
12.2
Subject demographics and other baseline characteristics......................................82
12.3
Treatments .............................................................................................................82
12.4
Analysis of the primary endpoint(s) ......................................................................83
12.4.1
Definition of primary endpoint(s).........................................................83
12.4.2
Statistical model, hypothesis, and method of analysis..........................83
12.4.3
Handling of missing values/censoring/discontinuations.......................84
12.4.4
Sensitivity and Supportive analyses......................................................84
12.5
Analysis of secondary endpoints ...........................................................................84
12.5.1
Key secondary objective .......................................................................84
12.5.2
Efficacy and/or Pharmacodynamic endpoint(s)....................................85
12.5.3
Safety endpoints....................................................................................86
12.5.4
Pharmacokinetics ..................................................................................88
12.6
Interim analyses.....................................................................................................89
12.7
Sample size calculation..........................................................................................89
12.7.1
Primary endpoint(s)...............................................................................89
12.7.2
Secondary endpoint(s)...........................................................................90
12.7.3
Sample size considerations for PK analysis..........................................90
13 Ethical considerations and administrative procedures ......................................................90
13.1
Regulatory and ethical compliance........................................................................90
13.2
Responsibilities of the investigator and IRB/IEC..................................................90
13.3
Publication of study protocol and results...............................................................91
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13.4
Quality Control and Quality Assurance.................................................................91
14 Protocol adherence ............................................................................................................91
14.1
Protocol amendments.............................................................................................92
15 References (available upon request)..................................................................................93
16 Appendices ........................................................................................................................95
16.1
Appendix 1 – Concomitant Medications...............................................................95
16.2
Appendix 2 - Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) ..99
16.2.1
Introduction.........................................................................................101
16.2.2
Efficacy assessments...........................................................................101
16.2.3
Efficacy definitions .............................................................................110
16.2.4
Data handling and programming rules................................................120
16.2.5
References (available upon request) ...................................................124
List of tables
Table 1
Protocol summary .................................................................................16
Table 2-1
Objectives and related endpoints ..........................................................27
Table 4-1
Estimated Cmax and mean QTcF change from baseline at different 
dose regimens of ribociclib...................................................................29
Table 6-1
Investigational and combination drug...................................................37
Table 6-2
Dose modification guidelines................................................................44
Table 6-3
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions (CTCAE v4.03).................................45
Table 6-4
Ribociclib dose adjustment and management recommendation for 
hepatic toxicities (CTCAE v4.03).........................................................46
Table 6-5
Ribociclib dose adjustment and management recommendation for 
QTcF prolongation (CTCAE v4.03) .....................................................47
Table 6-6
Ribociclib dose adjustment and management recommendation for 
ILD/pneumonitis (CTCAE v4.03) ........................................................49
Table 6-7
Ribociclib dose adjustment and management recommendation for 
all other adverse reactions.....................................................................49
Table 8-1
Assessment Schedule ............................................................................54
Table 8-2
Imaging collection plan.........................................................................62
Table 8-3
Assessments & Specifications...............................................................65
Table 8-4
ECOG performance status.....................................................................66
Table 8-5
Clinical laboratory parameters collection plan .....................................67
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Table 8-6
Central ECG collection plan .................................................................68
Table 8-7
Schedule of extensive pharmacokinetic blood collection.....................70
Table 8-8
Schedule of non-extensive pharmacokinetic blood collection..............71
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................79
Table 12-1
Non-compartmental pharmacokinetic parameters ................................88
Table 12-2
Primary endpoint: Overall Response rate (ORR)..................................89
Table 12-3
Operating characteristics for the key secondary endpoint: ∆QTcF at 
Cycle 1 Day 15 (2 h post-dose). Probability of the upper 90% CI < 
20 ms under different value to True QTcF with a sample size of 
175 patients in Arm 1............................................................................90
Table 16-1
List of prohibited medications during study drug treatment.................95
Table 16-2
List of medications to be used with caution during study drug 
treatment................................................................................................97
Table 16-3
Glossary...............................................................................................100
Table 16-4
Response criteria for target lesions .....................................................106
Table 16-5
Response criteria for non-target lesions..............................................108
Table 16-6
Overall lesion response at each assessment ........................................109
Table 16-7
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................117
Table 16-8
Options for event dates used in PFS, TTP, duration of response........118
List of figures
Figure 3-1
Study Design .........................................................................................28
Figure 4-1
Simulated absolute neutrophil count (ANC) mean profiles at 
different regimens of ribociclib.............................................................30
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List of abbreviations
aBC
advanced breast cancer
AE
adverse event
AESI
adverse events of special interest
AI
aromatase inhibitor
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
BC
breast cancer
BCRP
breast cancer resistance protein
BOR
Best Overall Response
BSEP
bile salt export pump
CABG
coronary artery bypass graft
CBP
childbearing potential
CBR
Clinical Benefit Rate
CDK
cyclin-dependent kinase
CFR
Code of Federal Regulation
CI
confidence interval
CISH
chromogenic in situ hybridization
Cmax
maximum concentration
CMO & PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
central nervous system
CR
Complete Response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTT
Clinical Trial Team
CV
coefficient of variation
CYP
cytochrome P450
DDE
direct data entry
DDI
drug-drug interaction
DHEA
Dehydroepiandrosterone
DILI
drug-induced liver injury
DOR
Duration of Response
EBV
Epstein–Barr virus
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EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
End of Treatment
ER
estrogen receptor
eSAE
Electronic Serious Adverse Event
ET
endocrine therapy
EU
European Union
FAS
Full Analysis Set
FDG-PET
Flouro-deoxyglucose positron emission tomography
FISH
fluorescence in situ hybridization
FPFV
first patient first visit
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GI
gastrointestinal
GnRH
Gonadotropin-releasing hormone
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HER2
Human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hormone receptor
HSV
herpes simplex virus
i.v.
intravenous
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IN
Investigator Notification
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LDH
lactate dehydrogenase
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LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
LPLV
last patient last visit
LVEF
Left Ventricular Ejection Fraction
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities
MI
myocardial infarction
MRI
Magnetic Resonance Imaging
MUGA
multiple gated acquisition
NaF PET
Sodium fluoride positron emission tomography
NASH
nonalcoholic steatohepatitis
NCI
National Cancer Institute
NI
non-inferiority margin
NR
not reportable
NSAI
non-steroidal aromatase inhibitor
NTI
narrow therapeutic index
ORR
Overall Response Rate
OS
Overall Survival
p.o.
oral
PAS
Pharmacokinetic Analysis Set
PD
progressive disease
PET
positron emission tomography
PFS
Progression Free Survival
PgR
progesterone receptor
PK
pharmacokinetic(s)
PPS
Per-Protocol Set
PR
Partial Response
PT
Prothrombin time
QD
Quaque Die (every day)
QMS
Quality Management System
Rb
retinoblastoma
RFS
Recurrence-Free Survival
RoW
rest of world
s.c.
subcutaneous
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
Steering Committee
SD
stable disease
SEC
safety event categories
SGOT
serum glutamic oxaloacetic transaminase
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SGPT
serum glutamic pyruvic transaminase
SISH
silver in situ hybridization
SMQ
Standardized MedDRA Query
SOP
standard operating procedure
StD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBIL
total bilirubin
TdP
Torsades de Pointe
Tmax
The time at which the maximum observed concentration (Cmax) occurs
TTR
Time to Response
ULN
upper limit of normal
US FDA
United States Food and Drug Administration
WBC
white blood cell(s)
WHO
World Health Organization
β-hCG
beta-human chorionic gonadotropin
Δ QTcF
change from baseline in QT interval in the ECG (corrected according to the formula 
of Fridericia)
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up), which 
applies across all arms of a study
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and 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 patient, corresponding to a 
specific treatment arm assignment
Screen Failure
A patient who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the patient came in for a final evaluation visit or when 
study drug was discontinued whichever is later
Study drug 
discontinuation
Point/time when patient permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature patient withdrawal
Study 
drug/treatment
Any drug (or combination of drugs) administered to the patient as part of the 
required study procedures; includes investigational drug, active drug run-ins 
or background therapy.
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Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient
Subject number
A number assigned to each patient who enrolls in the study. When combined 
with the center number, a unique identifier is created for each patient in the 
study
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
patient, corresponding to a specific treatment arm
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of 
consent (Woc)
Withdrawal of consent from the study is defined as when a patient does not 
want to participate in the study any longer, and does not want any further 
visits or assessments, and does not want any further study related contact, 
and does not allow analysis of already obtained biologic material
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Amendment 1 (24-Jan-2020)
Study CLEE011A2207 enrolled the first patient on 11-Jun-2019 and enrollment is currently 
ongoing with 125 patients in the study as of 24-Jan-2020.
Amendment rationale 
The purpose of this amendment is to capture the new safety information and other changes 
included below.
!
Interstitial Lung Disease (ILD)/pneumonitis has been observed across all CDK4/6 
inhibitors treatment (Please refer to IB ed.14 for more information) therefore a new 
table - Table 6-6, ‘Ribociclib dose adjustment and management recommendation for 
ILD/pneumonitis’, has been added.
!
Toxic Epidermal Necrolysis (TEN) has been reported in the post-marketing setting in 
a well-documented literature case report. No case was observed in the clinical trials.  
(Please refer to IB ed.14 for more information). The protocol section 6.3.1.4, Guidance 
for all other adverse reactions, has been updated with clear guidance to discontinue 
ribociclib if TEN is diagnosed.
!
If a patient is on tamoxifen/toremifene, the following have beenupdated:
o
Included tamoxifen/toremifene as examples of neo-/adjuvant anti-cancer 
therapy that must be stopped for a washout period of 5 half-lives before 
randomization due to risk of QT prolongation (note to exclusion criterion 2).
o
Criteria for assessing post-menopausal status, in line with NCCN v4 2018
guidelines.
!
Requirement for assessing sodium and phosphorus levels removed from inclusion 
criteria as abnormal sodium or phosphorus levels have no significant impact on QT 
prolongation.
!
Concurrent Hormone Replacement Therapy (HRT) use added as an exclusion criterion 
due to its impact on breast cancer.
!
Patients with named toxicities related to previous anticancer treatment that are not 
considered safety risks, allowed in to the study.
!
Uncorrected hypocalcemia included to exclusion criterion 14 as one of the risks factors 
for QT prolongation.
!
Guidance on corticosteroid use updated to be consistent with ‘Concomitant 
medications’ section.
!
Guidance on contraception updated to indicate that hormonal contraceptives are not 
allowed due to their impact on breast cancer.
!
For women who choose vasectomy of their male partner as the highly effective
method of contraception, the requirement to medically confirm vasectomy added as 
per the current Clinical Trial Facilitation Group (CTFG)guidelines.
!
Guidance updated on how to assess eligibility of patients participating in other medical 
research.
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!
Lists of prohibited medications and medications to be used with caution during study 
drug treatment.
!
Added the sample size justification for PK analysis. 
!
Other editorial changes throughout the document.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
!
Section 5.1: Updated the following inclusion criteria:  
!
8: Removed sodium and phosphorus as laboratory values that must be within normal 
limits before first dose of study drug.
!
13: Clarified contraception requirements. Vasectomy of male partners should be 
medically confirmed. Intrauterine systems (IUS) are not permitted.
!
14: Clarified how to determine postmenopausal status for patients taking tamoxifen 
or toremifene and age <60.
!
Section 5.2: Updated the following exclusion criteria:
!
2: Clarified permitted prior neo-/adjuvant therapy with exemestane. Added neo-
/adjuvant tamoxifen/toremifene as examples requiring a washout period of 5 half-
lives before randomization due to risk of QT prolongation.
!
6: Added exception, permitting patients with grade 1 taxane-induced neuropathy.
!
7: Added exclusion of patients with 25% of the bone marrow previously irradiated.
!
14: Added uncorrected hypocalcemia as an excluded risk factor for Torsades de 
Pointe (TdP).
!
16: Clarified exclusion of patients participating in other studies involving 
investigational drugs and in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
!
17: Clarified exception that a short duration of systemic corticosteroids is permitted 
at any dose. 
!
18: Added criteria excluding patients concurrently using hormone replacement 
therapy.
!
Table 6-1: Corrected provision of supplies to be either globally by sponsor or locally.
!
Section 6.2.1.1.3: Added that cumulative courses of radiotherapy should not encompass 
>25% of irradiated bone marrow. 
!
Table 6-2: Corrected ribociclib capsules to ribociclib tablets.
!
Table 6-6: Added ribociclib dose adjustment and management recommendations for 
ILD/pneumonitis.
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!
Section 6.5.1.2: Clarified that ribociclib should be discontinued if TEN is diagnosed.
!
Section 8.1: Clarified ECG evaluations used to determine eligibility can be repeated within 
the screening window for results out of the defined range before screen failing the patient.
!
Section 8.4.2: Updated that ECG for eligibility assessment should be performed at least 72 
hours before scheduled randomization date. Clarified that if QTcF value as the average of a 
triplicate ≥ 481 ms, study treatment must be interrupted, ECG repeated and management 
guidelines followed.
!
Section 8.4.3: Clarified that FSH, estradiol, serum and urine pregnancy tests are to be 
performed locally.
!
Section 8.5.1: Specified the number of evaluable patients required for the extensive PK 
analysis
!
Section 12.7.3: Added the sample size justification of PK cohort.
!
Table 16-1: List of prohibited medications updated.
!
Table 16-2: List of medications to be used with caution updated.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Protocol summary
Table 1
Protocol summary
Protocol number
LEE011A2207
Full Title
A phase II, multicenter, randomized, open-label study to evaluate the safety 
and efficacy of 400 mg of ribociclib in combination with non-steroidal 
aromatase inhibitors for the treatment of pre- and postmenopausal women 
with hormone receptor-positive, HER2-negative advanced breast cancer who 
received no prior therapy for advanced disease
Brief title
Study of safety and efficacy of 400 mg of ribociclib in combination with non-
steroidal aromatase inhibitors (NSAIs) in pre- and postmenopausal women 
with hormone receptor-positive, HER2-negative advanced breast cancer who 
received no prior therapy for advanced disease
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
QT interval prolongation and neutropenia are considered to be important 
concentration dependent identified risks for ribociclib (Kisqali® Prescribing 
Information, Investigator Brochure). This study compares the currently 
approved dosing regimen of ribociclib 600 mg orally QD, 3 weeks on/1 week 
off in combination with NSAI (control arm) to ribociclib 400 mg orally QD, 3 
weeks on/1 week off in combination with NSAI (experimental arm).
The purpose of the study is to evaluate if the reduced dosing regimen of 400 
mg ribociclib maintains efficacy of ribociclib in combination with an NSAI in 
pre- and postmenopausal women with HR-positive, HER2-negative aBC who 
have received no prior therapy for advanced disease while decreasing the 
risk of QTc prolongation. The risks of other AESI, such as neutropenia and 
hepatobiliary toxicity will be evaluated in this study as well. 
Primary 
Objective(s) 
The primary objective of this study is to determine whether the overall 
response rate (ORR) in the experimental arm (400 mg) is non-inferior to the 
control arm (600 mg) based on local tumor assessments (RECIST version 
1.1) for all patients that have been treated for at least 6 months or have 
discontinued the study treatment.
Secondary 
Objectives
Key secondary objective:
To evaluate QTc (with Fridericia's correction) prolongation in the 
experimental arm based on ∆QTcF at Cycle 1 Day 15 (at 2 h post-dose) 
Other secondary objectives:
To evaluate each treatment arm with respect to:
!
Safety and tolerability based on frequency/severity of AEs including AEs 
of special interest (e.g. hepatobiliary toxicities, neutropenia), laboratory 
abnormalities, and the totality of ECG data observed including all post-
baseline time points and the notable QTcF elevations
!
Progression-free survival (PFS), Clinical benefit rate (CBR), Time to 
response (TTR) and Duration of response (DOR) per RECIST 1.1
!
Pharmacokinetics (PK) of ribociclib when given in combination with NSAI 
based on PK parameters such as Cmax, Tmax, and AUC0-24h for 
ribociclib
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Study design
This is a phase II, multicenter, randomized, open-label study to evaluate the 
safety and efficacy of a reduced ribociclib dose of 400 mg in combination 
with an NSAI (letrozole or anastrozole) for the treatment of pre- and 
postmenopausal women with HR-positive, HER2-negative aBC who have 
received no prior therapy for advanced disease. Premenopausal women will 
also be receiving goserelin in both treatment arms.
Patients will be randomly assigned to one of the below treatment arms in a 
1:1 ratio:
!
Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off 
+ NSAI (+ goserelin in premenopausal women)
!
Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off 
+ NSAI (+ goserelin in premenopausal women)
Randomization will be stratified by the presence of lung and/or liver 
metastases (yes versus no). In each stratum, patients will be randomly 
assigned to the experimental arm or the control arm in a 1:1 ratio.
Population
Pre- and postmenopausal women with HR-positive, HER2-negative 
advanced (i.e. loco-regionally recurrent or metastatic) breast cancer who 
have received no prior ET for advanced disease. Patients must be ≥ 18 
years-old at the time of informed consent. Approximately 350 patients will be 
randomly assigned in a 1:1 ratio to either the Experimental (175 patients) or 
Control arms (175 patients).
Key Inclusion 
criteria
Refer to Section 5.1 for details on inclusion criteria.
!
Patient has advanced (loco-regionally recurrent or metastatic) breast 
cancer not amenable to curative therapy.
!
Patient has a histologically and/or cytologically confirmed diagnosis of 
ER-positive and/or PgR-positive breast cancer based on the most 
recently analyzed tissue sample, and all tested by local laboratory.
!
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.
!
Patient must have measurable disease, i.e., at least one measurable 
lesion according to RECIST version 1.1. (a lesion in a previously 
irradiated site may only be counted as a target lesion if there is clear 
evidence of progression since the irradiation).
!
Patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status 0 or 1.
!
Standard 12-lead ECG values defined as the mean of the triplicate ECGs 
and assessed by the central laboratory: 
!
QTcF interval at screening < 450 ms (QT interval using Fridericia’s 
correction)
!
Mean resting heart rate 50 to 90 bpm (determined from the ECG)
!
Women of childbearing potential (CBP), defined as all women 
physiologically capable of becoming pregnant, must have confirmed 
negative serum pregnancy test (for β-hCG) within 14 days prior to 
randomization.
!
Women of CBP must be willing to use highly effective methods of 
contraception.
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Key Exclusion 
criteria
Refer to Section 5.2 for details on exclusion criteria.
!
Patient with symptomatic visceral disease or any disease burden that 
makes the patient ineligible for endocrine therapy per the investigator’s 
judgment.
!
Patient who received any prior systemic anti-cancer therapy (including 
endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. 
Patients who received neo-/adjuvant therapy for breast cancer are 
eligible.
!
Patient is concurrently using other anti-cancer therapy.
!
Patient has had major surgery within 14 days prior to starting study drug 
or has not recovered from major toxicities.
!
Patient has received extended-field radiotherapy ≤ 4 weeks 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 has a concurrent malignancy or malignancy within 3 years of the 
randomization date, with the exception of adequately treated basal or 
squamous cell skin carcinoma, or curatively resected cervical carcinoma 
in situ.
!
Patients with central nervous system (CNS) involvement unless they 
meet specific stability criteria.
!
Patient has clinically significant, uncontrolled heart disease and/or 
cardiac repolarization abnormality.
!
Patient is currently receiving or has received systemic corticosteroids ≤ 2 
weeks prior to starting study drug, and has not fully recovered from side 
effects of such treatment.
Study treatment
"Study treatment” in this study refers to the combination of drugs and 
includes investigational drug (ribociclib) as well as NSAIs and goserelin. For 
this study, the term “investigational drug” refers to Novartis drug ribociclib 
(LEE011). The other drugs to be used in this study are NSAIs (letrozole or 
anastrozole) and premenopausal women will also be required to receive 
goserelin. Patients will be assigned at visit Cycle 1 Day 1 to one of the 
following two treatment arms: 
!
Arm 1: Ribociclib 400 mg (2 x 200 mg tablets by mouth) QD on days 1 to 
21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) 
+ letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by 
mouth QD continuously (+ goserelin 3.6 mg subcutaneously once every 
4 weeks for premenopausal women)
!
Arm 2: Ribociclib 600 mg (3 x 200 mg tablets by mouth) QD on days 1 to 
21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) 
+ letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by 
mouth QD continuously (+ goserelin 3.6 mg subcutaneously once every 
4 weeks for premenopausal women)
Efficacy 
assessments
Efficacy assessments for the primary endpoint will include the following:
!
CT/MRI with contrast (Chest, Abdomen and Pelvis) every 8 weeks for the 
first 18 months, then every 12 weeks  until 36 months and thereafter as 
clinically indicated until disease progression, death, withdrawal of 
consent, loss to follow-up, or subject/guardian decision (±7 days for all 
intervals).
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!
Brain CT or MRI as clinically indicated.
!
Whole body bone scan at screening if not collected previously within 42 
days prior to randomization; as clinically indicated thereafter.
!
Bone x-ray, CT or MRI (if bone lesion at screening) every 8 weeks for the 
first 18 months and then every 12 weeks  until 36 months and thereafter 
as clinically indicated (±7 days for all intervals).
!
Skin color photography (if skin lesions at screening) every 8 weeks 
during the first 18 months and then every 12 weeks  until 36 months and 
thereafter as clinically indicated (±7 days for all intervals).
!
CT/ MRI for any disease outside of the chest, abdomen, pelvis (if lesion 
identified at screening) every 8 weeks for the first 18 months and then 
every 12 weeks  until 36 months and thereafter as clinically indicated (±7 
days for all intervals).
Key safety 
assessments
!
Physical examinations
!
ECOG performance status
!
Height, weight, and vital signs
!
12 lead Electrocardiograms
!
Laboratory assessments including hematology, chemistry, coagulation 
via International normalized ratio (INR) and pregnancy.
Pharmacokinetic 
assessments 
!
Blood collections for PK assessment of ribociclib will be obtained from all 
patients according to schedule of PK blood collection (Section 8.5.1.1.1).
!
In a subset of patients (~20 patients per arm), extensive PK blood 
sampling will be performed and samples will be collected as specified in 
Table 8-7. In all the remaining patients, PK samples will be collected 
matching the ECG measurement time points as specified in Table 8-8.
Data analysis
Refer to section 12 for details on data analysis and statistical methods.
!
The primary efficacy endpoint of the study is to evaluate the non-
inferiority of Arm 1 compared to Arm 2, based on the ratio of ORR 
between the two arms based on local tumor assessment. The 
experimental arm (Arm 1) will be considered to be non-inferior to the 
control arm (Arm 2) if the lower 90% CI limit of the ratio of the ORR in 
Arm 1 to Arm 2 is > 0.814. The CI of ORR ratio will be constructed using 
Mantel-Haenszel method to include lung/liver metastasis as the 
stratification factor. The non-inferiority (NI) margin of 0.814 was chosen
to demonstrate that ribociclib 400mg in combination with NSAI retains at 
least 50% of the treatment effect in terms of ORR of ribociclib 600mg in 
combination with NSAI vs. NSAI alone.
!
The Per-Protocol Set (PPS) is a subset of patients of the Full Analysis
Set (FAS) without major protocol deviations. The PPS will be used for the 
analysis of the primary efficacy endpoint.
!
Other efficacy analyses including PFS, CBR, TTR and DOR will be 
analyzed using FAS which is comprised of all patients to whom study 
treatment has been assigned by randomization. According to the intent to 
treat principle, patients will be analyzed according to the treatment and 
strata they have been assigned to.
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!
For the key secondary endpoint of the study, the objective of mitigating 
QT prolongation will be met if the upper 90% CI limit of the ∆QTcF at 
Cycle 1 Day 15 (2 h post-dose) in Arm 1 is less than 20 ms. Change from 
baseline of QTcF at other time points will also be summarized. Notable 
elevations of QTcF will be summarized based on all on-treatment ECG 
assessments. The totality of the safety data obtained in Arms 1 and 2, 
generated from each time point as outlined in the ECG monitoring and 
assessment schedule, will be compared as part of the overall 
assessment for QT prolongation risk mitigation.
!
The assessment of other safety endpoints will be based mainly on the 
frequency of adverse events and on the number of laboratory values that 
fall outside of pre-determined ranges. 
!
The Safety Set 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/assigned treatment if the patient took at least one dose of 
that treatment or the first treatment received if the randomized/assigned 
treatment was never received. 
!
The Pharmacokinetic Analysis Set consists of all patients who received 
at least one dose of ribociclib and provide at least one evaluable PK 
concentration. PK parameters of ribociclib (and any relevant metabolites) 
will be listed by treatment and patient.
Key words
HR-positive, HER2-negative, ER-positive, PgR-positive, advanced breast 
cancer, ribociclib, NSAI, goserelin, letrozole, anastrozole, CDK4/6, Phase II, 
premenopausal and postmenopausal.
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1
Introduction
1.1
Background
1.1.1
Breast cancer epidemiology and current treatment landscape
Breast cancer (BC) is the most common form of cancer affecting women, accounting globally 
for 25% of all cancers and approximately 15% of all cancer deaths (Bray et al 2018).
It is a phenotypically diverse disease, the predominant subtype being the one whose tumor cells 
overexpress estrogen (ER) and/or progesterone (PgR) receptors. Approximately 70% of 
invasive breast cancers in women >50 years of age express ER and/or PgR, but not Human 
epidermal growth factor receptor 2 (HER2), and are termed hormone receptor-positive (HR-
positive), HER2-negative (Howlader et al 2014).
Endocrine therapy (ET) is the core treatment modality for patients with HR-positive, HER2-
negative advanced breast cancer (aBC) (NCCN guidelines, 2018).
However, endocrine 
resistance eventually develops in virtually all patients and newer treatment modalities to 
overcome such resistance have been developed, such as the combined use of cyclin-dependent 
kinase (CDK) 4/6 inhibition and ET, leading to a substantially improved efficacy. Additionally, 
given that a substantial proportion of women with newly diagnosed aBC have few symptoms 
related to their cancer, measures to mitigate any increased treatment-related toxicity are 
important.
1.1.2
Role of the CDK4/6 pathway in BC
Dysregulation of the cyclin-dependent kinase (CDK)4/6-Retinoblastoma (Rb)- E2F pathway is 
an important contributor to ET resistance in BC. The luminal A and B subtypes of BC (85% of 
which are ER-positive and HER2-negative) have high rates of cyclin D/CDK activation; in the 
luminal A and B subtypes, cyclin D1 (CCND1) amplifications were observed in 29% and 58%, 
and CDK4 amplifications were observed in 14% and 25%, respectively (Holm et al 2012,
Cancer Genome Atlas 2012, Cancer Genome Atlas 2012). Luminal A subtype tumors also have 
loss of CDKN2A, which encodes p16INK4A, a CDK inhibitor (Beroukhim et al 2010). The 
luminal subtypes also maintain expression of Rb, which is essential for benefit from treatment 
with a CDK4/6 inhibitor (Thangavel et al 2011).
Dysregulation of cell cycle checkpoints may have clinical and therapeutic significance. For 
example, patients with HR-positive BC exhibiting a gene expression signature of Rb loss had a 
shorter recurrence-free survival (RFS) following adjuvant tamoxifen (Bosco et al 2007). A 
tumor gene expression signature of E2F activation is also associated with higher residual tumor 
cell proliferation following neoadjuvant aromatase inhibitor (AI) therapy. Therefore, activation 
of the CDK4/6-Rb-E2F pathway promotes endocrine resistance, and treatment with a CDK4/6 
inhibitor or knockdown of CDK4 expression leads to reactivation of Rb, binding back of E2F 
and subsequent cell cycle arrest, thus abrogating endocrine-resistant cell proliferation.
Selective inhibitors of CDK4/6, such as palbociclib, abemaciclib and ribociclib, demonstrated 
synergy with ET in preclinical studies and efficacy in clinical studies and have been approved 
as initial therapy (in combination with an AI) or after disease progression following prior ET 
(in combination with fulvestrant) in patients with HR-positive, HER2-negative aBC 
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(Turner et al 2015, 
Loibl et al 2016, 
Goetz et al 2017, 
Hortobagyi et al 2016, 
Slamon et al 2018, Finn et al 2016) (refer to the current ribociclib Investigator’s Brochure (IB) 
and the current Kisqali® prescribing information for more information about the efficacy of 
ribociclib).
Considering the demonstrated efficacy of CDK4/6 inhibitors in combination with endocrine 
therapy in the treatment of both pre and postmenopausal patients with HR-positive, HER2-
negative aBC, co-targeting the CDK4/6-Rb-E2F pathway with CDK4/6 inhibitors may be a 
viable strategy to enhance endocrine responsiveness and prevent or delay the development of 
acquired resistance in both pre and postmenopausal women.
1.1.3
Overview of Investigational Treatment and Other Trial Treatments
This study includes treatment with ribociclib (LEE011) and ET using non-steroidal aromatase 
inhibitors (NSAI: anastrozole or letrozole) +/- goserelin (in premenopausal women only).
1.1.3.1
Overview of Ribociclib
Ribociclib is an orally bioavailable and highly selective small molecule inhibitor with highly 
specific nanomolar inhibitory activity against the CDK4/cyclin-D1 and CDK6/cyclin-D3 
enzyme complexes.
In the United States, Ribociclib (Kisqali®) has been approved by the United States Food and 
Drug Administration (U.S. FDA) in combination with:
!
an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women 
with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial ET
or
!
fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative 
advanced or metastatic breast cancer, as initial ET or following disease progression on ET.
In EU, Ribociclib (Kisqali®) has been approved by the European Commission as an initial ET 
for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or 
metastatic BC in combination with an AI.
1.1.3.1.1 Clinical experience
Ribociclib is being investigated in patients with BC and other solid tumors in multiple clinical 
trials at different phases of development. Three large phase III studies in patients with aBC have 
led to regulatory approvals as detailed above.
1.1.3.1.2 Clinical safety
Clinical safety of ribociclib with endocrine agents such as letrozole, tamoxifen, exemestane, 
fulvestrant, and goserelin has been evaluated in several combination trials. The safety profile 
of ribociclib in combination with NSAI (+/- goserelin) was investigated in two phase III trials 
in aBC (MONALEESA-2 [CLEE011A2301] and MONALEESA-7 [CLEE011E2301]). 
Important identified risks for ribociclib treatment include corrected QT (QTc) interval 
prolongation, hepatotoxicity, and myelosuppression, mainly neutropenia.
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In a pooled dataset of patients treated with ribociclib plus NSAI in MONALEESA-2 
(CLEE011A2301), 
MONALEESA-7 
(CLEE011E2301) 
and 
the 
phase 
II 
study 
CLEE011X2107 (n=629), 4.7% and 1.0% of patients had at least one post-baseline ECG 
showing QTcF > 480 ms and > 500 ms, respectively. The corresponding frequencies were 0.9% 
and 0% in patients in the placebo plus NSAI group (n=577). Furthermore, 5.0% of patients 
treated with ribociclib plus NSAI had at least one episode of > 60 ms QTcF prolongation 
compared with 0.2% in patients treated with placebo plus NSAI. The proportion of patients with 
hepatobiliary toxicity events was also higher in ribociclib group than the placebo group (24.6% 
vs. 17.2%). The most frequently reported events in this category included increased ALT 
(16.1% vs. 6.4%) and increased AST (15.3% vs. 6.9%). Additionally, any grade neutropenia 
occurred in 78.2% of patients treated with ribociclib plus NSAI, compared with 6.6% of patients 
in the pool treated with placebo plus NSAI. Febrile neutropenia was reported in 1.6% and 0.3% 
of patients respectively.
Irrespective of grade and causality, the AEs experienced by a higher proportion (with ≥ 10% 
difference) of patients in the ribociclib plus NSAI group (n=629) compared to the placebo plus 
NSAI group (n=577) included: neutropenia (+56.9%), decreased neutrophil count (+24.3%), 
nausea (+18.3%), decreased WBC count (+15.0%), alopecia (+13.7%), anemia (+13.6%), and 
leukopenia (+13.2%).
For a comprehensive review of the safety profile of ribociclib in combination with endocrine 
agents, please refer to the current ribociclib IB and Kisqali® prescribing information, as 
appropriate.
1.1.3.1.3 Clinical efficacy
Efficacy of ribociclib with endocrine agents has been evaluated in three published phase III 
combination trials in patients with aBC, two of them evaluating the combination of ribociclib 
with NSAI (+/- goserelin).
MONALEESA-2 (CLEE011A2301) is a phase III, double-blind, placebo-controlled, 
multicenter study of the combination of ribociclib or placebo with letrozole in postmenopausal 
women with HR-positive, HER2-negative aBC who have not received prior therapy for their 
advanced disease. The study met its primary objective at a pre-specified interim analysis where 
ribociclib in combination with letrozole demonstrated statistically significant benefit over 
placebo in combination with letrozole in prolonging investigator-assessed progression free 
survival (PFS); (Hazard ratio = 0.556, 95% CI: 0.429, 0.720; one sided p-value = 3.29×106). An 
updated PFS analysis performed approximately 12 months later, demonstrated continued 
efficacy of ribociclib, with the median PFS prolonged by 9.3 months, from 16.0 months in 
the placebo with letrozole arm to 25.3 months in the ribociclib with letrozole arm. While 
the overall survival (OS) data was still immature at time of the updated PFS analysis, there was 
numerically lower number of deaths in the ribociclib with letrozole arm compared to 
the placebo with letrozole arm.
Similarly, MONALEESA-7 (CLEE011E2301) is a randomized double-blind phase III study of 
ribociclib or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase 
inhibitor (NSAI) and goserelin for the treatment of pre- and perimenopausal women with HR-
positive, HER2-negative, aBC who received no prior hormonal therapy for advanced 
disease. The study met its primary endpoint by increasing median PFS (per investigator 
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assessment) from 13.0 months (95% CI: 11.0 to 16.4) with placebo to 23.8 months (95% CI: 
19.2 - NR) with ribociclib (P = 9.83×10–8; hazard ratio = 0.55; 95% CI: 0.44 - 0.69). The results 
were consistent in the subgroup of patients who received NSAI as endocrine combination 
partner with a 43.1% relative risk reduction (hazard ratio = 0.569; 95% CI 0.436, 0.743) and a 
13.7-month prolongation in median PFS.
Please, refer to the current ribociclib IB and Kisqali® prescribing information for additional 
details on the efficacy profile of ribociclib.
1.1.3.1.4 Clinical Pharmacokinetics of Ribociclib
The clinical pharmacokinetics (PK) of ribociclib have been evaluated in a phase I study in 
patients with advanced solid tumors or lymphomas (CLEE011X2101). Following repeated 
daily oral administration, steady-state of ribociclib was achieved by approximately Day 8. 
LEQ803, an active metabolite of ribociclib, has similar PK characteristics as the parent drug. 
Neither ribociclib nor LEQ803 accumulate substantially following repeated daily 
administration.
Ribociclib undergoes extensive hepatic metabolism via CYP3A in humans based on in vitro
and in vivo studies. Ribociclib is mainly eliminated via hepatic clearance, with renal clearance 
playing a lesser role in humans. The majority of the administered dose was excreted in feces 
(69.1%), with a minor amount excreted in urine (22.6%). Ribociclib accounted for 
approximately 23% of the total radioactivity in plasma (CLEE011A2102). The most prominent 
metabolites in plasma are CCI284 (N-hydroxylation), LEQ803 (N-demethylation), and M1 
(secondary glucuronide), each representing <10% of total radioactivity. The clinical activity 
(pharmacological and safety) following ribociclib treatment 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 
strong CYP3A4 inhibitor (ritonavir) increased ribociclib AUC by 3.2-fold following a single 
oral dose of 400 mg ribociclib (CLEE011A2101). Co-administration of a strong CYP3A4 
inducer (rifampicin) decreased ribociclib AUCinf by 89% following a single oral dose of 600 
mg ribociclib (CLEE011A2101).
Ribociclib is a moderate to strong inhibitor of CYP3A4, but did not have a substantial effect on 
CYP1A2 substrates in humans (CLEE011A2106). Co-administration of midazolam (CYP3A4 
substrate) with multiple doses of ribociclib (400 mg) increased midazolam exposure by 3.8-
fold. Co-administration of caffeine (CYP1A2 substrate) with multiple doses of ribociclib (400 
mg) increased caffeine exposure by 20% (1.2-fold). Concurrent use of sensitive CYP3A4 
substrates with a narrow therapeutic index should be avoided. Concurrent use of CYP1A2 
substrates is not expected to lead to clinically important drug-drug interaction (DDI).
Food does not affect the PK of ribociclib administered as a capsule or tablet formulation; 
therefore ribociclib capsules or tablets can be taken without regard to meals (CLEE011A2111, 
CLEE011A2103).
No apparent drug-drug interaction (DDI) was observed between ribociclib and the combination 
partner letrozole or anastrozole based on PK data in the MONALEESA-2 and -7 trials. Based 
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on the population PK analysis, concomitant use of letrozole or anastrozole had no impact on 
ribociclib exposure.
Refer to the current ribociclib IB and Kisqali® prescribing information for additional details.
1.1.3.2
Overview of Non-steroidal Aromatase Inhibitors (NSAIs) and GnRH 
agonists
The following sections provide general information on Letrozole and Anastrozole (NSAIs) and 
goserelin (GnRH agonist). Refer to the current local prescribing information and local clinical 
guidelines for comprehensive safety and efficacy information and guidance for each medication.
1.1.3.2.1 Overview of Letrozole
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole 
acts by highly selective inhibition of the conversion of androgens (mainly from adrenal glands, 
the primary source of estrogens in postmenopausal women) to estrogens. Letrozole induces a 
75% to 95% decrease of estrogen levels after two weeks of treatment with daily doses of 0.1 to 
5 mg, with no significant clinical and laboratory toxicities or changes in levels of other 
hormones.
Letrozole is administered orally once daily at a dose of 2.5 mg. It is rapidly and completely 
absorbed from the GI tract. Concomitant intake of food has no effect on the extent of its 
absorption. Letrozole is metabolized via CYP3A4 to a pharmacologically-inactive metabolite 
and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of 
letrozole clearance.
Letrozole (2.5 mg daily) and ribociclib (600 mg daily, 3 weeks on/1 week off) did not affect 
metabolism of each other in a phase Ib/II dose escalation/expansion study (CLEE011X2107).
The most frequently reported adverse events (AE) for letrozole in clinical trials were hot flushes, 
arthralgia/arthritis and myalgia. In the first line setting, the most frequently reported adverse 
events include musculoskeletal pain (bone/back pain and arthralgia), hot flushes, nausea and 
dyspnea. In general, the observed adverse reactions are mild to moderate in nature.
Refer to the current local prescribing information for more information on letrozole.
1.1.3.2.2 Overview of Anastrozole
Anastrozole, like letrozole, is a selective NSAI. It significantly lowers serum estradiol 
concentrations with no detectable effect on the formation of adrenal corticosteroids or 
aldosterone.
Anastrozole is administered orally once daily at a dose of 1 mg, taken with or without food. 
Anastrozole is metabolized by N-dealkylation, hydroxylation and glucuronidation. Hepatic 
metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination 
accounts for approximately 10% of total clearance. The major circulating metabolite of 
anastrozole lacks pharmacologic activity. Anastrozole metabolism occurs mainly via CYP3A4 
and UGT1A4 based on in vitro data. Therefore, anastrozole metabolism may potentially be 
affected by co-administration with ribociclib. However, anastrozole has been studied up to 
doses of 10 mg/day (10-times daily dose) and all doses evaluated were well tolerated with no 
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serious acute toxicities attributed to anastrozole. Additionally, no evidence of a PK interaction 
between ribociclib and anastrozole was observed in MONALEESA-7 (CLEE011E2301).
Refer to the current local prescribing information for more information on anastrozole.
1.1.3.2.3 Overview of Goserelin
GnRH agonists are synthetic analogues of gonadotropin-releasing hormone that by continuous 
stimulation of the GnRH receptor achieve desensitization of the pituitary gland to GnRH. GnRH 
agonists differ from the naturally-occurring GnRH by modifications in the decapeptide structure 
(usually by amino acid substitution in position 6, but also in positions 9 and 10) to decrease 
degradation of the molecule.
Goserelin is the GnRH agonist to be used in this study. Goserelin is administered 
subcutaneously every 28 days at a dose of 3.6 mg. Following subcutaneous administration of 
goserelin (3.6 mg for 2 months), Tmax was 8 to 22 days post-dose in female subjects. The most 
common AEs occurring in women treated with goserelin include hot flushes, headache, 
sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, 
seborrhea and peripheral edema.
The metabolism of goserelin is not CYP-mediated; rather hydrolysis of C-terminal amino acids 
is the major clearance mechanism. No formal clinical DDI studies have been conducted or 
reported with goserelin. Based on the available information, no DDI between goserelin and 
ribociclib is expected (Zoladex® Prescribing Information).
Refer to the current local prescribing information and/or clinical guidelines for more 
information on goserelin.
1.2
Purpose
QT interval prolongation and neutropenia are considered to be important identified risks for 
ribociclib (Kisqali® Prescribing Information, Investigator Brochure). The approved dosing 
regimen of ribociclib (Kisqali®) is 600 mg daily (QD) on a 3 weeks on/1 week off schedule.
The purpose of the study is to explore a reduced dosing regimen of 400 mg ribociclib orally QD 
3 weeks on/1 week off that may decrease the risk of QTc prolongation without compromising 
the efficacy of ribociclib in combination with an NSAI in pre- and postmenopausal women with 
HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease. 
The risks of other AEs of special interest, such as neutropenia and hepatobiliary toxicity will 
be evaluated in this study as well.
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
!
To determine whether the overall 
response rate (ORR) in the 
experimental arm is non-inferior to the 
control arm.
!
ORR is based on local tumor assessments 
(RECIST version 1.1) for all patients that have 
been treated for at least 6 months or have 
discontinued the study treatment. 
Secondary objective(s)
Endpoint(s) for secondary objective(s)
!
Key secondary objective:
To evaluate QTc (with Fridericia's 
correction) prolongation in the experimental 
arm
!
Key Secondary endpoint:
∆QTcF at Cycle 1 Day 15 (at 2h post-dose)
!
Other Secondary objectives:
To evaluate each treatment arm with 
respect to:
!
Other Secondary endpoints:
!
Safety and tolerability (including 
hepatobiliary toxicities and neutropenia)
!
Frequency/ severity of AEs, including AEs of 
special interest (e.g. hepatobiliary toxicities, 
neutropenia)
Laboratory abnormalities
Summary of ∆QTcF at timepoints other than 
Cycle 1 Day 15 (at 2hr post-dose)
ECG notable values based on all post baseline 
assessments.
!
Progression-free survival (PFS)
!
PFS per RECIST 1.1
!
Clinical benefit rate (CBR)
!
CBR per RECIST 1.1
!
Time to response (TTR)
!
TTR per RECIST 1.1
!
Duration of response (DOR)
!
DOR per RECIST 1.1
!
Pharmacokinetics (PK) of ribociclib 
when given in combination with NSAI
!
PK parameters such as Cmax, Tmax, and AUC0-
24h for ribociclib
3
Study design
This is a phase II, multicenter, randomized, open-label study to evaluate the safety and efficacy 
of a reduced starting ribociclib dose of 400 mg in combination with an NSAI (letrozole or 
anastrozole) for the treatment of pre- and postmenopausal women with HR-positive, HER2-
negative aBC who have received no prior therapy for advanced disease. Premenopausal women 
will also be required to receive goserelin in both treatment arms.
Approximately 350 patients will be randomly assigned to one of the below treatment arms in a 
1:1 ratio (Figure 3-1):
!
Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ 
goserelin in premenopausal women): 175 patients
!
Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin 
in premenopausal women): 175 patients
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Randomization will be stratified by the presence of lung and/or liver metastases (yes versus no).
Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
This study compares the currently approved dosing regimen of ribociclib 600 mg orally QD, 3 
weeks on/1 week off to ribociclib 400 mg orally QD, 3 weeks on/1 week off.
The study will include pre- and postmenopausal women with hormone receptor-positive, 
HER2-negative aBC who received no prior therapy for advanced disease that will be 
randomized in a 1:1 ratio to the control and experimental arms.
The inclusion of a control arm (600 mg) is necessary in order to provide a contemporaneous 
comparator for assessment of efficacy, ∆QTcF and other descriptive comparisons. The 400 mg 
dosing regimen in the experimental arm is expected to maintain an efficacy benefit in patients 
with HR-positive, HER2-negative metastatic BC, with the potential for an improved safety 
profile by reducing QTcF prolongation and frequency of other AEs such as neutropenia.
The two-arm randomized design minimizes allocation bias, balancing both known and 
unknown prognostic factors in the assignment of treatments. Randomization is stratified by lung 
and/or liver involvement (yes versus no). This stratification factor was selected because of its 
well-recognized prognostic value in aBC. The primary analysis will be conducted when patients 
have been treated for at least 6 months from randomization or have discontinued study treatment. 
This is based on data from the MONALEESA-2 (CLEE011A2301) study that show that the 
majority of responses occur within this timeframe.
4.2
Rationale for dose/regimen and duration of treatment
Clinical studies show that ribociclib-induced QTcF interval prolongation is concentration-
dependent (current ribociclib IB and Kisqali® prescribing information).
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Based on pharmacokinetic (PK)-QTcF modeling, the 400 mg dose of ribociclib is estimated to 
result in a lower mean ∆QTcF (Table 4-1).
Table 4-1
Estimated Cmax and mean QTcF change from baseline at different 
dose regimens of ribociclib
Ribociclib dosing regimen
Estimated geometric mean 
Cmax (ng/mL)
Estimated mean ΔQTcF (ms) 
(90% CI) of ribociclib + NSAIa
600 mg QD 3 weeks on/1 week 
off (approved dosing regimen)
1870
22.6 (21.06, 24.06)
400 mg QD 3 weeks on/1 week 
off
1080
18.9 (17.65, 20.11)
a Estimated by PK-QT model based on the pop-PK model predicted Cmax,ss. Both models were 
developed based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, 
CLEE011A2301, CLEE011E2301 and CLEE011F2301. In MONALEESA-2 (CLEE011 A2301) 
observed ΔQTcF was 19.6 ms (90% CI: 18.0, 21.2).
Neutropenia is another important identified risk of ribociclib. In the Kisqali® prescribing 
information, ribociclib dose modification recommendations are provided for managing 
neutropenia based on the severity grade as per Common Terminology Criteria for Adverse 
Events (CTCAE). To assess the impact of the proposed 400 mg dose on neutropenia, modeling 
was performed for the parameter absolute neutrophil count (ANC) at different dosing regimens 
of ribociclib. Simulation of ANC profiles shows that ribociclib 400 mg QD leads to a smaller 
ANC decrease than the 600 mg QD dose (Figure 4-1).
Hepatobiliary toxicity, mostly manifested as transient increases in serum transaminases levels, 
is also an important identified risk of ribociclib, and dose modification recommendations are 
provided for its management in the prescribing information (Kisqali® Prescribing Information ). 
While simulation of hepatotoxicity at different doses of ribociclib was not performed due to 
low numbers of events of this toxicity and no relationship has yet been observed between 
ribociclib exposure and serum transaminases increases (data from MONALEESA-2), it is 
reasonable to presume that the incidence and severity of this toxicity may also decrease with a 
lower daily dose of ribociclib, thus potentially contributing to a better overall safety profile.
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Figure 4-1
Simulated absolute neutrophil count (ANC) mean profiles at different 
regimens of ribociclib
Note: Mean ANC profiles are predicted by the ANC exposure-response model developed based on 
data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, 
CLEE011E2301 and CLEE011F2301.
With regards to efficacy, post-hoc exploratory analyses of studies MONALEESA-2 
(CLEE011A2301), 
MONALEESA-3 
(CLEE011F2301) 
and 
MONALEESA-7 
(CLEE011E2301) suggest that patients who started ribociclib at 600 mg but had their dose 
reduced (e.g. due to AE) to 400 mg and 200 mg continued to experience treatment benefit, in 
terms of PFS and ORR .While these observations should be interpreted with caution due to the 
potential confounding factor of the 600 mg QD starting dose, they do provide insights regarding 
the potential effectiveness of lower ribociclib dose regimens.
Supporting this, there was no clear relationship between ribociclib exposure and efficacy 
endpoints based on exposure-efficacy analysis in either MONALEESA-7 or MONALEESA-3 
as well as in a pooled analysis of MONALEESA-2, MONALEESA-7 and MONALEESA-3.
In the exposure-efficacy analysis in each of MONALEESA-7 and MONALEESA-3, no clear 
relationship was observed between Ctrough_avg_ss quartile (geometric mean of Ctrough values 
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from C1D15 and C3D15 concentrations for MONALEESA-7 and C2D15 for MONALEESA-
3) and PFS or TTR in patients treated with ribociclib. In addition, there was no clear relationship 
between ribociclib exposure and efficacy from pooled population PK analyses.
In summary, based on the PK-QTcF modeling, exploratory PFS and ORR analyses, and 
supported by the PK-ANC modeling, the 400 mg total daily dose of ribociclib may be associated 
with less toxicity (e.g. lower ∆QTcF, lower incidence of neutropenia and possibly other adverse 
events) than the 600 mg daily dose, while potentially maintaining efficacy. Therefore, the 
ribociclib dosing regimen of 400 mg QD 3 weeks on/ 1 week off will be explored in patients 
with HR-positive, HER2-negative aBC in this study.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The control arm is ribociclib 600 mg QD 3 weeks on/1 week off on a 28-day cycle in 
combination with an NSAI (letrozole or anastrozole) and goserelin (for pre-menopausal women 
only), according to the approved Kisqali® label (prescribing information). The efficacy and 
toxicity of the control arm regimen have been assessed in Phase III studies that have led to 
regulatory approval of the regimen for this patient population. It represents one of the preferred 
treatment
options in this patient population according to international guidelines 
(NCCN guidelines 2018, Cardoso et al 2018) and it is an appropriate contemporaneous 
comparator for the experimental arm.
4.4
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned for this study. Refer to Section 12.6.
4.5
Risks and benefits
Based on clinical data, treatment of ribociclib in combination with NSAI is expected to be 
tolerable and toxicities of the treatment are expected to be manageable and reversible with 
treatment interruption, ribociclib dose reduction, or discontinuation. The 600 mg dose of 
ribociclib in combination with an NSAI has been investigated in the MONALEESA-2 and 
MONALEESA-7 Phase III studies in post- and premenopausal women with aBC respectively 
(see Section 1.1.3.1.2 and Section 1.1.3.1.3 for a summary of safety and efficacy respectively). 
Further details can be found in the prescribing information. Less toxicity is expected in Arm 1 
compared to Arm 2, given the decreased ribociclib dose, with the study aiming to demonstrate 
that this can be achieved while maintaining efficacy.
Patients in this study will be carefully monitored for key toxicities that have been observed with 
ribociclib (refer to the current ribociclib IB and Kisqali® prescribing information, as 
appropriate) and risks will be further minimized by adherence to inclusion/exclusion selection 
criteria ( Section 5 ), avoidance of prohibited medications ( Section 6.2.2 ), close safety 
monitoring ( Section 10 ) and dose modification guidelines ( Section 6.5 ).
As per the inclusion/exclusion selection criteria, 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 must agree that in order to participate in the study they must 
adhere to the contraception requirements outlined in the inclusion criteria. If there is any 
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question that the patient will not reliably comply, they should not be entered or continue in the 
study.
A Steering Committee (SC) will be established and it will be comprised of investigators and 
Novartis personnel participating in the trial, to ensure transparent management of the study 
according to the protocol through recommending and approving modifications as outlined 
in Section 10.2.1.
5
Population
Pre- and postmenopausal women with HR-positive, HER2-negative advanced (i.e. loco-
regionally recurrent or metastatic) breast cancer who have received no prior ET for advanced 
disease. 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:
1. Signed informed consent must be obtained prior to any screening procedures.
2. Patient is an adult female ≥18 years-old at the time of informed consent.
3. Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable 
to curative therapy.
4. Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or 
PgR-positive breast cancer based on the most recently analyzed tissue sample, and all 
tested by local laboratory.
5. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or 
an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or 
SISH) test is required by local laboratory testing and based on the most recently analyzed 
tissue sample.
6. Patient must have measurable disease, i.e., at least one measurable lesion according to 
RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a 
target lesion if there is clear evidence of progression since the irradiation).
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
8. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory for eligibility):
!
Absolute neutrophil count ≥ 1.5 × 109/L
!
Platelets ≥ 100 × 109/L
!
Hemoglobin ≥ 9.0 g/dL
!
INR ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the 
therapeutic range of intended use for that anticoagulant within 7 days prior to the first 
dose of study drug).
!
Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the 
Modification of Diet in Renal Disease (MDRD) formula
!
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.
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!
Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver metastases, 
who are only included if the AST is <5 × ULN.
!
Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver metastases, 
who are only included if the ALT is < 5 × ULN.
!
Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements (the central laboratory value should be 
documented within normal limits after the correction) before the first dose of study 
drug: 
!
Potassium
!
Magnesium
!
Total calcium (corrected for serum albumin)
9. Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by 
the central laboratory:
!
QTcF interval at screening < 450 ms (QT interval using Fridericia’s correction)
!
Mean resting heart rate 50-90 bpm (determined from the ECG)
10. Patient must be able to swallow ribociclib tablets.
11. Patient must be able to communicate with the investigator and comply with the 
requirements of the study procedures.
12. Women of childbearing potential (CBP), defined as all women physiologically capable of 
becoming pregnant, must have confirmed negative serum pregnancy test (for β-hCG) 
within 14 days prior to randomization.
13. Women of CBP must be willing to use highly effective methods of contraception. 
Contraception must continue 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.
!
Female sterilization - surgical bilateral oophorectomy with or without hysterectomy, 
total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study
treatment. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. See the 
definition of CBP below for more information.
!
Male partner sterilization (at least 6 months prior to randomization). For patients on 
the study, the vasectomized male partner should be the sole partner for that patient
and the vasectomy must be medically confirmed as per local practice.
!
Placement of an intrauterine device (IUD).
Notes:
!
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.
!
Women are considered of CBP unless: they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, 
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history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks 
prior to randomization. In the case of oophorectomy alone, only after the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment, is 
she considered not of CBP.
14. Patient has a known menopausal status at the time of informed consent form (ICF) 
signature. Patient is considered postmenopausal if: i) she has had prior bilateral 
oophorectomy; ii) is age ≥ 60 years; iii) is age <60 years and has had amenorrhea for 12 or 
more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian 
suppression) and follicle stimulating hormone (FSH) and estradiol in the postmenopausal 
range per local normal ranges; iv) if taking tamoxifen or toremifene and age <60, then 
FSH and plasma estradiol level in postmenopausal range. (NCCN v15 2018). All other 
patients who do not meet the criteria for postmenopausal status are considered 
premenopausal and must receive goserelin in addition to the NSAI. 
15. 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 with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s judgment.
2. Patient who received any prior systemic anti-cancer therapy (including endocrine therapy, 
chemotherapy, prior CDK4/6 inhibitors) for aBC.
Note:
!
Patients who received neo-/adjuvant therapy for breast cancer are eligible. Neo-
/adjuvant therapy with letrozole, anastrozole, or exemestane must be stopped at least
12 months prior to the date of randomization. Prior neo-/adjuvant therapy with 
CDK4/6 inhibitors is not permitted.
!
Any other prior neo-/adjuvant anti-cancer therapy (e.g. tamoxifen or toremifene) must 
be stopped at least 5 half-lives or 7 days, whichever is longer, before the date of 
randomization.
!
Patients who received 14 or less days of letrozole or anastrozole for advanced disease 
prior to the date of randomization are eligible.
!
Patients who received 28 days or less of goserelin for advanced disease prior to the 
date of randomization are eligible. Patients who are receiving goserelin for reasons 
other than aBC (e.g. endometriosis or as adjuvant treatment) are also eligible.
3. Patient with a known hypersensitivity to any of the excipients of ribociclib (eg. ribociclib 
tablets coating contains soya lecithin, and therefore should not be taken by patients who 
are allergic to peanuts or soya), letrozole or anastrozole or goserelin (premenopausal 
women only).
4. Patient is concurrently using other anti-cancer therapy.
5. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major toxicities.
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6. Patient has not recovered from acute clinical and laboratory toxicities related to prior 
anticancer therapies to NCI CTCAE v4.03 grade ≤ 1 (except for patients with grade 1 
taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not 
considered a safety risk for the patient at investigator's discretion).
7. Patient has received extended-field radiotherapy ≤ 4 weeks 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). Patients in whom ≥ 
25% (Ellis 1961) of the bone marrow has been previously irradiated are also excluded.
8. Patient has a concurrent malignancy or malignancy within 3 years of the randomization 
date, with the exception of adequately treated basal or squamous cell skin carcinoma, or 
curatively resected cervical carcinoma in situ.
9. Patient has a history of HIV infection (testing is not mandatory unless required by local 
regulations).
10. Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is 
not mandatory unless required by local regulations).
11. Patients with central nervous system (CNS) involvement unless they meet the following 
two criteria:
!
At least 4 weeks have elapsed from CNS-directed prior therapy completion (e.g. 
including radiation and/or surgery) to study treatment start.
!
Clinically stable CNS tumor at the time of screening and not receiving steroids and/or 
enzyme inducing anti-epileptic medications for brain metastases.
12. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection).
13. Patient has any other concurrent severe and/or uncontrolled medical condition that would 
in the investigator’s judgment, cause unacceptable safety risks to the patient, 
contraindicate patient participation in the clinical study, or compromise compliance with 
the protocol.
14. Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormality, including any of the following:
!
History of documented myocardial infarction (MI), angina pectoris, symptomatic 
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study 
entry
!
Documented cardiomyopathy
!
Left Ventricular Ejection Fraction (LVEF) < 50% as determined by the multiple gated 
acquisition (MUGA) scan or echocardiogram (testing is not mandatory)
!
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
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!
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, whichever is longer)
!
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 (SBP) >160 or <90 mmHg
15. Patient is currently receiving any of the following substances and cannot be discontinued 7 
days prior to Cycle 1 Day 1:
!
Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pomelos, 
star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of 
CYP3A4/5;
!
Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5.
16. 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.
17. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, and has not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted:
!
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).
!
A short duration (< 5 days) of systemic corticosteroids.
18. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or 
breast-feed during the study.
19. Patient is concurrently using hormone replacement therapy.
6
Treatment
6.1
Study treatment
“Study treatment” in this study refers to the combination of drugs and includes investigational 
drug (ribociclib) as well as NSAIs and goserelin.
The term “investigational drug” refers to Novartis drug ribociclib (LEE011). The other drugs 
to be used in this study are NSAIs (letrozole or anastrozole) and goserelin.
Ribociclib (LEE011) will be supplied by Novartis or its designee in the form of 200 mg tablets 
as individual patient supply packaged bottles. Letrozole, anastrozole, and goserelin will be 
procured locally as they are commercially available in each participating country according to 
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local practices and regulations. Storage conditions are described in the medication labels. 
Medication labels will comply with the legal requirements of each country and be printed in the 
local language.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and combination drug
Investigational/ 
Combination 
Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Global or Local
Ribociclib 
(LEE011) 200 mg
Tablet
Oral use
Open label 
patient specific 
supply; Bottle
Sponsor - Global
Letrozole 2.5 mg
Tablet
Oral use
Open label 
patient packs
Local
Anastrozole 1 mg
Tablet
Oral use
Open label 
patient packs
Local
Goserelin 3.6 mg
Implant, in pre-
filled syringe
Subcutaneous 
use
Open label 
patient packs
Local
6.1.2
Additional study treatments
No other treatments beyond ribociclib and endocrine therapy (NSAI +/- goserelin) are included 
in this study.
6.1.3
Treatment arms/group
Patients will be assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a 
ratio of 1:1.
!
Arm 1:
!
Ribociclib 400 mg (2 x 200 mg tablets by mouth) QD on days 1 to 21 of a 28-day 
cycle, followed by 7 days off ribociclib (Days 22 to 28).
in combination with:
Endocrine therapy consisting of:
!
For postmenopausal women: 
!
Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD 
continuously.
!
For premenopausal women: 
!
Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD 
continuously, combined with:
!
Goserelin 3.6 mg subcutaneously once every 4 weeks.
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!
Arm 2:
!
Ribociclib 600 mg (3 x 200 mg tablets by mouth) QD on days 1 to 21 of a 28-day 
cycle, followed by 7 days off ribociclib (Days 22 to 28).
in combination with
Endocrine therapy consisting of: 
!
For postmenopausal women: 
!
Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD 
continuously.
!
For premenopausal women: 
!
Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD 
continuously, combined with:
!
Goserelin 3.6 mg subcutaneously once every 4 weeks.
Ribociclib, letrozole, anastrozole, and goserelin will be administered as a flat-fixed dose, and 
not by body weight or body surface area. The choice of letrozole or anastrozole is at the 
Investigator's discretion but switching from one to the other while on the study, is not allowed.
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). Drug accountability must be performed on a regular basis. 
Patients will be instructed to return unused study drugs to the site during their next scheduled 
visit. The site personnel will ensure that the appropriate dose of each study drug is provided at 
each scheduled visit.
6.1.3.1
General dosing guidelines
The study treatment should be taken as follows:
!
Ribociclib is dosed for the first 21 days out of the 28 day cycle.
!
On scheduled visit days, patients must take study treatment in the clinic under the 
supervision of the Investigator or designee. On all other days patients may take study 
treatment at home.
!
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. Up to Cycle 1 Day 15, study 
treatment must be taken in the morning due to PK assessments. Once the PK assessments 
have been completed, patients can determine if they prefer morning or early afternoon 
dosing, but should maintain a consistent time. Evening doses are strongly not 
recommended.
!
Ribociclib can be administered with or without food.
!
Patients should be instructed to swallow the ribociclib tablets whole and not to chew, 
crush or open them.
!
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the eCRF. Refer to 
Section 6.2.1.1.4 for use of anti-emetic medications.
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!
Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day.
!
Patients must avoid consumption of grapefruit, grapefruit hybrids, pomelos/pummelos, 
starfruit, Seville oranges or products containing their juice during the entire study. If 
consumed at baseline, they must be discontinued at least 7 days before the first dose of 
study treatment (Note: Orange juice is allowed).
!
Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or 
those with a known risk of QT prolongation are not permitted. Multivitamins are 
permitted.
!
Goserelin implant should be administered as a subcutaneous injection every 28 days using 
an aseptic technique under the supervision of a physician. Administration technique 
should be in accordance with the locally approved label (prescribing information).
6.1.3.2
Additional dosing guidelines for pharmacokinetic 
sampling/ECG/Chemistry panel collection
On days with PK, ECG sampling, and/or chemistry panel sampling, the following additional 
guidelines should be followed:
!
On a day when PK blood collection is scheduled at the clinic, patients must take study 
treatment in the clinic under the supervision of the Investigator or designee.
!
On a day of chemistry panel sampling, patients must be fasting from all food and drink for 
at least 8 hours overnight. Water is allowed during all fasting periods; however coffee, tea 
and juice are not permitted during the fasting period. Patients must also take study 
treatment in the clinic under the supervision of the Investigator or designee.
!
The patient may take the study treatment with or without food; however, dietary habits 
around the time of dosing should be as consistent as possible on days of PK sampling.
!
If a pre-dose ECG measurement should be collected, then the ECG measurement should 
occur before dosing of the study treatment.
!
If a pre-dose PK sample should be obtained, then the sample should be collected after the 
ECG and before dosing of the study treatment.
!
Pre-dose samples should be drawn prior to dosing. The sampling time of the PK samples 
and the dosing time must be precisely recorded in the eCRF. Furthermore, the dosing date 
and time the study treatment was taken on the day before the PK assessment must be 
precisely recorded in the eCRF.
!
Post-dose PK samples should be collected after dosing of the study treatment. PK sample 
collection will be performed according to Section 8.5.1.
6.1.4
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.5 .
Patients who permanently discontinue the NSAI (letrozole or anastrozole) for any reason must 
discontinue ribociclib and/or goserelin and move to End-of-Treatment Phase. Patients who 
permanently discontinue ribociclib for any reason other than disease progression, may continue 
on a NSAI (and goserelin if premenopausal) within the Treatment Phase per investigator’s 
discretion until disease progression, unacceptable toxicity, death or discontinuation from study 
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treatment due to any other reason and continue to be followed for safety and/or efficacy. Patients 
who only discontinue goserelin (e.g. after bilateral oophorectomy), if postmenopausal status is 
confirmed and with the Sponsor's agreement, may continue on ribociclib and NSAI per 
investigator's discretion in the Treatment Phase as described above.
6.1.5
Treatment duration
Patients will receive study treatment until disease progression (radiologically documented 
according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the 
study treatment for any other reason.
6.1.5.1
Treatment beyond disease progression
Continuation of study treatment beyond initial disease progression (RECIST 1.1) will not be 
allowed.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications (other than study drugs), procedures, and significant non-drug therapies 
(including vitamins, physical therapy and blood transfusions) administered within 30 days of 
study entry and during the study must be recorded on the eCRFs.
The patient must be told to notify the investigational site about any new medications she takes 
after the start of the study treatment.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication lists (see Table 16-1 in Section 16.1, these lists are not comprehensive and are only 
meant to be used as a guide. Please contact the medical monitor with any questions).
Patients taking a concomitant medication chronically should be maintained on the same dose 
and dose schedule throughout the study period, as much as it is medically feasible and indicated. 
Any change in the dose or schedule of any concomitant medication throughout the study period 
should be clearly documented.
6.2.1.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, antiemetics and anti-diarrheals are allowed. 
Please consult the list of prohibited medications and the list of use with caution medications for 
further guidance. Potential drug interaction between ribociclib and concomitant medications 
should always be taken into consideration when prescribing such medications.
6.2.1.1.1 Bisphosphonates and denosumab
Bisphosphonates and denosumab are generally allowed with the following comments:
!
Chronic concomitant bisphosphonate/denosumab therapy for the prevention of bone 
metastasis is not permitted.
!
Bisphosphonate/denosumab therapy for the treatment of osteoporosis is permitted.
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!
Bisphosphonate/denosumab therapy for the prevention of skeletal related events for 
patients with bone metastases is permitted.
The days of PK blood sampling should be representative of the other study days with regard to 
the use of the chronically administered concomitant medications. However, if a concomitant 
medication is used intermittently during the study, this medication should be avoided on the 
days of PK sampling, if medically feasible.
6.2.1.1.2 Hematopoietic growth factors
Prophylactic use of white blood cell (WBC) growth factors with ribociclib is not recommended.
6.2.1.1.3 Palliative radiotherapy
Palliative radiation is permitted. It should not be delivered to a target lesion. Cumulative courses
of radiotherapy should not encompass >25% of irradiated bone marrow. (see Section 16.2). 
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use must 
be clearly documented and progression as per RECIST 1.1 must be ruled out.
No dose modification of study treatment is needed during palliative radiotherapy.
6.2.1.1.4 Use of antiemetic medications
Ribociclib has low to minimal emetogenic potential according to the 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, v3.2018; 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 16.1 for a list of medications 
that are prohibited or allowed to be used with caution.
6.2.1.2
Permitted concomitant therapy requiring caution and/or action
Medications to be used with caution during combined ribociclib, NSAI, and goserelin treatment 
in this study are listed below (see Table 16-2 in Section 16.1, this list is not comprehensive and 
is only meant to be used as a guide. Please contact the medical monitor with any questions). 
These medications should be excluded from patient use if possible. If they must be given based 
on the investigator’s judgment, then use with caution and consider a ribociclib interruption if 
the concomitant medication is only needed for a short time.
!
Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib 
exposure, respectively)
!
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib 
may increase exposure to these medications)
!
Strong inhibitors of BSEP (based on in vitro data co-administration with ribociclib may 
lead to intrahepatic cholestasis)
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!
Medications that carry a possible risk for QT prolongation (may precipitate QT 
prolongation and TdP)
!
Sensitive substrates of the renal transporters MATE1/2 and OCT1/2 (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 this transporter, although no animal or clinical data are available to support 
these statements)
6.2.1.2.1 Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially reducing ribociclib drug exposure to sub-
therapeutic levels. Systemic corticosteroid treatment should not be given during the study 
treatment with ribociclib, except for:
!
Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), 
eye drops or local injections (e.g. intra-articular);
!
A short duration (< 5 days) of systemic corticosteroids (e.g. for chronic obstructive 
pulmonary disease or as an antiemetic).
6.2.2
Prohibited medications
The following medications are prohibited during study treatment (see Table 16-1 in 
Section 16.1, 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 from 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 anti-neoplastic therapies.
!
Herbal medications/preparations or dietary supplements that are strong inhibitors or 
inducers of CYP3A4/5 or those with a known risk of QT prolongation. These include, but 
are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 
Patients should stop using these preparations/medications at least 7 days prior to first dose 
of study treatment.
!
Hormonal contraception, or hormonal medications used as a hormonal replacement 
therapy for symptoms of menopause, phytoestrogens (as these have potential to reduce 
efficacy of ET).
It is important to consider potential DDIs when using concomitant medications to treat hot 
flushes and other anticipated symptoms associated with the use of ET and/or goserelin.
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6.2.3
Drug with QT prolongation
As far as possible, avoid co-administering medications with a “Known”, “Possible” or 
“Conditional” risk of TdP or any other medication with the potential to increase the risk of drug-
related QT prolongation (e.g. via a potential drug-drug interaction (DDI) increasing the 
exposure of ribociclib or the exposure of the QT prolonging drug).
If concomitant administration of drugs with a known risk of QT prolongation or TdP is required 
and cannot be avoided, ribociclib must be interrupted.
If during the course of the study, concomitant administration of a drug with “Possible” or 
“Conditional” risk of QT prolongation or TdP is required, based on the Investigator’s 
assessment and clinical need, ribociclib 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).
Refer to the ribociclib Investigators Brochure and drug package insert and Section 16.1 for 
information on possible interactions with other drugs.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout her entire participation in the study. The Subject No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential subject number 
suffixed to it. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available.
6.3.2
Treatment assignment, randomization
At Cycle 1 Day 1 visit, all eligible patients will be randomized via Interactive Response 
Technology (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. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the patient.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment.
Patients will be randomized to one of the two treatment arms ( Section 3 and Section 6.1 ). 
Randomization will be stratified by the presence of lung and/or liver metastasis.
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The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Treatment assignment will be open to patients, investigator staff, persons performing the 
assessments, and the clinical trial team (CTT).
6.5
Dose modification
6.5.1
Dose modifications
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. Refer to Table 6-2 for 
guidance. Ribociclib dose must not be re-escalated once decreased.
Dose reductions are not planned for goserelin, or the NSAIs. For information on goserelin or 
NSAIs and management of their related adverse events, refer to prescribing information.
Any changes to the dose or interruption of dosing must be recorded on the Dosage 
Administration Record eCRF.
6.5.1.1
Ribociclib
Patients in Arm 1 can only have one ribociclib dose reduction from 400 mg to 200 mg. Patients 
in Arm 2 can have two sequential ribociclib dose reductions from 600 mg to 400 mg and then 
from 400 mg to 200 mg. If a patient on 200 mg has an adverse event that necessitates further 
dose reduction, the patient must be permanently discontinued from ribociclib.
Table 6-2
Dose modification guidelines
Arm 1 – Ribociclib 400 mg
Dose
Number of tablets & strength
Starting dose
400 mg
2 x 200 mg tablets
First dose reduction
200 mg
1 x 200 mg tablet
Second dose reduction
Not applicable
Patient must permanently 
discontinue
Arm 2 – Ribociclib 600 mg
Starting dose
600 mg
3 x 200 mg tablets
First dose reduction
400 mg
2 x 200 mg tablets
Second dose reduction
200 mg
1 x 200 mg tablet
Recommendations for dose reduction, interruption or discontinuation of ribociclib in the 
management of study drug related adverse reactions are summarized in Table 6-3, Table 6-4, 
Table 6-5, Table 6-6. No dose re-escalation is permitted.
Clinical judgment of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. However, for events requiring discontinuation, 
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treatment must be discontinued. If dosing was interrupted for > 28 days due to ribociclib-related 
toxicity, ribociclib must be discontinued.
Table 6-3
Ribociclib dose adjustment and management recommendations for 
hematological adverse reactions (CTCAE v4.03)
Toxicity/Grade
Dose Adjustment and Management 
Recommendations
Thrombocytopenia
Grade 1(≥75 x 109/L)
No dose adjustment required.
Grade 2 (≥50 x 109/L – <75 x 109/L)
Dose interruption until recovery to grade ≤1. Re-
initiate ribociclib at the same dose.
Grade 3 (≥25 x 109/L - <50 x 109/L)
Dose interruption until recovery to grade ≤1. Re-
initiate ribociclib at the same dose level. If toxicity 
recurs at grade 3: temporary dose interruption until 
recovery to grade ≤1 and reduce ribociclib to the next 
lower dose level.
Grade 4(<25 x 109/L)
Dose interruption until recovery to grade ≤1. Re-
initiate ribociclib at the next lower dose level. If toxicity 
recurs at grade 4: discontinue ribociclib.
Absolute neutrophil count (ANC)
Grade 1 (≥1.5 x 109/L)
No dose adjustment required.
Grade 2 (≥1.0 - <1.5 x 109/L)
No dose adjustment required.
Grade 3 (≥0.5 - <1.0 x 109/L)
Dose interruption until recovery to ≥1.0 x 109/L. Re-
initiate ribociclib at the same dose level. If toxicity 
recurs at grade 3: temporary dose interruption until 
recovery to ≥ 1.0 x 109/L.
If resolved in ≤7 days, then maintain dose level.
If resolved in >7 days, then reduce ribociclib dose to 
the next lower dose level.
Grade 4 (<0.5 x 109/L)
Dose interruption until recovery to ≥ 1.0 x 109/L. Re-
initiate ribociclib at the next lower dose level. 
Febrile neutropenia
Grade ≥3 ANC (<1.0 x 109/L) with a single 
temperature of >38.3 ºC (101 ºF) or a 
sustained temperature of ≥38 ºC (100.4 ºF) 
for more than one hour
Dose interruption until improvement of ANC ≥ 1.0 x 
109/L and no fever. Restart at the next lower dose 
level. If febrile neutropenia recurs, discontinue 
ribociclib.
Grade 4 Life-threatening consequences; 
urgent intervention indicated
Discontinue ribociclib.
Anemia (Hemoglobin)
Grade 1 (≥10.0 – LLN g/dL)
No dose adjustment required.
Grade 2 (≥8.0 – <10.0 g/dL)
No dose adjustment required.
Grade 3 (<8.0 g/dL)
Dose interruption until recovery to grade ≤2. Re-
initiate ribociclib at the same dose.
Grade 4 Life-threatening consequences; 
urgent intervention indicated
Discontinue ribociclib.
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Table 6-4
Ribociclib dose adjustment and management recommendation for 
hepatic toxicities (CTCAE v4.03)
Grade
Dose Adjustment and Management 
Recommendations
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN) (confirmed 48-72h 
later)
Maintain dose level with LFTs monitored every 
two weeks.
Grade 2 (> 1.5 – 3.0 x ULN)
Dose interruption of ribociclib. If resolved to ≤ 
grade 1 in ≤ 21 days, then maintain dose level. If 
resolved to ≤ grade 1 in > 21-28 days or toxicity 
recurs, then reduce 1 dose level.
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption.
If toxicity recurs after two dose reductions (one 
for the 400 mg arm), or recovery to ≤ grade 1 is 
> 28 days, discontinue ribociclib.
Grade 3 (> 3.0 – 10.0 x ULN)
Dose interruption of ribociclib, until resolved to ≤ 
grade 1, then lower 1 dose level of ribociclib.
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption.
If resolved to ≤ grade 1 in > 28 days or toxicity 
recurs, discontinue ribociclib.
Grade 4 (> 10.0 x ULN)
Discontinue ribociclib.
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded 
before dose interruption/reduction. They include but are not limited to: evidence of liver metastases, 
evidence of obstruction, such as elevated ALP and GGT typical of gallbladder or bile duct disease, 
hyperbilirubinemia due to the indirect component only (i.e. direct bilirubin component ≤ 1 x ULN) 
due to hemolysis or Gilbert Syndrome, other pharmacologic treatment, viral hepatitis, alcoholic or 
autoimmune hepatitis, other hepatotoxic drugs. For patients with Gilbert Syndrome, these dose 
modifications apply to changes in direct bilirubin only. Bilirubin will be fractionated if elevated.
AST or ALT
AST or ALT without bilirubin elevation > 2 x ULN
Same grade as baseline or increase from 
baseline grade 0 to grade 1 (confirmed 48 – 72 
h later)
No dose adjustment required with LFTs 
monitored per protocol if same grade as 
baseline or every two weeks in case of increase 
from baseline grade 0 to 1.
Increase from baseline grade 0 or 1 to grade 2 
(> 3.0 – 5.0 x ULN) 
Dose interruption of ribociclib. If resolved to ≤ 
baseline grade in ≤ 21 days, then maintain dose 
level. If resolved to ≤ baseline grade in > 21 
days or toxicity recurs, then reduce 1 dose level.
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption.
If toxicity recurs after two dose reductions (one 
for the 400 mg arm) or recovery to ≤ baseline 
grade is > 28 days, discontinue ribociclib.
Increase from baseline grade 0 or 1 to grade 3 
(> 5.0 – 20.0 x ULN)
Dose interruption of ribociclib until resolved to ≤ 
baseline grade, then lower 1 dose level of 
ribociclib.
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Grade
Dose Adjustment and Management 
Recommendations
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption.
If recovery to ≤ baseline grade is > 28 days, 
discontinue ribociclib.
If toxicity recurs, discontinue ribociclib.
Increase from baseline grade 2 to grade 3 (> 5.0 
– 20.0 x ULN) 
Dose interruption of ribociclib until resolved to ≤ 
baseline grade, then lower 1 dose level of 
ribociclib.
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption.
If toxicity recurs after two dose reductions (one 
for the 400 mg arm) or recovery to ≤ baseline 
grade is > 28 days, discontinue ribociclib.
Grade 4 (> 20.0 x ULN)
Discontinue ribociclib.
AST or ALT and concurrent Bilirubin
For patients with normal ALT and AST and total 
bilirubin at baseline: AST or ALT >3.0 x ULN 
combined with total bilirubin > 2 x ULN without 
evidence of cholestasis Or
For patients with elevated AST or ALT or total 
bilirubin at baseline: [AST or ALT >2 x baseline 
AND >3.0x ULN] OR [AST or ALT 8.0 x ULN]-
whichever is lower- combined with [total 
bilirubin > 2 x baseline AND >2.0 x ULN]
Discontinue ribociclib.
Confounding factors and/or alternative causes for increased transaminases should be excluded 
before dose interruption/reduction. They include but are not limited to: concomitant medications, 
herbal preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new or 
progressive liver metastases, and alcohol intake.
Table 6-5
Ribociclib dose adjustment and management recommendation for 
QTcF prolongation (CTCAE v4.03)
Grade
Dose Adjustment and Management Recommendations
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.
Consider collecting a time matched PK sample; record date 
and time of last study drug intake.
1* QTcF 450-480 ms
Perform steps 1-4 as directed in “For All Grades” No dose 
adjustment required.
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Grade
Dose Adjustment and Management Recommendations
2* QTcF 481-500 ms
Follow the dose modification guidelines applicable to the 
corresponding treatment arm:
!
Arm 1 (ribociclib 400mg)
Interrupt ribociclib. Perform steps 1-4 as directed in “For All 
Grades.”
Perform a repeat ECG within one hour of the first QTcF of ≥ 
481 ms.
Repeat ECG as clinically indicated until the QTcF returns 
to < 481 ms. Reinitiate at the same dose level. No dose 
adjustment required for first occurrence.
If QTcF ≥ 481 ms recurs (i.e. a second occurrence), ribociclib 
should be reduced by 1 dose level.
If QTcF ≥ 481 ms recurs again (i.e. third occurrence), ribociclib 
must be permanently discontinued.
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.
!
Arm 2 (ribociclib 600mg)
Interrupt ribociclib. Perform steps 1-4 as directed in "For All 
Grades."
Performed a repeat ECG within one hour of the first QTcF of ≥ 
481 ms.
Repeat ECG as clinically indicated until the QTcF returns 
to < 481 ms and then reinitiate ribociclib reducing 1 dose 
level.
If QTcF ≥ 481 ms recurs (i.e. a second occurrence), ribociclib 
should be reduced again by 1 dose level.
If QTcF ≥481 ms recurs again (i.e. third occurrence), ribociclib 
must be permanently discontinued.
Repeat ECGs 7 days and 14 days after dose resumption (then 
as clinically indicated) for any patients who had 
therapy interrupted due to QTcF ≥ 481 ms.
3* QTcF ≥ 501 ms on at least two 
separate ECGs
Interrupt ribociclib. Perform steps 1-4 as directed in “For All 
Grades.”
Transmit ECG immediately and confirm 
prolongation/abnormalities with central assessment.
Perform a repeat ECG within one hour of the first QTcF of ≥ 
501 ms.
If QTcF remains ≥ 501 ms, consult with a cardiologist (or 
qualified specialist) and repeat cardiac monitoring as indicated 
until the QTcF returns to < 481 ms.
!
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 
dose level.
!
If QTcF remains ≥ 481 ms after performing steps 1-4 as 
directed in “For All Grades,” discontinue ribociclib.
Repeat ECGs 7 days and 14 days after dose resumption (then 
as clinically indicated) for any patients who had 
therapy interrupted due to QTcF ≥ 501 ms
If QTcF of ≥ 501 ms recurs, discontinue ribociclib.
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Grade
Dose Adjustment and Management Recommendations
4* [QT/QTcF ≥ 501 or > 60 ms 
change from baseline] and 
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms of 
serious arrhythmia]
Discontinue ribociclib. Perform steps 1-4 as directed in “For All 
Grades.”
!
Obtain local cardiologist (or qualified specialist) 
consultation and repeat cardiac monitoring as indicated 
until the QTcF returns to <481 ms.
*All values refer to the average of triplicate measurements
Table 6-6
Ribociclib dose adjustment and management recommendation for 
ILD/pneumonitis (CTCAE v4.03)
Grade
Dose Adjustment and Management Recommendations
1 (asymptomatic)
No dose adjustment required. Initiate appropriate medical therapy and monitor 
as clinically indicated.
2
(symptomatic)
Interrupt ribociclib dose until recovery to Grade ≤1, then resume ribociclib at 
the next lower dose level*. 
3 and 4
(severe)
Discontinue ribociclib
* An individualized benefit-risk assessment should be performed before resuming ribociclib
6.5.1.2
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.
Patients who experience renal impairment (suspected to be related to study treatment of grade 
2 or higher during the treatment period), should discontinue treatment and should be followed 
for safety assessments.
For all other adverse events, including Toxic Epidermal Necrolysis (TEN), which is a grade 4 
event by CTCAE, please follow recommendations in Table 6-7.
Table 6-7
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.
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6.5.2
Follow-up for toxicities
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered a clinically important event.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
values. Patients meeting any of the following criteria will require further follow-up as outlined 
below:
!
For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN
!
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
or hepatocellular liver injury or mixed type injury.
In the absence of cholestasis, patients must be immediately discontinued from study drug 
treatment, and repeat Liver Function Tests (LFTs) performed 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 consideration of the possibility of 
progression of liver metastases 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; progressing or new liver metastases and biliary tract disease.
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!
Obtaining a history of exposure to environmental chemical agents.
!
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).
!
Considering gastroenterology or hepatology consultations.
!
Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction.
!
Obtaining a PK sample, as close as possible to last dose of study drug.
!
Considering a liver biopsy, as clinically indicated to assess pathological change and 
degree of potential liver injury.
All cases of potential DILI meeting the laboratory criteria defined above, with no other 
alternative cause explaining the LFT abnormalities identified, should be considered as 
“medically significant”, thus meeting the definition of SAE (Section 10.1.2), and must be 
reported as SAE using the term “potential drug-induced liver injury”. All events must be 
followed up with the outcome clearly documented. Results of tests as well as other clinically 
important information will be recorded in the eCRF.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if she is 
unable for any reason to take the study treatment as prescribed. Compliance will be assessed by 
the investigator and/or study personnel at each visit using pill counts (if applicable) and 
information provided by the patient. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log.
On days when the patient is administered the study treatment during a visit at the study center, 
compliance will be assured by the investigator or his/her designee. Pharmacokinetic parameters 
(measures of treatment exposure) will be determined in all patients treated with ribociclib, as 
detailed in pharmacokinetics section.
6.6.2
Emergency breaking of assigned treatment code
Not applicable as this is an open-label study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the patient by contacting 
the IRT 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 
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personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
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. 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. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the study. 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.
6.7.1.2
Handling of additional treatment
Not applicable.
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/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 
her understanding. If the patient is capable of doing so, 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.
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.
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Information about common side effects already known about the investigational drug can be 
found in the current ribociclib IB and Kisqali® prescribing information, as appropriate. This 
information will be included in the patient 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 CBP 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.
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
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the patient’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. Missed or rescheduled visits should not 
lead to automatic discontinuation. Patients who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all dispensed investigational 
product should be reconciled, and the adverse event and concomitant medications recorded on 
the eCRF.
Allowed visit windows are specified as follows (unless otherwise specified):
!
Screening assessments must occur within 28 days prior to randomization or within 14 days 
prior to randomization for selected assessments (note: the 28-day screening period does 
not apply to the informed consent process).
!
There will be no visit window for Cycle 1 Day 1.
!
Radiological assessments 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).
!
For all other visits, a ± 3 days window is permitted for the applicable assessments, to take 
into account scheduling issues (applicable assessments should be performed and reviewed 
prior to dosing).
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Table 8-1
Assessment Schedule
Period
Screening
Treatment phase
Post treatment phase
Visit Name
Screening
Cycle 
1
Cycle 
2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 7 
and every 
third 
cycle
End of 
treatment 
(within 15 
days from 
the last 
dose of 
study 
treatment)
Safety 
follow up 
from the 
last dose 
of study 
treatment 
+ 30 days
Efficacy follow up
Days
-28 to -1
-14 to -1
1
15
1
1
15
1
1
1
1
-
-
-
Informed consent
X (before 
screening)
IRT Screening (after ICF)
X
Disposition
X
X
X
Demographics
X
Inclusion / Exclusion criteria
         X
Medical History
X
Diagnosis and extent of 
cancer
X
Prior antineoplastic therapies
X
Concomitant medications
Continuous - up to 30 days after the last dose of study treatment
Prior or concomitant non-drug 
therapies/procedures
Continuous - up to 30 days after the last dose of study treatment
Eligibility checklist (within IRT)
S
IRT Randomization
X
IRT study drug dispensation
X
X
X
X
X
X
X
IRT discontinuation ribociclib
X
Physical Examination
S
S
S
S
S
S
S
ECOG performance status
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
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Period
Screening
Treatment phase
Post treatment phase
Visit Name
Screening
Cycle 
1
Cycle 
2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 7 
and every 
third 
cycle
End of 
treatment 
(within 15 
days from 
the last 
dose of 
study 
treatment)
Safety 
follow up 
from the 
last dose 
of study 
treatment 
+ 30 days
Efficacy follow up
Days
-28 to -1
-14 to -1
1
15
1
1
15
1
1
1
1
-
-
-
Body Weight
X
X
X
X
Body Height
X
Hematology
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
Coagulation
X
As clinically indicated
Serum pregnancy test 
(women CBP)
S
S
Urine pregnancy test (women 
CBP)
S
S
S
S
S
S
S
S
Tumor assessment
X
Every 8 weeks during the first 18 months, every 12 weeks until 36 months, and thereafter as clinically indicated 
until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision and EOT1
(±7 days for all intervals)
Body fluid / tissue collection / 
results
As clinically indicated until disease progression
Whole body bone scan
X (within 42 days prior 
to randomization)
As clinically indicated
Adverse Events
Continuous – up to 30 days after last dose of study treatment
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Period
Screening
Treatment phase
Post treatment phase
Visit Name
Screening
Cycle 
1
Cycle 
2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 7 
and every 
third 
cycle
End of 
treatment 
(within 15 
days from 
the last 
dose of 
study 
treatment)
Safety 
follow up 
from the 
last dose 
of study 
treatment 
+ 30 days
Efficacy follow up
Days
-28 to -1
-14 to -1
1
15
1
1
15
1
1
1
1
-
-
-
Electrocardiogram (ECG)2
X3
X
X
X
X
X
X
X
X
X (only for 
patients 
with
average
QTcF ≥ 
481 ms 
any time
point prior 
to cycle 7, 
then 
assessed 
Day 1 of 
every 
cycle)
X
PK blood collection
X
Ribociclib
Days 1-21 of every cycle
NSAI
Daily
Goserelin (if applicable)
Day 1 of every cycle
Antineoplastic therapies since 
discontinuation of study 
treatment
X
X
X
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Period
Screening
Treatment phase
Post treatment phase
Visit Name
Screening
Cycle 
1
Cycle 
2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 7 
and every 
third 
cycle
End of 
treatment 
(within 15 
days from 
the last 
dose of 
study 
treatment)
Safety 
follow up 
from the 
last dose 
of study 
treatment 
+ 30 days
Efficacy follow up
Days
-28 to -1
-14 to -1
1
15
1
1
15
1
1
1
1
-
-
-
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 For patients with documented disease progression (either during the treatment phase or post treatment phase), an additional efficacy assessment should be performed 
according to the regularly scheduled interval (every 8 weeks during the first 18 months and every 12 weeks until 36 months) but not later than 12 weeks from the efficacy 
assessment at which progressive disease was determined (±7 days for all intervals).
2 Triplicate recording, standard 12-lead.
3 Screening ECG should be performed or repeated after any electrolyte abnormalities are corrected as per the inclusion criteria.
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8.1
Screening
After signing the study ICF, the screening assessments will be done within 28 days prior to 
randomization or within 14 days prior to randomization for selected assessments (see Table 8-
1 for list of assessments to be performed).
Re-screening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (i.e. IRT randomization). In this case a new subject number 
will be generated, and a specific rescreen form will be added in eCRF, to collect the original 
subject number. This data will be used to link the two subjects for reporting and validation.
For laboratory and ECG evaluations used to determine eligibility, a repeated evaluation within 
the screening window is permitted for screening results out of the defined range before screen 
failing the patient. If the repeated laboratory result meets the criteria, that result may be used to 
determine eligibility. If the repeated laboratory result does not meet the criteria, the patient will 
be considered a screening failure. In case rescreening occurs, all evaluations re-assessed should 
meet the eligibility criteria. A new informed consent must be signed if the investigator chooses 
to re-screen the patient following a screen failure.
If a new informed consent form is signed, adverse events and medical history will be assessed 
relative to the new informed consent date.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization (including before signing the main study ICF) can be considered 
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 but fail to be started on treatment for any reason, will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a serious adverse event during the screening phase (see SAE section 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.
8.2
Subject demographics/other baseline characteristics
The data that will be collected on patient characteristics at screening include:
!
Demography (age, sex, race, ethnicity)
!
Diagnosis and extent of cancer (including staging at initial diagnosis and 
histology/cytology)
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!
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.
!
Menopausal status
!
ER, PgR and HER2 status
!
All prior antineoplastic therapies including anticancer surgical interventions, radiation 
therapies, and/or systemic treatments 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 Concomitant medications eCRF page 
or concomitant non-drug therapies/procedures eCRF page and updated on a continuous
basis if there are any new changes to the medications.
Furthermore, the following assessments will be performed:
!
Vital signs
!
Height and weight
!
Physical examination
!
Performance status (ECOG)
!
Laboratory evaluations (hematology, chemistry, coagulation, serum pregnancy test for 
women of CBP)
!
ECG
!
Radiological assessments (e.g. CT Scan)
8.3
Efficacy
8.3.1
Imaging tumor assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Section 16.2) based on RECIST Version 1.1 (Eisenhauer et al 2009). The local 
investigator’s assessment will be used for treatment decision making and determination of 
progressive disease. The imaging assessment collection plan is presented in Table 8-2.
Imaging data for all patients will be centrally collected and checked for quality by an imaging 
Contract Research Organization (CRO) designated by Novartis. The central review of the scans 
will be carried out in a blinded fashion for all patients. Details regarding blinded independent 
review committee (BIRC) assessment will be provided in the BIRC charter. Please refer to the 
site imaging operations manual for additional information on the image acquisition and data 
collection by the imaging CRO.
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline images 
for review by the independent radiologist. Sites must ensure the data entered on the form is 
consistent with the data entered in the clinical database.
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Information regarding cytology results should be transmitted to the imaging CRO via the 
Cytology Form for all visits, when applicable, for review by the independent radiologist. Sites 
must ensure the data entered on the form is consistent with the data entered in the clinical 
database.
Physical exam tumor assessments, photography, pathology and histology/cytology results, as 
well as, information regarding prior interventions, pre-existing radiographic findings that mimic 
metastatic disease at baseline/screening and on-study interventions may be transmitted to the 
imaging CRO as part of the BIRC review.
Patients should have at least one documented measurable lesion (per RECIST 1.1).
Imaging assessments will be performed at screening within 28 days prior to randomization and 
subsequently every 8 weeks following randomization during the first 18 months and every 12 
weeks until 36 months, then as clinically indicated. Any imaging assessments already 
completed during the regular work-up of the patient within 28 days prior to randomization (and 
within 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. The 8-week and 12 week indicated intervals 
should be respected regardless of whether study treatment is temporarily withheld. Partial 
Response (PR) and Complete Response (CR) must be confirmed by repeat assessments 
performed not less than 4 weeks after the criteria for objective response are first met. In the case 
that tumor assessment is performed <8 weeks from the first assessment of an objective response 
to confirm PR/CR, subsequent tumor assessments should revert back to the protocol schedule 
outlined in Table 8-1 . See Table 8-2 for details of assessments.
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.
For all patients with radiological documentation of progression of disease (either during the 
treatment phase or post treatment phase), for confirmatory purposes an additional efficacy 
assessment should be performed according to the regularly scheduled interval (every 8 weeks 
during the first 18 months and every 12 weeks until 36 months) but not later than 12 weeks 
from the efficacy assessment at which progressive disease was determined.
If a patient discontinues treatment for reasons other than radiological documentation of 
progression of disease, an efficacy assessment should be performed at the time of EOT unless 
a CT/MRI for tumor measurement was performed within 21 days from EOT visit. Efficacy 
assessments should continue according to the scheduled visit per Table 8-1 and Table 8-2.
To the extent possible, each lesion should be assessed using the same imaging method 
throughout the study.
All patients will undergo CT or MRI of the chest, abdomen and pelvis at baseline and 
subsequent scheduled visits per Table 8-1 and Table 8-2. The preferred imaging methodology 
is CT with intravenous (i.v.) contrast. However, if at baseline, a patient is known to have a 
contraindication to CT i.v. contrast media or develops a contraindication during the study, 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.
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A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, fluoro-deoxyglucose positron emission tomography (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 baseline. These should be followed throughout the study according 
to the schedule outlined in Table 8-2.
Other metastatic disease sites will be followed by CT or MRI, as clinically indicated.
Chest x-ray or ultrasound should not be used to assess tumor lesions. 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 (Section 16.2). 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.
Results from tissue or body fluid collection should be recorded in the eCRF to complement 
radiographic findings.
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers.
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Table 8-2
Imaging collection plan
Procedure
Screening: Day -
28 to Day -1
Treatment 
Phase1
End of 
Treatment1,2
Post-Treatment 
Phase2
CT or MRI with 
contrast
(Chest, 
Abdomen, Pelvis)
Mandated
Every 8 weeks 
during the first 18 
months, then 
every 12 
weeks until 36 
months and 
thereafter as 
clinically 
indicated (± 7 
days for all 
intervals)
Mandated.
Every 8 weeks 
during the first 18 
months, every 12 
weeks until 36 
months, and 
thereafter as 
clinically 
indicated until 
disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
patient/guardian 
decision (± 7 
days for all 
intervals). In the 
absence of 
disease 
progression, 
continue the 
assessment even 
if a new anti-
neoplastic 
therapy is started 
until disease 
progression, only 
in this case a ±14 
days window is 
allowed.
Brain CT or MRI
Mandated at 
screening if 
history of, 
existing or 
suspected brain 
metastases
If brain lesion at 
screening: every 
8 weeks during 
the first 18 
months, then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated (± 7 
days for all 
intervals)
Mandated only if 
brain lesion at 
screening.
If brain lesion at 
screening: Every 
8 weeks during 
the first 18 
months. then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated until 
disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
patient/guardian 
decision (± 7 
days for all 
intervals). In the 
absence of 
disease 
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Procedure
Screening: Day -
28 to Day -1
Treatment 
Phase1
End of 
Treatment1,2
Post-Treatment 
Phase2
progression, 
continue the 
assessment even 
if a new anti-
neoplastic 
therapy is started 
until disease 
progression, only 
in this case a ±14 
days window is 
allowed.
Whole body bone 
scan3
Mandated (Day -
42 to Day -1)
As clinically indicated
Bone X-ray, CT 
or MRI
Only if skeletal 
abnormalities 
identified by 
whole body bone 
scan3 at 
screening, which 
are not visible in 
the chest, 
abdomen, pelvis 
CT/MRI.
If bone lesion at 
screening, every 
8 weeks during 
the first 18 
months, then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated (± 7 
days for all 
intervals)
Mandated only if 
bone lesion at 
screening.
If bone lesion at 
screening, every 
8 weeks during 
the first 18 
months, then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated until 
disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
patient/guardian 
decision (± 7 
days for all 
intervals). In the 
absence of 
disease 
progression, 
continue the 
assessment even 
if a new anti-
neoplastic 
therapy is started 
until disease 
progression, only 
in this case a ±14 
days window is 
allowed.
Skin color 
Photography
Only if skin 
lesions at 
screening
If skin lesions at 
screening, every 
8 weeks during 
the first 18 
months, then 
every 12 weeks 
until 36 months 
Mandated if skin 
lesions at 
screening.
If skin lesions at 
screening, every 
8 weeks during 
the first 18 
months, then 
every 12 weeks 
until 36 months 
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Procedure
Screening: Day -
28 to Day -1
Treatment 
Phase1
End of 
Treatment1,2
Post-Treatment 
Phase2
and thereafter as 
clinically 
indicated (± 7 
days for all 
intervals)
and thereafter as
clinically 
indicated until 
disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
patient/guardian 
decision (± 7 
days for all 
intervals). In the 
absence of 
disease 
progression, 
continue the 
assessment even 
if a new anti-
neoplastic 
therapy is started 
until disease 
progression, only 
in this case a ±14 
days window is 
allowed.
CT or MRI of any 
disease outside 
of chest, 
abdomen and 
pelvis (e.g., neck)
Only if suspected 
lesion at 
screening
If lesion identified 
at screening, 
every 8 weeks 
during the first 18 
months, then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated (± 7 
days for all 
intervals)
Mandated if 
lesion at 
screening.
If lesion identified 
at screening, 
every 8 weeks 
during the first 18 
months, then 
every 12 weeks 
until 36 months 
and thereafter as 
clinically 
indicated until 
disease 
progression, 
death, withdrawal 
of consent, loss 
to follow-up, or 
patient/guardian 
decision (± 7 
days for all 
intervals). In the 
absence of 
disease 
progression, 
continue the 
assessment even 
if a new anti-
neoplastic 
therapy is started 
until disease 
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Procedure
Screening: Day -
28 to Day -1
Treatment 
Phase1
End of 
Treatment1,2
Post-Treatment 
Phase2
progression, only 
in this case a ±14 
days window is 
allowed.
1Tumor evaluation at End of treatment (EOT) is required for patients who discontinue study 
treatment before the first scheduled post-baseline tumor assessment (week 8) and for patients 
whose previous tumor assessment did not demonstrate progressive disease (PD) and was done 
more than 21 days prior to end of treatment visit.
2For patients with documented disease progression (either during the treatment phase or post 
treatment phase), an additional efficacy assessment should be performed according to the regularly 
scheduled interval (every 8 weeks during the first 18 months and every 12 weeks until 36 months) 
but not later than 12 weeks from the efficacy assessment at which progressive disease was 
determined (±7 days for all intervals).
3Whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, NaF PET or FDG-PET.)
8.3.2
Appropriateness of efficacy assessments
The measurements are standard based on the New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). (Eisenhauer et al 2009).
8.4
Safety and tolerability
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-3
Assessments & Specifications
Assessment
Specification
Physical examination
The physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Information 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 eCRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure, pulse measurement, and body 
temperature. Blood pressure (systolic and diastolic) and pulse should be 
measured after the patient has been sitting for five minutes.
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 as specified in 
Table 8-1.
ECOG Performance status scale will be used as described 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
8.4.1
Laboratory evaluations
Clinical laboratory analyses (Hematology, Chemistry, Coagulation) are performed by the 
central laboratory according to the Assessment schedule outlined in Table 8-1. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. Visit windows of +/- 3 days are allowed for all visits 
except at Cycle 1 Day 1.
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.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used with the exception of FSH and plasma estradiol levels to determine 
menopausal status and pregnancy testing, if applicable. eGFR will be done using the 4-variable 
MDRD formula: eGFR in mL/min per 1.73 m2 = 175 x SerumCr-1.154 in mg/dL x age-0.203 x 
1.212 (if patient is black) x 0.742 (female).
Unscheduled local laboratory assessments may be performed if medically indicated to 
document an adverse event (potential) or when the treating physician cannot wait for central 
laboratory results for decision making (e.g. dose modifications). In this particular situation, if 
possible, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis.
The results of the local laboratory will be recorded in the eCRF if they are used for treatment 
decisions and any the following criteria are met:
!
There are no concomitant central results available, or
!
Local lab results document an adverse event not reported by the central lab, or
!
Local lab results document an adverse event where the severity is worse than the one 
reported by the central lab
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
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interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the CTCAE version 4.03. Additional 
analyses are left to the discretion of the investigator.
Table 8-5
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute value 
preferred, %s are acceptable))
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Calcium, Total Calcium 
(corrected for albumin), Magnesium, Phosphorus, Sodium, Potassium, 
Creatine Kinase, Creatinine, Direct Bilirubin, Total Bilirubin, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting)
Coagulation
International normalized ratio [INR]), Activated partial thromboplastin time 
(APTT), Prothrombin time (PT)
Pregnancy Test
Serum and Urine pregnancy test
FSH and estradiol for confirmation of menopausal status (pre/post) Note: FSH 
and estradiol are not recorded in eCRF, but used to determine menopausal 
status, if needed
8.4.2
Electrocardiogram (ECG)
Standard triplicate 12 lead ECG assessments will be performed after the patient has been resting 
for 5-10 min prior to each time point indicated in Table 8-6 below. Triplicate ECGs should be 
taken approximately 2 minutes apart. The combined QTcF values from these triplicate ECGs 
will be averaged to provide a single value for each time point.
Timing of study procedures (* if applicable):
*ECG assessments are to be done prior PK sampling (if applicable).
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Table 8-6
Central ECG collection plan
Cycle
Patients
Day
Time
ECG Type
Screening
All
-14 to -1
Anytime
Triplicate 12 Lead
1
All
Day 1
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
4 h post-dose (± 15 min)
Triplicate 12 Lead
All
Day 152
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
4 h post-dose (± 15 min)
Triplicate 12 Lead
2
All
Day 1
Pre-dose1
Triplicate 12 Lead
3
All
Day 1
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
Day 15
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
4
All
Day 1
Pre-dose1
Triplicate 12 Lead
5
All
Day 1
Pre-dose1
Triplicate 12 Lead
6
All
Day 1
Pre-dose1
Triplicate 12 Lead
2h post-dose (± 15 min)
Triplicate 12 Lead
All other cycles³
Patients with 
average QTcF ≥ 
481 ms at any 
time point prior 
to cycle 7
Day 1
Pre-dose1
(At every cycle)
Triplicate 12 Lead
2h post-dose (± 15 min)
[starting at cycle 10 and 
every 3rd cycle only3]
Triplicate 12 Lead
EOT
Anytime
Triplicate12 Lead
Unscheduled ECG
Anytime1
Triplicate 12 Lead
1The exact date and time of dosing must be recorded on the appropriate eCRF
2ECG assessments are to be done prior to PK sampling
3 Pre-dose ECG on the first day of every cycle. Additionally, 2 h post-dose in every 3rd cycle (i.e. 
Cycle 10, 13, 16, 19, etc.)
Note:
In order to ensure ECG evaluation is received by the central laboratory for eligibility assessment, 
it is advisable to perform the ECG at least 72 hours prior the scheduled randomization date.
If a QTcF value of ≥ 481 ms is obtained (as the average of a triplicate) at any time after 
randomization, study treatment must be interrupted, repeat ECG(s) and follow management 
guidelines detailed in Table 6-5.
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected in triplicate. Local cardiologist ECG assessment may be performed at any 
time during the study at the discretion of the investigator.
All ECGs including unscheduled triplicate ECGs with clinically relevant findings, collected 
during the study should be transmitted to a central laboratory and will be centrally reviewed by 
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an independent reviewer. The results of the centrally assessed ECGs are automatically 
transferred into the clinical database.
The results of the local ECGs will be recorded in the eCRF if they are used for treatment 
decisions and any of the following criteria are met:
!
There are no concomitant central results available, or
!
Local ECG results document an adverse event not reported by the central lab, or
!
Local ECG results document an adverse event where the severity is worse than the one 
reported by the central lab
Any original ECG not transmitted to a central laboratory should be forwarded for central review. 
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 
eCRF page. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the Adverse Events eCRF page.
In the event that a QTcF value of > 500 ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure.
8.4.3
Pregnancy and assessments of fertility
When applicable, FSH, estradiol, serum and urine pregnancy tests are to be performed locally 
according to Table 8-1 and Table 8-5.
At screening and EOT visit, a serum pregnancy test should be performed for women of CBP. 
During the treatment phase and at safety follow-up visit, a urine pregnancy test is sufficient.
If applicable, FSH and estradiol will be done at screening for clarification of CBP and 
confirmation of menopausal status (see Section 5.1, Criteria 13 and 14).
8.5
Additional assessments
8.5.1
Pharmacokinetics
Blood samples will be collected from all study patients for the analysis of plasma concentrations 
of ribociclib and assessment of ribociclib pharmacokinetics. In a subset of patients (~20 patients 
per arm), extensive PK blood sampling will be performed to provide approximately 12 
evaluable patients to characterize PK per arm and samples will be collected as specified in 
Section 8.5.1.1.1. In all the remaining patients, PK samples will be collected matching the ECG 
measurement time points as specified in Table 8-8.
An unscheduled PK blood sample may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the investigator’s discretion. If a patient discontinues 
from the study treatment due to toxicities related to study treatment, an unscheduled PK blood 
sample may be obtained as soon as possible after the last dose and the date and time of last dose 
recorded. In addition, an unscheduled blood sample may be collected if additional ECG 
measurements are conducted.
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The date and exact time of dosing as well as the date and actual time of blood sampling for PK 
collection (including both scheduled and unscheduled PK samples) must be recorded on the 
appropriate eCRF pages. In addition, the exact time of dosing on the previous day must be 
precisely recorded.
Any sampling problems (e.g., subject refused, technical collection issue, physician decision or 
other issue) have to be recorded on the eCRF.
If vomiting occurs, the date and exact time of vomiting should be recorded if it occurs within 4 
hours of dosing on the day before or the day of PK sampling.
PK parameters, such as Cmax, Tmax, and AUC0-24h, will be estimated (when feasible) from 
individual plasma concentration-time profiles using appropriate methods and software; a 
detailed description of the planned analyses is given in Section 12.5.4.
8.5.1.1
Pharmacokinetic blood collection and handling
For detailed instructions for the collection, handling, and shipment of PK samples, please refer 
to the PK laboratory manual.
8.5.1.1.1 PK blood collection
Blood collections for PK assessment of ribociclib will be obtained according to Table 8-7 and 
Table 8-8. The exact clock time of dosing, as well as actual sample collection date and time will 
be entered on the PK blood collection summary page and dosage administration page of the 
eCRF. Sampling problems will be noted in the relevant field of the eCRF.
Table 8-7
Schedule of extensive pharmacokinetic blood collection
Cycle
Day
Scheduled Time 
Point Relative to 
Dosing
Dose Reference ID 
for ribociclib
PK Sample 
No. for 
ribociclib
Blood 
Volume 
(mL)
1
15
Pre-dose (0 h)a
111
11b
101
2
1
15
2 h post-dose (± 15 
min)
111
102
2
1
15
4 h post-dose (± 30 
min)
111
103
2
1
15
6 h post-dose (± 30 
min)
111
104
2
1
15
24 h post-dose (± 2 
h)a
111
105
2
NA
NA
Unscheduled: PK 
samples related to a 
QTcF > 500 msecc
NA
1001+c
2
NA
NA
Unscheduled: 
Anytimed
NA
2001+d
2
NOTE: One single blood draw will be obtained from each patient at each time point. Sampling time 
is relevant to ribociclib dose.
a Collect PK sample approximately 24 h (± 2 h) after last dose and immediately before drug 
administration.
b Dose reference ID to collect last dose.
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Cycle
Day
Scheduled Time 
Point Relative to 
Dosing
Dose Reference ID 
for ribociclib
PK Sample 
No. for 
ribociclib
Blood 
Volume 
(mL)
c Unscheduled PK samples related to a prolonged QT will be uniquely, sequentially numbered 1001, 
1002, 1003, etc.
d Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, 
sequentially numbered 2001, 2002, 2003, etc.
Table 8-8
Schedule of non-extensive pharmacokinetic blood collection
Cycle
Day
Scheduled Time 
Point Relative to 
Dosing
Dose Reference ID 
for ribociclib
PK Sample 
No. for 
ribociclib
Blood 
Volume 
(mL)
1
15
Pre-dose (0 h)a
222
22 b
201
2
1
15
2 h post-dose (± 15 
min)
222
202
2
1
15
4 h post-dose (± 30 
min)
222
203
2
NA
NA
Unscheduled: PK 
samples related to 
a QTcF > 500 
msecc
NA
3001+c
2
NA
NA
Unscheduled: 
Anytimed
NA
4001+d
2
NOTE: One single blood draw will be obtained from each patient at each time point. Sampling time 
is relevant to ribociclib dose.
a Collect PK sample approximately 24 h (± 2 h) after last dose and immediately before drug 
administration.
b Dose reference ID to collect last dose.
c Unscheduled PK samples related to a prolonged QT will be uniquely, sequentially numbered 3001, 
3002, 3003, etc.
d Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, 
sequentially numbered 4001, 4002, 4003, etc.
8.5.1.2
Analytical method
The concentrations of ribociclib will be measured in human plasma using a liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of 
quantification (LLOQ) of approximately 1.0 ng/mL for ribociclib.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when all study treatment components 
(ribociclib, NSAI, and goserelin, if applicable) are permanently stopped.
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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:
!
Patient/guardian decision
!
Pregnancy
!
Use of prohibited treatment as per recommendations in the prohibited treatment section
!
Adjustments to study treatment due to toxicity that result in discontinuation as per 
recommendations in the dose modifications sections
!
Any situation in which study participation might result in a safety risk to the patient
!
Progressive disease
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 'Withdrawal 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, 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.
Patients who discontinue study treatment (i.e. ribociclib +NSAI, and goserelin, if applicable), 
should undergo 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 visit will be performed. 
For details of assessments refer to the Assessment Schedule. If the decision to discontinue the 
patient occurs at a regularly scheduled visit, that visit may serve as the EOT visit rather than 
having the patient return for an additional visit.
The 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 evaluation of adverse events occuring during the 30 days (±3 days) following the 
last dose of study treatment.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment within 2 days of the EOT visit.
9.1.2
Safety evaluations follow-up
All patients will be followed up for safety for at least 30 days (±3 days) after last dose of study 
treatment. Patients whose treatment is permanently discontinued due to an adverse event, 
including abnormal laboratory value, must be followed until resolution or stabilization of the 
event, whichever comes first. This could include all study assessments appropriate to monitor 
the event. Data collected should be added to the Adverse Events eCRF and the Concomitant 
Medications eCRF.
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9.1.3
Efficacy follow-up
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed every 8 weeks after randomization during the first 18 months and every 12 weeks 
until 36 months, then as clinically indicated until disease progression, death, lost to follow-up, 
or withdrawal of consent. If a patient starts a new anti-cancer therapy prior to progression, tumor 
evaluations should continue as per the Assessment Schedule until disease progression is 
documented. In addition, all new anticancer therapies given after the last dose of the study 
treatment, until disease progression, death, lost to follow-up, or withdrawal of consent 
(whichever comes first) will be recorded in the eCRFs.
9.1.4
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 allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.5
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 
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calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.6
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 early termination be 
necessary, patients must be seen as soon as possible and treated as a prematurely 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 study.
9.2
Study completion and post-study treatment
Study completion for a patient occurs when the patient completes the safety and efficacy follow-
up periods (as applicable) and any repeat assessments associated with these visits have been 
documented and followed-up appropriately by the Investigator. In the event of an early study 
termination decision, the date of that decision must be documented.
All randomized and/or treated patients should have a safety follow-up visit conducted at 30 
days (±3 days) after last administration of study treatment (ribociclib, NSAI, and goserelin, if 
applicable). 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 be conducted when all patients have been treated for at least 6 months 
from randomization or have discontinued study treatment. The primary analysis data will be 
summarized in the primary clinical study report (CSR).
Following the cut-off date for the primary analysis reported in the primary CSR, the study will 
remain open. All additional data for patients that continue to receive study treatment past the 
data cut-off date for the primary analysis, as allowed by the study protocol, will be reported in 
the final CSR at the end of the study.
End of study will be declared as the earliest occurrence of one of the following:
!
All patients have died or discontinued from the study or have been followed up for 
approximately 3 years from randomization.
!
Patients who in the opinion of the investigator are still deriving clinical benefit in this 
study can continue provision of study treatment through an alternative setting.
!
Another clinical study becomes available that can continue to provide ribociclib in this 
patient population and all patients ongoing are eligible to be transferred to that clinical 
study.
Post-study antineoplastic treatment will be at the investigator’s discretion.
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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 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. 
Serious adverse events (SAEs) are defined in Section 10.1.2.
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 study 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 10.1.2):
1. Adverse events will be assessed and graded according to the CTCAE version 4.03. If 
CTCAE grading does not exist for an adverse event, the severity of mild, moderate, 
severe, life-threatening, and death corresponding to Grades 1 - 5, will be used. Information 
about deaths will also be collected through a Death eCRF.
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 
lack of efficacy or progression of underlying illness are i) not caused by the study drug, ii) 
they happen in spite of its administration and/or iii) 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 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.
5. Action taken with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:
!
Dose not changed
!
Dose reduced
!
Drug interrupted/withdrawn
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6. Its outcome (i.e. recovery status or whether it was fatal).
If the event worsens, it should be reported a second time in the eCRF noting the start date when 
the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower 
grade is determined, a new entry for this event should be reported in the eCRF noting the start 
date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in the 
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 at least 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 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to
study treatment, the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (i.e. 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
10.1.2
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:
!
Is fatal.
!
Is life-threatening (i.e. the adverse event, in the view of the investigator, places the patient 
at immediate risk of death).
!
Requires inpatient hospitalization or prolongation of existing hospitalization.
!
Results in persistent or significant disability/incapacity.
!
Constitutes a congenital anomaly/birth defect.
!
Is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
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Note that hospitalizations for the following reasons should not be reported as SAEs:
!
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.
!
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent.
!
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition.
!
Treatments occurring on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given 
above.
All cases of confirmed of DILI (see Section 6.5.2.1) must be reported as SAE regardless of the 
severity.
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 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
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 of whether a clinical event has occurred.
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 following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence.
Screen Failures:
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 the time the patient signs ICF until 30 days after the patient has 
discontinued or stopped study treatment.
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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.
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each 
reoccurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continued, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical Office 
and Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 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 ECs in accordance with 
EU Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.
10.1.4
Pregnancy reporting
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 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 Drug Exposure in Pregnancy Form and reported by the 
investigator to the Novartis 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 for any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported.
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10.1.5
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 eCRF irrespective of whether or not they are associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse information 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 
eCRF (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
Refer to Section 6.5.2.1 for follow up on potential DILI cases. 
10.2.1
Steering Committee
A Steering Committee (SC) will be established and it will be comprised of investigators and 
Novartis personnel participating in the trial. The SC will ensure transparent management of the 
study according to the protocol through recommending and approving modifications as 
circumstances require. The SC will be consulted for protocol amendments as appropriate. 
Together with the clinical trial team, the SC will also develop recommendations for publications 
of study results including authorship rules. The details of the role of the SC will be defined in 
the SC charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
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be given access to the electronic data capture (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 (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.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization (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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Randomization codes and data about all study treatment (s) dispensed to the patient and all 
dosage changes will be tracked using an Interactive Response Technology (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.
Blood samples for laboratory data and PK assessments will be collected by sites and sent to the 
Novartis designated central laboratory for processing. The laboratory results will be sent 
electronically to Novartis (or a designated CRO).
Imaging data will be collected at the sites and the data will be transmitted to a designated CRO 
(if any) for centralized analysis, as well as further processing. Note: Once the radiology review 
from the blinded independent review committee has been completed, patients’ radiological and 
photography data images should no longer be transmitted to the imaging CRO. Novartis will 
notify all sites when central imaging submission for the trial is complete.
ECG data will be collected via 12-lead digital ECG machines. The data will be transmitted to 
Novartis and a designated CRO for centralized cardiac safety analysis, as well as further 
processing and data reconciliation.
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. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management.
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11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
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 GCP, 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 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 study 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 eCRFs 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 eCRFs 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
The primary efficacy and safety analyses will be performed after all patients have been treated 
for at least 6 months or have discontinued study treatment. Any additional data for patients 
continuing to receive study treatment past this time and for patients continuing for efficacy 
follow up (PFS ), as allowed by the protocol, will be further summarized in a final study report 
at the end of the study. 
It is planned that the data from all centers participating in the study 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 the investigator should 
be submitted to Novartis before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) is comprised of all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and strata they have been assigned to.
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FAS will be the default analysis set for all efficacy analysis except the primary endpoint.
The Per-Protocol Set (PPS) is a subset of patients of the Full Analysis Set without major 
protocol deviations. The PPS will be used for the analysis of the primary efficacy endpoint.
Patients with any of the following protocol deviations may be excluded from the PPS:
!
Written informed consent not obtained;
!
Patient without HR-positive and HER2-negative advanced breast cancer at baseline;
!
Patient received prior CDK4/6 inhibitor;
!
Patient without measurable disease at baseline;
!
Patient received any prior hormonal anti-cancer therapy for advanced breast cancer, 
except for ≤ 14 days of a NSAI and/or ≤ 28 days of goserelin prior to randomization for 
pre-menopausal patients;
!
Patient received chemotherapy for advanced breast cancer;
!
Patient received different treatment throughout the study than the one randomized to
!
Patient had dose reduction of ribociclib within cycle 1
All protocol deviations or conditions leading to exclusion from the PPS will be detailed in the 
data handling plan and the statistical analysis plan (SAP).
The Safety Set 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/assigned treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never received.
The Pharmacokinetic Analysis Set (PAS) consists of all patients who received at least one 
dose of study medication defined as ribociclib and provide at least one evaluable PK 
concentration.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics/prognostic data will be 
listed and summarized descriptively by treatment group for the FAS. The summary will also be 
produced for PPS if the FAS and PPS differ.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical history and current medical conditions at baseline will be summarized 
separately 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, minimum, and maximum will be presented.
The duration of exposure to ribociclib,NSAI and goserelin, as well as dose intensity (computed 
as the ratio of actual dose received to actual duration) and the relative dose intensity (computed 
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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 ribociclib, NSAI and goserelin 
for each patient will be summarized using descriptive statistics (e.g. mean, median, and mode).
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 by treatment group. These summaries will include 
medications starting on or after the start of study treatment or medications starting prior to the 
start of study treatment and continuing after the start of study treatment. Any prior concomitant 
medications or significant non-drug therapies starting and ending prior to the start of study 
treatment will be listed.
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(s)
The primary objective in the study is to determine whether the dosing regimen of ribociclib 400 
mg QD 3 week-on/1 week-off in combination with NSAI (Arm 1) is non-inferior to the 
currently approved regimen of 600 mg QD 3 week-on/1 week-off in combination with NSAI 
(Arm 2) in terms of ORRs assessed by local investigators. As such, the primary efficacy 
endpoint of the study is to evaluate the non-inferiority of Arm 1 compared to Arm 2, based on 
the ratio of ORR between the two arms. The experimental arm (Arm 1) will be considered to 
be non-inferior to the control arm (Arm 2) if the lower 90% CI limit of the ratio of the ORR in 
Arm 1 to Arm 2 is greater than 0.814. The non-inferiority (NI) margin of 0.814 was chosen to 
demonstrate the retention of at least 50% of the active treatment effect in terms of ORR for 
ribociclib in combination with NSAI vs. NSAI alone.
12.4.1
Definition of primary endpoint(s)
The primary endpoint of the study is overall response rate (ORR), defined as the proportion of 
patients with best overall response (BOR) of confirmed complete response (CR) or partial 
response (PR) assessed by local investigators according to RECIST 1.1 (See Section 16.2 for 
further details for RECIST 1.1). ORR is based on the tumor evaluations from patients who have 
been treated for at least 6 months or have discontinued treatment.
12.4.2
Statistical model, hypothesis, and method of analysis
The following statistical hypotheses will be tested to address the primary objective based on the 
non-inferiority decision rule:
H01: θ1 < = 0.814 vs. HA1 : θ1 > 0.814
where θ1 is the ratio of ORR in Arm 1 to ORR in Arm 2. The non-inferiority of Arm 1 to Arm 
2 will be established if the lower 90% CI limit of θ1 is greater than the pre-specified NI margin 
0.814.
The primary efficacy variable, ORR, will be based on the PPS population according to the 
randomized treatment group. The CI of ORR ratio will be constructed using Mantel-Haenszel 
method to include lung/liver metastasis as the stratification factor.
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12.4.3
Handling of missing values/censoring/discontinuations
In the primary analysis, all the eligible overall responses will be considered for the evaluation 
of best overall response. Only patients with confirmed best overall response as CR or PR will 
be considered as responders for ORR calculation, and all other patients will be considered as 
non-responders including patients with best overall response (BOR) as unknown or missing.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
As a sensitivity analysis, the primary analysis for ORR will be repeated in the FAS.
Supportive analyses
As a supportive analysis, the primary analysis will be repeated using Blinded Independent 
Review Committee (BIRC) assessment.
Proportions of patients with ORR will be presented by treatment group along with approximate 
95% confidence intervals. The analysis will be conducted in both PPS and FAS, and the 
analysis will be conducted using the assessment from local investigators as well as BIRC.
Subgroup analyses to assess the homogeneity of treatment effect based on demographic and 
baseline disease characteristics may be performed; details about the subgroups to be included 
will be provided in the study SAP. The analysis will be conducted in both PPS and FAS.
12.5
Analysis of secondary endpoints
12.5.1
Key secondary objective
ECG data will be collected via 12-lead digital ECG machines. The data will be transmitted to a 
designated CRO for centralized cardiac safety analysis.
The key secondary objective of the study is to evaluate the QTc (with Fridericia's correction) 
profile of the experimental arm. The objective of mitigating QT prolongation will be met if the 
upper 90% CI limit of the ∆QTcF at Cycle 1 Day 15 (2 h post-dose) compared to baseline 
(Cycle 1 Day 1 pre-dose) is less than 20 ms (FDA 2015).This analysis will be based on all 
patients in the Safety Set that have a non-missing QT assessment performed at baseline and 
Cycle 1 Day 15 (2h post-dose).
Change from baseline of QTcF at other time points will also be summarized. Notable elevations 
of QTcF will be summarized based on all on-treatment ECG assessments. The totality of the 
safety data obtained in Arms 1 and 2, generated from each time point as outlined in the ECG 
monitoring and assessment schedule, will be compared as part of the overall assessment for QT 
prolongation risk mitigation.
The last available ECG assessment before the start of study treatment will be used as the 
‘baseline’ assessment. Assessments specified to be collected post-dose on the first date of 
treatment are not considered as baseline values.
In addition to QTcF, other ECG related endpoints will be summarized including PR, QRS, QT, 
and RR intervals. The summary includes:
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1. 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.
2. Shift table baseline to worst on-treatment result for overall assessments
3. Table with descriptive statistics at baseline, post-baseline time points and change from 
baseline to post-baseline time points.
All ECG data will also be listed by treatment group, patient and visit/time; abnormalities will 
be flagged.
12.5.2
Efficacy and/or Pharmacodynamic endpoint(s)
Progression free survival (PFS) is defined as the time from the date of randomization to the 
date of the first documented disease progression or death due to any cause. PFS will be censored 
if no PFS event is observed. The censoring date will be the date of the last adequate tumor 
assessment (see Section 16.2 for further details). Clinical deterioration without objective 
radiological evidence will not be considered as documented disease progression. PFS will be 
assessed via a local radiology assessment as well as BIRC according to RECIST 1.1.
PFS will be analyzed in the FAS population according to the randomized treatment group. The 
PFS 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.
Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response 
of complete response (CR), or partial response (PR), or an overall response of stable disease 
(SD), lasting for at least 24 weeks. CR, PR, and SD are defined as per local review as well as 
BIRC according to RECIST 1.1 (see Section 16.2 for details).
CBR will be calculated based on the FAS. CBR and its 95% confidence interval will be 
presented by treatment group.
Time to response (TTR) is defined as the time from the date of randomization to the first 
documented response of either complete response (CR) or partial response (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 Section 16.2 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.
Duration of response (DOR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data 
per local review. The start date is the date of first documented response of CR or PR (i.e. the 
start date of response, not the date when response was confirmed), and the end date is defined 
as the date of the first documented progression or death due to underlying cancer. Patients 
continuing without progression or death due to underlying cancer will be censored at the date 
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of their last adequate tumor assessment. DOR will be listed and summarized by treatment group 
for all patients in the FAS with confirmed BOR of CR or PR (see Section 16.2 for details).
12.5.3
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 deaths, including on treatment and 
post treatment deaths will be provided.
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:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment.
2. On-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study treatment.
3. Post-treatment period: starting at day 31 after last dose of study treatment.
Adverse events
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. All information obtained 
on adverse events will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment emergent adverse events will be 
summarized in the following ways:
!
by treatment, primary system organ class and preferred term.
!
by treatment, primary system organ class, preferred term and maximum severity.
!
by treatment, Standardized MedDRA Query (SMQ) and preferred term.
A patient with multiple adverse events within a primary system organ class is only counted once 
towards the total of the primary system organ class.
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated.
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All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
AESI will be considered. Such categories consist of one or more well-defined safety events 
which are similar in nature and for which there is a specific clinical interest in connection with 
the study treatment(s). AESI will be defined at project level and may be regularly updated. The 
grouping of AEs in AESI according to project standards will be specified in the Case-Retrieval 
Sheet (CRS) and/or the study statistical analysis plan.
For each specified AESI, number and percentage of patients with at least one event part of the 
AESI will be reported by treatment group
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) 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 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher.
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.
The following summaries will be generated separately for hematology, and chemistry tests:
!
Listing of all laboratory data with values flagged to show the corresponding 
CTCAE v4.03 grades if applicable and the classifications relative to the laboratory normal 
ranges
For laboratory tests where grades are defined by CTCAE v4.03:
!
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 v4.03 grades to compare baseline to the worst on-treatment 
value.
For laboratory tests where grades are not defined by CTCAE v4.03:
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!
Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example, 
figures plotting time course of raw values or change in laboratory tests over time or box plots 
might be specified in the analysis plan.
12.5.4
Pharmacokinetics
Ribociclib plasma concentration data (and any relevant metabolites such as LEQ803) will be 
listed by treatment, patient, and visit/sampling time point. Descriptive summary statistics will 
be provided by treatment and visit/sampling time point.
Summary statistics will include mean (arithmetic and geometric), SD (standard deviation), CV 
(arithmetic and geometric), median, minimum, and maximum. The geometric mean and 
arithmetic mean (SD) plots will also be graphically presented for concentration-time data 
(concentration time profiles).
Plasma samples will be assayed for LEE011 concentrations by Novartis or Novartis designated 
laboratory using validated LC-MS/MS methods with a LLOQ of approximately 1.00 ng/mL for 
ribociclib. All concentrations below the LLOQ will be displayed in listings as zero with a flag 
and handled as zero in any calculations of summary statistics, but handled as missing for the 
calculation of the geometric means and their CV.
In approximately 20 patients per arm, extensive PK sampling for ribociclib will be performed 
as detailed in Section 8.5.1.
For these patients, PK parameters (if available) of ribociclib (and any relevant metabolites), 
including but not limited to those listed in Table 12-1, will be calculated from the individual 
concentration-time profile. Pharmacokinetic parameters will be listed by treatment and patient. 
Any missing PK parameter data will not to be imputed. Descriptive summary statistics will 
include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, 
minimum, and maximum. An exception to this is Tmax where median, minimum, and 
maximum will be presented.
PAS will be used in all pharmacokinetic data analysis and PK summary statistics.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUC0-24
The AUC from time zero to 24 hours (ng*h/mL)
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(ng*h/mL)
AUCinf
The AUC from time zero to infinity (ng*h/mL)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (h)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (h).
CL/F
The total body clearance of drug from the plasma (L/h)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) (L)
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12.6
Interim analyses
No formal interim analysis is planned for this study. The primary analysis will be performed 
after all patients have been treated for 6 months or have discontinued study treatment and afinal 
analysis will be performed after efficacy follow up is complete. Refer to Section 9.2.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
A total sample size of approximately 350 patients is planned for this study, randomly allocated 
in a 1:1 ratio between Arm 1 (175 patients) and Arm 2 (175 patients). Assuming an enrollment 
rate of 20 patients per month, the primary analysis cut-off would be expected to be 
approximately 24 months from the randomization of first patient. The sample size calculations 
are proposed such as to meet the non-inferiority margin of 0.814 with 80% power and one-sided 
5% level of significance under the assumptions of an ORR of 48.3% in Arm 1 (experimental 
arm) and 43.9% in Arm 2 (control arm) and that 10% patients will not be evaluable for 
ORR. The details of operating characteristics are described below (EAST 6.3).
Table 12-2
Primary endpoint: Overall Response rate (ORR)
Ratio of
ORR from Arm 1/Arm 2*
The ORR in Arm 1 based on the 
ORR ratio
Probability of lower 90% CI 
limit of the ratio of ORR Arm 
1/ Arm 2> 0.814 *
1.1
48.3%
80.0%
1.05
46.1%
66.5%
1
43.9%
50.1%
0.95
41.7%
32.5%
0.9
39.5%
18.5%
0.814
35.7%
5.1%
* ORR in the control arm (Arm 2) is set to be 43.9% based on the pooled historical data from 
CLEE011A2301 and CLEE011E2301 (NSAI only).
For the calculation of non-inferiority margin, the ORRs of ribociclib in combination with NSAI 
vs NSAI alone were estimated by combining the historical 6-month overall response rate 
observed in patients with the measurable disease from the following two studies:
!
Study CLEE011A2301, where ribociclib was investigated at a starting dose of 600 mg QD 
3 week-on/1 week-off in combination with letrozole in postmenopausal women; and
!
Study CLEE011E2301 (NSAI only) where ribociclib was investigated at a starting dose of 
600 mg QD 3 week-on/1 week-off in combination with NSAI and goserelin in 
premenopausal women.
In both studies, the patient population is similar to the one proposed for this study, as all patients 
have HR-positive, HER2-negative advanced breast cancer with no prior treatment for advanced 
disease; and the ORRs are also very similar in CLEE011A2301 and CLEE011E2301 despite 
the difference in the menopausal status of study populations. The ORR up to 6-months was 
estimated to be 43.9% in ribociclib in combination with NSAI and 29.1% in NSAI alone by 
pooling patients with measurable disease from studies CLEE011A2301 and CLEE011E2301. 
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As such, the NI margin is calculated based on 50% retention on the log-scale of the ratio of 
43.9% to 29.1%, which leads to the NI margin of 0.814 (FDA 2016).
12.7.2
Secondary endpoint(s)
The key secondary endpoint of the study is to evaluate if the upper 90% Confidence interval for 
the QTcF change from baseline at Cycle 1 Day 15 (2h post-dose) is less than 20 ms for the 
experimental dosing arm (Arm 1). Assuming that the ∆QTcF standard deviation is 20 ms, the 
probability of meeting this threshold under different scenarios of ∆QTcF at the Cmax is 
presented in Table 12-3.
Table 12-3
Operating characteristics for the key secondary endpoint: ∆QTcF at 
Cycle 1 Day 15 (2 h post-dose). Probability of the upper 90% CI < 20 
ms under different value to True QTcF with a sample size of 175 
patients in Arm 1
True mean ( QTcF, ms)
Probability of upper 90% CI limit < 20 ms
15.5
90.6%
16
84.1%
17.5
50.0%
18
37.2%
18.8
19.9%
19.9
5.6%
12.7.3
Sample size considerations for PK analysis
Blood samples will be collected from all study patients for the analysis of plasma concentrations 
of ribociclib and assessment of ribociclib pharmacokinetics. In a subset of patients (~20 patients 
per arm), extensive PK blood sampling will be performed to provide approximate 12 evaluable 
patients to characterize PK per arm, and the PK collection schedule is specified in protocol 
Section 8.5.1.1.1. No hypothesis will be tested and therefore no specific sample size calculation 
has been performed. The choice of sample size and sampling time points were selected based 
on historical data and PK profile of ribociclib and is expected to represent the PK in the targeted 
treatment group.
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 International Conference on Harmonisation (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 study, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the study 
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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.
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 (defined as last patient last visit) 
and finalization of the study report the results of this study 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 study 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 (SOP) 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 study. The clinical audit process uses a knowledge/risk based approach.
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.
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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 informed 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 (available upon request)
Beroukhim R, Mermel CH, Porter D, et al (2010) The landscape of somatic copy-number 
alteration across human cancers. Nature p. 899-905.
Bosco EE, Wang Y, Xu H, et al (2007) The retinoblastoma tumor suppressor modifies the 
therapeutic response of breast cancer. J. Clin. Invest. p. 218-28.
Bray F, Ferlay J, Soerjomataram I, et al (2018) Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J 
Clin p. 394-424.
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast 
tumours. Nature p. 61-70.
Cardoso F, Senkus E, Costa A, et al (2018) 4th ESO-ESMO International Consensus 
Guidelines for Advanced Breast Cancer (ABC 4)†. Ann. Oncol. p. 1634-1657.
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer p. 228-47.
Ellis F (1961) Modern radiobiology and the radiotherapist. Proceedings of the Royal Society 
of Medicine; 54:1133-42.
FDA (2015) Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers (Guidance for Industry).
FDA (2016) Non-Inferiority Clinical Trials to Establish Effectiveness (Guidance for 
Industry).
Finn RS, Martin M, Rugo HS, et al (2016) Palbociclib and Letrozole in Advanced Breast 
Cancer. N. Engl. J. Med. p. 1925-1936.
Goetz MP, Toi M, Campone M, et al (2017) MONARCH 3: Abemaciclib As Initial Therapy 
for Advanced Breast Cancer. J. Clin. Oncol. p. 3638-3646.
Grunberg SM, Warr D, Gralla RJ, et al (2011) Evaluation of new antiemetic agents and 
definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer p. S43-
7.
Holm K, Staaf J, Jönsson G, et al (2012) Characterisation of amplification patterns and target 
genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. 
Breast Cancer Res. Treat. p. 583-94.
Hortobagyi GN, Stemmer SM, Burris HA, et al (2016) Ribociclib as First-Line Therapy for 
HR-Positive, Advanced Breast Cancer. N. Engl. J. Med. p. 1738-1748.
Howlader N, Altekruse SF, Li CI, et al (2014) US incidence of breast cancer subtypes defined 
by joint hormone receptor and HER2 status. J. Natl. Cancer Inst.
Loibl S, Turner NC, Ro J, et al (2016) Palbociclib (PAL) in combination with fulvestrant (F) 
in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior 
progression on endocrine therapy – results from Paloma-3 p. 524-524.
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National Comprehensive Cancer Network (2018) Antiemesis (Version 3.2018). Available 
from: https//wwwnccn.org/professionals/physician_gls/pdf/antiemesis.pdf.
National Comprehensive Cancer Network. Breast Cancer (Version 1.2018) [Internet]. NCCN , 
2018 [cited 2018 Jun 26] Available from: 
https//wwwnccn.org/professionals/physician_gls/pdf/breast.pdf
Roila F, Molassiotis A, Herrstedt J, et al (2016) 2016 MASCC and ESMO guideline update 
for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of 
nausea and vomiting in advanced cancer patients. Ann. Oncol. p. v119-v133.
Slamon DJ, Neven P, Chia S, et al (2018) Phase III Randomized Study of Ribociclib and 
Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-
Negative Advanced Breast Cancer: MONALEESA-3. J. Clin. Oncol. p. 2465-2472.
Thangavel C, Dean JL, Ertel A, et al (2011) Therapeutically activating RB: reestablishing cell 
cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer p. 333-45.
Turner NC, Huang Bartlett C, Cristofanilli M (2015) Palbociclib in Hormone-Receptor-
Positive Advanced Breast Cancer. N. Engl. J. Med. p. 1672-3.
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16
Appendices
16.1
Appendix 1 – Concomitant Medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or ribociclib.
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on Novartis PK Sciences Memorandum Drug-Drug Interaction (DDI) 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//wwwfda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m292362.pdf), 
and 
the 
University 
of 
Washington’s 
Drug 
Interaction 
Database 
(http//wwwdruginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(www.qtdrugs.org/). Please contact the medical monitor with any questions.
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, troleandomycinvoriconazole
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 or dietary supplements
known as strong inducers or inhibitors of CYP3A4/5 or 
those with a known risk of QT prolongation are prohibited 
throughout the study. These include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, 
black cohosh, and ginseng. Patients should stop using 
these herbal medications or dietary supplements 7 days 
prior to first dose of study drug.
Other investigational and 
antineoplastic therapies
Other investigational therapies must not be used while the 
patient is on the study. Anticancer therapy (chemotherapy, 
hormonal therapy, including but not limited to all SERMS 
[including raloxifene], biologic or radiation therapy [except 
for palliative radiotherapy as outlined in the protocol], and 
surgery) other than the study treatments must not be given 
while the patient is on the study medication. If such agents 
are required, then the patient must discontinue the study 
drug.
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes) or drugs which have <2-fold difference in the minimum toxic concentrations and 
effective concentrations in the blood
2 Herbal product
3 P-gp inducer
4 The list provided is as of December 2019.Check https www. crediblemeds.org/healthcare-
providers/drug-list for the most updated list.
5 Drug has warning for risk of hepatotoxicity.
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential 
to increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the 
exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a 
known risk, possible risk, or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is 
available online at qtdrugs.org.
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana University 
“Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction Database, and FDA 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
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Table 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, nortriptyline, nusinersen, ofloxacin, 
olanzapineosimertinib, oxytocin, paliperidone, 
palonosetron, panabinostat, pasireotide, pazopanib, 
perflutren lipid microspheres, perphenazine, pilsicainide, 
pimavanserin, pipamperone, promethazine, prothipendyl, 
quetiapine, ranolazine, rilpivirine, risperidone, romidepsin, 
sertindole, sorafenib, sunitinib, tamoxifen, telavancin,
tetrabenazine, tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene, trimipramine, tropisetron, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone
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Category
Drug Name
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, zidovudine
BCRP substrates
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, pitavastatin, 
rosuvastatin, irinotecan, ethinyl estradiol, 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.
5Lopinavir and atazanavir is prohibited when combined with ritonavir (see Table 16-1).
6 Based on data 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)
Novartis Oncology
Clinical Development, Biometrics and Data Management, Drug Regulatory Affairs & 
Oncology Clinical Imaging
Study no: CLEE011A2207
Harmonization of Efficacy Analysis of Solid Tumor Studies
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: February 11, 2016
Version 3.1: November 29, 2011
Version 3: October 19, 2009
Version 2: January 18, 2007
Version 1: December 13, 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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Table 16-3
Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
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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 16.2.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.2.3.2 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 16.2.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.2.2
Efficacy assessments
Tumor evaluations are made based on RECIST 1.1 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).
16.2.2.1 Definitions
16.2.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.
!
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 16.2.3.2.9.
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 < 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.
!
Cystic lesions: 
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!
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.
16.2.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.2.3.2.9.
16.2.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:
!
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, 
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regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.
!
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according
to the following algorithm: 
!
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
!
No FDG-PET at baseline with a positive FDG-PET at follow-up: 
!
If new disease is indicated by a positive PET scan but is not confirmed by CT (or 
some other conventional technique such as MRI) at the same assessment, then 
follow-up assessments by CT will be needed to determine if there is truly 
progression occurring at that site. In all cases PD will be the date of confirmation 
of new disease by CT (or some other conventional technique such as MRI) rather 
than the date of the positive PET scan. If there is a positive PET scan without any 
confirmed progression at that site by CT, then a PD cannot be assigned.
!
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD.
!
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
!
Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.
!
Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.
!
Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.
!
Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
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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 /histology: Cytology and histology can be used to differentiate between PR and 
CR in rare cases (i.e., after treatment to differentiate between residual benign lesions and 
residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).
!
Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
16.2.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:
!
Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline
!
Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.2.2.1.1.
!
Nodal target: See Section 16.2.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
!
Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
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16.2.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-4) and non-target lesions (Table 16-5) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-6) as well as the presence or absence of new lesions.
16.2.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
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 
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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.
16.2.2.4.2
Determination of target lesion response
Table 16-4
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, 
any pathological lymph nodes assigned as target lesions 
must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target 
lesions, taking as reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all 
measured target lesions, taking as reference the smallest 
sum of diameter of all target lesions recorded at or after 
baseline. In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 
mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an 
increase in lesions which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more 
target lesions have not been assessed or have been 
assessed using a different method than baseline.3
1SOD for CR may not be zero when nodal lesions are part of target lesions 
2Following 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
3In 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 16.2.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:
!
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
!
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 16-4 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 
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applies to patients who have not achieved target response of CR. For patients who have 
achieved CR, please refer to last bullet in this section.
!
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
!
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
!
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
!
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.
!
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced
!
The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.
!
Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.
!
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 
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have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria.
16.2.2.4.3
Determination of non-target lesion response
Table 16-5
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all 
lymph nodes assigned a non-target lesions must be non-
pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more 
non-target lesions have not been assessed or have been 
assessed using a different method than baseline2.
1 The assignment of PD solely based on change in non-target lesions in light of target lesion response 
of CR, PR or SD should be exceptional. In such circumstances, the opinion of the investigator or 
central reviewer does prevail.
2 It is recommended that the investigator and/or central reviewer should use expert judgment to assign 
a Non-UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response
!
The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.
!
The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).
!
Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
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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 16.2.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
16.2.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page.
!
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion
!
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.2.2.5).
A lymph node is considered as a “new lesion” and, therefore, indicative of progressive disease 
if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 mm absolute 
increase. FDG-PET: can complement CT scans in assessing progression (particularly possible 
for ‘new’ disease). See Section 16.2.2.2.
16.2.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 16-
6.
Table 16-6
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overalllesion 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
1This overall lesion response also applies when there are no non-target lesions identified at baseline.
2Once confirmed PR was achieved, all these assessments are considered PR.
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Target lesions
Non-target lesions
New Lesions
Overalllesion response
3As defined in Section 16.2.2.4 .
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
16.2.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.2.3.2.9 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.2.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
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:
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!
CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required
!
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required
!
SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).
!
PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).
!
UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ≥20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient.
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
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Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:
!
Investigator overall lesion response
!
Central Blinded Review overall lesion response
!
Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The time point 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).
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16.2.3.2 Time to event variables
16.2.3.2.1
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, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.
16.2.3.2.2
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.
16.2.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
16.2.3.2.4
PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
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document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues with respect to foreseeable censoring.
16.2.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
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.
16.2.3.2.6
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis, et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
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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.
16.2.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.2.3.2.6. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.
!
at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)
!
at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
16.2.3.2.8
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 
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CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:
!
Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:
!
Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).
!
Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.
!
Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.
!
Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.2.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.
!
Date of discontinuation is the date of the end of treatment visit.
!
Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.
!
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery
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16.2.3.2.9
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 non-
measurable disease is derived slightly differently according to Table 16-7.
Table 16-7
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 16.2.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
16.2.3.2.10
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 
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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 SAP 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 16.2.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
Table 16-8
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
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Situation
Options for end-date 
(progression or 
censoring)1
(1) = default unless 
specified differently 
in the protocol or 
RAP
Outcome
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)
1Definitions can be found in Section 16.2.3.2.8.
2After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.2.3.2.8.
3The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.
!
(C1) taking the actual progression or death date, in the case of only one missing 
assessment.
!
(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
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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 16-8 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 SAP documentation.
16.2.4
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).
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16.2.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
SAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the SAP 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 SAP 
documentation before database lock).
16.2.4.2 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
!
Subject/guardian decision
!
Progressive disease
!
Study terminated by the sponsor
!
Non-compliant with study treatment
!
No longer requires treatment
Death is a reason which “must” lead to discontinuation of patient from trial.
16.2.4.3 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
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!
Subject/guardian decision
!
Death
!
Progressive disease
!
Study terminated by the sponsor
16.2.4.4 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 
SAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.2.4.5 Programming rules
The following should be used for programming of efficacy results:
16.2.4.5.1
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.
16.2.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
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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 16.2.3.2.7). 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.
16.2.4.5.3
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.
16.2.4.5.4
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)’.
16.2.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
16.2.4.5.6
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:
!
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 16-8)
!
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 16.2.3.2.7. 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 
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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.
16.2.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response and 
early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16
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CLEE011A2207
Clinical Development
LEE011/Ribociclib/Kisqali®
CLEE011A22071&7
A phase II, multicenter, randomized, open-label study to evaluate 
the safety and efficacy of 400 mg of ribociclib in combination with 
non-steroidal aromatase inhibitors for the treatment of pre-and 
postmenopausal women with hormone receptor-positive, HER2-
negative advanced breast cancer who received no prior therapy for 
advanced disease
Statistical Analysis Plan (SAP)
Amendment 2
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
02-Aug-2021
Number of pages:
49
Property of Novartis
For business use only
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May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
14-
May-
2019
Prior 
to 
DB 
lock
Creation 
of 
final version
N/A - First version
NA
11-
Jan-
2021
Prior 
to 
DB 
lock
Considerations 
of COVID-19
impact 
on 
analyses
New protocol deviations resulting 
from 
COVID-19
pandemic 
and 
corresponding detailed relationship 
have been defined
and will be 
summarized.
Baseline demographic characteristics, 
diagnosis and extent of cancer, and 
prior anti-neoplastic therapy will be 
summarized for patients randomized 
before and after the start of the
pandemic.
Section 
2.2.3 
and 
Section 
2.5.6
02-
Aug-
2021
Prior 
to 
DB 
lock
Exclude 
protocol 
deviaition 
“patients dose 
reduced in the 
first cycle”.
Change ORR 
95% 
CI 
calculation 
method due to 
small smaple 
in 
some 
subgroups. 
Child 
bear 
status was not 
collected in the 
CRF. 
Dose reduction in the first cycle was 
changed to a condition to exclude the 
subject from PPS not a protocol 
deviation.
Child bearing status was removed from 
listing.
For subgroup analysis, the 95% CI will 
be calculated by exact method.
The best response to last prior 
antineoplastic therapy will not be 
summarized due to most responses is 
unkown, missing or not applicable.
Section 
2.2.1, 
Section 
2.2.5,
Section 
2.2.6, 
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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................12
2.2.1
Patient classification..............................................................................12
2.2.2
Withdrawal of informed consent...........................................................13
2.2.3
Protocol deviation summaries...............................................................13
2.2.4
Groupings for analysis ..........................................................................13
2.2.5
Subgroup of interest ..............................................................................14
2.3
Concomitant therapies with specific impact on the analysis.................................14
2.4
Implementation of RECIST...................................................................................15
2.4.1
Best overall response (BOR).................................................................15
2.4.2
Disease progression...............................................................................16
2.4.3
Change in imaging modality.................................................................16
2.4.4
Determination of missing adequate assessments ..................................17
2.4.5
No baseline tumor assessments.............................................................18
2.4.6
Construction of waterfall graphs...........................................................19
2.5
Patient disposition, demographics and other baseline characteristics ...................19
2.5.1
Patient disposition.................................................................................20
2.5.2
Basic demographic and background data..............................................20
2.5.3
Diagnosis and extent of cancer .............................................................20
2.5.4
Medical history......................................................................................21
2.5.5
Prior anti-neoplastic therapy .................................................................21
2.5.6
Other......................................................................................................21
2.6
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.6.1
Study treatment / compliance................................................................22
2.6.2
Concomitant therapy and post treatment anti-cancer therapies ............25
2.7
Analysis of the primary objective..........................................................................26
2.7.1
Primary endpoint...................................................................................26
2.7.2
Statistical hypothesis, model, and method of analysis..........................27


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2.7.3
Handling of missing values/censoring/discontinuations.......................27
2.7.4
Sensitivity and Supportive analyses......................................................27
2.8
Analysis of the key secondary objective ...............................................................28
2.9
Analysis of secondary efficacy objective(s)..........................................................28
2.9.1
Progression free survival (PFS) ............................................................28
2.9.2
Clinical benefit rate (CBR) ...................................................................29
2.9.3
Time to response (TTR)........................................................................29
2.9.4
Duration of response (DOR).................................................................29
2.9.5
ECOG performance status.....................................................................30
2.10
Safety analyses.......................................................................................................31
2.10.1
Adverse events (AEs)............................................................................31
2.10.2
Laboratory data .....................................................................................34
2.10.3
ECG and cardiac imaging data..............................................................35
2.10.4
Vital signs..............................................................................................37
2.10.5
Other safety data ...................................................................................37
2.11
Pharmacokinetic endpoints....................................................................................38
2.11.1
General principle...................................................................................38
2.11.2
PK concentrations .................................................................................39
2.11.3
PK parameters .......................................................................................39
2.11.1
Handling missing and invalid values ....................................................40
2.12
PD and PK/PD analyses.........................................................................................40
2.13
Patient-reported outcomes .....................................................................................40
2.14
Biomarkers.............................................................................................................40
2.15
Other Exploratory analyses....................................................................................40
2.16
Interim analysis......................................................................................................40
3
Sample size calculation .....................................................................................................41
3.1.1
Primary endpoint(s)...............................................................................41
3.1.2
Secondary endpoint(s)...........................................................................41
3.1.3
Sample size considerations for PK analysis..........................................42
4
Change to protocol specified analyses ..............................................................................42
5
Details of statistical analysis .............................................................................................42
5.1
Baseline comparability ..........................................................................................42
5.2
Mantel-Haenszel estimator for the ratio of ORR...................................................43
5.3
Time-to-event analyses..........................................................................................43
5.3.1
Analysis of time-to-event data with ties................................................44
5.3.2
Kaplan-Meier estimates ........................................................................44
5.3.3
The event/censor date for PFS analysis ................................................44


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5.4
Duration of follow-up............................................................................................45
5.5
Confidence intervals for response rate and clinical benefit rate............................45
5.6
Imputation rules.....................................................................................................45
5.7
AEs coding/grading ...............................................................................................45
5.7.1
Coding of AEs.......................................................................................45
5.7.2
Grading of AEs .....................................................................................45
5.8
Laboratory parameters derivations ........................................................................46
6
References .........................................................................................................................46
Appendix 1
CTC grades for laboratory values in Novartis Oncology......................48


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List of abbreviations
aBC
advanced breast cancer
AE
Adverse event
AI
aromatase inhibitor
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BC
breast cancer
BOR
Best overall response
CBR
Clinical benefit rate
CR
Complete response
CRS
Case retrieval strategy
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
ΔQTcF
Change from baseline in QTcF
DMC
Data Monitoring Committee
DOR
Duration of Response
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EOT
End of treatment
FAS
Full analysis set
HER2
Human epidermal growth factor receptor 2
HR
Hazard Ratio
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
NI
Non-inferiority 
NMQ
Novartis MedDRA queries
NSAI
Non-steroidal aromatase inhibitor 
ORR
Overall response rate
PAS
Pharmacokinetic analysis set
PD
Progressive disease
PDI
Planned dose intensity
PDS
Programming Datasets Specifications
PFS
Progression-Free Survival
PK
Pharmacokinetics


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PPS
Per-Protocol Set
PR
Partial response
PT
Preferred term
qd
Qua’que di’e / once a day
QTcF
QT interval corrected by Fridericia method
RAP
Report and Analysis Process
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SEC
Safety Event Categories
SMQ
Standardized MedDRA queries
SOC
System Organ Class
TA
Tumor assessment
TBIL 
Total Bilirubin
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, Listings
WHO
World Health Organization
UNK
Unknown


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1
Introduction
This document describes the detailed statistical methodology to be used for the clinical study 
report (CSR) for the primary analysis of study CLEE011A2207, a phase II, multicenter, 
randomized, open-label study to evaluate the safety and efficacy of 400 mg of ribociclib in 
combination with non-steroidal aromatase inhibitors (NSAI) for the treatment of pre- and 
postmenopausal women with hormone receptor-positive, HER2-negative advanced breast 
cancer (aBC) who received no prior therapy for advanced disease.
The content of this SAP is based on the CLEE011A2207 protocol amendment 1 released on 
Jan 24, 2020. All decisions regarding final analysis, as defined in this document, have been 
made prior to the database lock.
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in the Tables, Figures & Listings (TFL) shells and Programming Datasets 
Specification (PDS), respectively.
1.1
Study design
This is a phase II, multicenter, randomized, open-label study to evaluate the safety and efficacy 
of a reduced starting ribociclib dose of 400 mg in combination with an NSAI (letrozole or 
anastrozole) for the treatment of pre- and postmenopausal women with HR-positive, HER2-
negative aBC who have received no prior therapy for advanced disease. Premenopausal women 
will also be required to receive goserelin in both treatment arms.
Approximately 350 patients will be randomly assigned to one of the below treatment arms in a 
1:1 ratio (Figure 1-1):

Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ 
goserelin in premenopausal women): 175 patients

Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin 
in premenopausal women): 175 patients
Randomization will be stratified by the presence of lung and/or liver metastases (yes versus no).
Figure 1-1
Study Design
The primary efficacy and safety analyses will be performed after all patients have been treated 


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for at least 6 months or have discontinued study treatment. Any additional data for patients 
continuing to receive study treatment past this time and for patients continuing for efficacy 
follow up (PFS ), as allowed by the protocol, will be further summarized in a final study report 
at the end of the study. No formal interim analysis is planned for this study.
1.2
Study objectives and endpoints
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To determine whether the overall 
response rate (ORR) in the 
experimental arm is non-inferior to the 
control arm.

ORR is based on local tumor assessments 
(RECIST version 1.1) for all patients that have 
been treated for at least 6 months or have 
discontinued the study treatment. 
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Key secondary objective:
To evaluate QTc (with Fridericia's 
correction) prolongation in the experimental 
arm

Key Secondary endpoint:
∆QTcF at Cycle 1 Day 15 (at 2h post-dose)

Other Secondary objectives:
To evaluate each treatment arm with 
respect to:

Other Secondary endpoints:

Safety and tolerability (including 
hepatobiliary toxicities and neutropenia)

Frequency/ severity of AEs, including AEs of 
special interest (e.g. hepatobiliary toxicities, 
neutropenia)
Laboratory abnormalities
Summary of ∆ QTcF at timepoint s other than 
Cycle 1 Day 15 (at 2hr post-dose)
ECG notable values based on all post baseline 
assessments.

Progression-free survival (PFS)

PFS per RECIST 1.1

Clinical benefit rate (CBR)

CBR per RECIST 1.1

Time to response (TTR)

TTR per RECIST 1.1

Duration of response (DOR)

DOR per RECIST 1.1

Pharmacokinetics (PK) of ribociclib 
when given in combination with NSAI

PK parameters such as Cmax, Tmax, and AUC0-
24h for ribociclib
2
Statistical methods
2.1
Data analysis general information
Novartis will perform the primary analyses and produce statistical outputs using SAS 9.4 or 
later version.
The primary efficacy and safety analyses will be performed after all patients have been treated 
for at least 6 months or have discontinued study treatment, and the corresponding on-treatment 


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scans have been collected. On-treatment scan refers to the scan taken within 30 days after the 
last dose of study treatment. The cut-off will accommodate the timing to perform any additional 
scan required to confirm the CR and PR per RECIST 1.1, even if that scan may be scheduled 
after 6 months, and will also take into account the time window of ± 1 week for the tumor scan 
as allowed by the protocol.
Statistical analyses will be performed using all data collected in the database up to the data cut-
off date. Any data collected beyond the cut-off date will not be included in the analysis and will 
not be used for any derivations.
Following the cut-off date for the primary analysis reported in the primary CSR, the study will
remain open. All additional data for patients that continue to receive study treatment past the
data cut-off date for the primary analysis, as allowed by the study protocol, will be included in
the final CSR at the end of the study.
2.1.1
General definitions
2.1.1.1
Study drug and study treatment
Study drug is defined as ribociclib either 600mg or 400mg.
Study treatment is defined as ribociclib 600mg + NSAI ± goserelin, or ribociclib 400mg + 
NSAI ± goserelin.
2.1.1.2
Date of first administration of study drug
The date of first administration of study drug is defined as the first date when a nonzero dose 
of study drug is administered and recorded on the dose administration DAR CRF. The date of 
first administration of study drug will also be referred to as start of study drug. Similar 
definitions apply for the other components of study treatment.
2.1.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on the DAR CRF date. Similar definitions apply for 
the other components of study treatment.
2.1.1.4
Date of first administration of study treatment
The date of first administration of study treatment is defined as the first date when a nonzero 
dose of any component of study treatment is administered and recorded on the DAR CRF. The 
date of first administration of study treatment will also be referred to as the start of study 
treatment.
2.1.1.5
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF.


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2.1.1.6
Study day
The study day will be calculated as:

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date; 

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) is the start of study treatment. (Note: 
if an adverse event starts before the start of study treatment, the study day displayed on the 
listing will be negative).
The reference start date for all other, non-safety assessments (i.e., tumor assessment, death, 
disease progression, tumor response and ECOG performance status) is the date of 
randomization. In other words, all efficacy time-to-event variables (e.g. progression-free 
survival, time to response) will be calculated from date of randomization. (Example: if 
randomization date is 15DEC2018, start of study drug is on 18DEC2018, and the date of death 
is 28DEC2018 then the study day when the death occurred is 14).
The study day will be displayed in data listings.
2.1.1.7
Baseline
For efficacy evaluations, the last available assessment on or before the date of randomization 
will be used as the “baseline” value or “baseline” assessment. In the context of baseline 
definition, the efficacy evaluations also include ECOG performance status. For RECIST-based 
endpoints (e.g. best overall response and PFS), a window of 7 days after the start of study 
treatment will be allowed, i.e. the baseline will also be considered valid if it occurs within +/-7 
days of the treatment start date.
For safety evaluations (e.g. laboratory assessments and ECG), the last available assessment 
before or at date of start of study treatment will be used as the ‘baseline’ assessment. 
Assessments specified to be collected post-dose on the first date of treatment are not considered 
as baseline values.
If patients have no value as defined above, the baseline results will be considered missing.
2.1.1.8
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. An on-treatment assessment/event is defined as any assessment/event in 
the following time interval: [date of first administration of study treatment, date of last 
administration of study treatment + 30 days], i.e. including the lower and upper limits. (Note: 
However, the calculation of study treatment duration will use different rules as specified in 
Section 2.6.1.1).
An AE starting in the screening phase and ongoing in the on-treatment phase will not be 
considered an on-treatment AE unless it has worsened.  
If the last date of study treatment is missing, any assessment/event occurring after the start of 
study treatment will be considered as on-treatment.


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Data listings will include all assessments/events, flagging those which are not on-treatment.
2.2
Analysis sets
The Full Analysis Set (FAS) is comprised of all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to.
FAS will be the default analysis set for all efficacy analysis except the primary endpoint.
The Per-Protocol Set (PPS) is a subset of patients of the Full Analysis Set without major 
protocol deviations. The PPS will be used for the analysis of the primary efficacy endpoint.
Patients with any of the following protocol deviations should be excluded from the PPS:

Written informed consent not obtained;

Patient without HR-positive and HER2-negative advanced breast cancer at baseline;

Patient received prior CDK4/6 inhibitor;

Patient without measurable disease at baseline;

Patient received any prior hormonal anti-cancer therapy for advanced breast cancer, 
except for ≤ 14 days of a NSAI and/or ≤ 28 days of goserelin prior to randomization for 
pre-menopausal patients;

Patient received chemotherapy for advanced breast cancer;

Patient received different treatment throughout the study than the one randomized to
The Safety Set 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
a. the randomized treatment if the patient took at least one dose of that treatment or
b. the first treatment received if the randomized treatment was never received.
The Pharmacokinetic Analysis Set (PAS) consists of all patients who received at least one 
dose of study medication defined as ribociclib and provided at least one evaluable PK 
concentration.
2.2.1
Patient classification
Patients may be excluded from the analysis sets defined above based on the protocol deviations 
entered in the database and/or on specific subject classification rules as defined in Table 2-1.
Table 2-1
Patient classification based on protocol deviations and non-protocol 
déviations criteria
Analysis set
Protocol deviations leading 
to exclusion
Non-protocol deviation 
criteria leading to exclusion
FAS 
No written informed consent
NA
Safety set
No written informed consent
No dose of study treatment
Per Protocol set
Any major protocol deviation as 
listed in definition of per 
protocol set
No dose of study treatment
Patient had dose reduction of 
ribociclib within cycle 1


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2.2.2
Withdrawal of informed consent
Any data collected in the clinical database after a patient withdraws informed consent from 
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.  
2.2.3
Protocol deviation summaries
The number and percentage of patients in the FAS with any protocol deviations will be tabulated 
by deviation category (as specified in the Study Specification Document) and by treatment arm.
Protocol deviations leading to exclusion from PPS (Per Protocol Set) will be tabulated 
separately by treatment arm. 
All protocol deviations, as well as protocol deviations leading to exclusion from the Per
Protocol Set, will be listed.
In addition to the pre-defined standard protocol deviation terms, 6 new protocol deviations and 
the corresponding relationship (health status related vs. site lockdown, patient concerns, etc.) 
to the COVID-19 pandemic have been defined  in alignment with “FDA Guidance on Conduct 
of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” (December
2020) and “Guidance on the management of clinical trials during the COVID-19 (coronavirus) 
pandemic” (April 2020) from EMA as listed below.

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Patient discontinuation due to COVID-19 situation
The number and percentage of patients with any protocol deviations in the FAS will be 
summarized by COVID-19 relationship (related or not-related) and by treatment arm in the 
post-text table. A cross-tabulation of COVID-19 related protocol deviation vs. corresponding 
detailed relationship will also be produced by treatment arm. The detailed relationship is listed 
as below:

COVID-19 health status related

COVID-19 situation: Site issue 

COVID-19 situation: Lockdown / Quarantine of patient 

COVID-19 situation: Patient concern 

COVID-19 situation: Drug supply issue 

COVID-19 situation: Other
2.2.4
Groupings for analysis
The number and percentage of patients in each analysis set will be summarized by treatment 
arm and randomization stratum. 


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2.2.5
Subgroup of interest
Subgroup analyses will be performed for efficacy as outlined below. The subgroup analyses 
will be performed in the PPS as well as in the FAS. Efficacy analyses in subgroups will be 
purely exploratory and are intended to explore the consistency of ORR in both arms.  No 
inferential analysis that compares ORR between the two treatment arms will be performed 
within these subgroups.
Subgroups will be formed using CRF data. This includes variables related to the stratification 
factor (i.e. lung/liver metastases), and CRF data will be used to define these subgroups. 
Analyses by stratification factor based on IRT data are covered by the analyses described in 
Section 2.7.4.
For ORR, exploratory subgroup analyses will be performed using the following:

Lung or liver involvement (Yes vs. No)

Menopausal status (pre vs postmenopausal)

Age group (< 40 vs ≥ 40 years, < 65 vs ≥ 65 years, < 75 vs ≥ 75 years)

Race (Asian vs. non-Asian)

Adjuvant or neo-adjuvant chemotherapy (Yes vs. No) 

Hormonal agent in (neo-)adjuvant setting  (Yes vs. No)

Region (Europe, North America and other)
For each of the subgroups, the following analyses will be performed:
ORR will be presented by treatment arm along with the two-sided exact binomial 95% 
confidence interval [Clopper and Pearson 1934].
2.3
Concomitant therapies with specific impact on the analysis
According to the study protocol, the following medications are prohibited while taking study 
treatment - ribociclib, NSAI, ± goserelin:

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 from 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 anti-neoplastic therapies.

Herbal medications/preparations or dietary supplements that are strong inhibitors or 
inducers of CYP3A4/5 or those with a known risk of QT prolongation. These include, but 
are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 
Patients should stop using these preparations/medications at least 7 days prior to first dose 
of study treatment.

Hormonal contraception, or hormonal medications used as a hormonal replacement 
therapy for symptoms of menopause, phytoestrogens (as these have potential to reduce 
efficacy of ET).


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These substances are listed in Table 16-1 in the study protocol. A corresponding list for 
programming purposes will be saved in a separate document. If there is an update to the list of 
prohibited medications (e.g.  protocol amendment), the most up-to-date list shall be used for the 
Clinical Study Report.
However, some patients may take these substances during the treatment period and these 
concomitant medications will be selected via programming and tabulated and listed in the 
Clinical Study Report. Treatment with the prohibited substances mentioned above will be 
identified in the database as protocol deviations. 
With the exception of palliative radiotherapy, administration of anti-neoplastic therapies (apart 
from study treatment) is not allowed during study treatment. Patients who take anti-neoplastic 
therapies after randomization will be identified through data review. Tumor assessments (TAs) 
made after the start of anti-neoplastic therapies (whether on study treatment or afterwards) will 
not be included in the efficacy analyses based on best overall response (i.e. Overall Response 
Rate (ORR), Clinical Benefit Rate (CBR), time to response, and duration of response) and time 
to event analysis of PFS.
2.4
Implementation of RECIST
Response and progression evaluation will be performed according to Novartis RECIST 
guideline (as described in detail in section 16.2 of the Clinical Study Protocol), which is based 
on  RECIST version 1.1 (Eisenhauer et al 2009). The text below gives instructions and rules to 
provide details needed for programming.
2.4.1
Best overall response (BOR)
The best overall tumor response will be assessed as per RECIST 1.1 criteria. The definitions 
and the details on the derivation are given in section 16.2 of the Clinical Study Protocol.
Only tumor assessments performed before the start of any anti-neoplastic therapies (i.e. any 
additional anti-neoplastic therapy or surgery) and within 30 days after the last administration of 
study treatment will be included in the assessment of best overall response. 

New anti-neoplastic therapies will be identified from the data collected on ‘Anti-neoplastic 
therapies since discontinuation of study treatment’ CRFs. 

Palliative radiotherapy is the only setting of radiotherapy allowed during the study. 
Therefore, palliative radiotherapy will not be considered as an anti-neoplastic therapy for 
assessment of BOR. As per RECIST 1.1, it should not be delivered to a target lesion. 

Continuation of combination partner therapy alone after end of study treatment will also not 
be considered as a new anti-neoplastic therapy. 
The standard definition of a best overall response evaluation of ‘stable disease’, ‘disease 
progression’ or ‘unknown’ given in the section 16.2 of the Clinical Study Protocol will be used 
for this study. Best overall response for each patient is determined from the sequence of overall 
(lesion) responses (as reported by the investigator for local BOR, and as reported by BIRC for 
central BOR) according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression.


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
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR).

SD = at least one SD assessment (or better) > 6 weeks after randomization (and not 
qualifying for CR or PR).

Non-CR/non-PD = at least one non-CR/non-PD assessment (or better) > 6 weeks after 
randomization date (and not qualifying for CR). This applies only for patients with non-
measurable disease alone at baseline. Non-CR/non-PD may only occur in the BIRC 
assessments given that measurable disease is one of the study inclusion criteria.

PD = progression 12 weeks after randomization (and not qualifying for CR, PR, SD and 
non-CR/non-PD)

UNK = all other cases (i.e. not qualifying for confirmed CR or PR  and without SD or 
non-CR/non-PD after more than 6 weeks or without progression within the first 12 
weeks).
Patients with best overall response “unknown” will be summarized by reason for having 
unknown status. The following reasons will be used:

No valid post-baseline assessment 

All post-baseline assessments have overall response UNK 

New anti-neoplastic therapy started before first post-baseline assessment 

SD too early (≤6 weeks after randomization) 

PD too late (>12 weeks after randomization and not qualifying for CR, PR and SD)
Special (and rare) cases where BOR is unknown due to both early SD and late PD will be 
classified as “SD too early”.
2.4.2
Disease progression
Progressive disease should only be assigned if it is confirmed by an assessment method as per 
RECIST 1.1 guidelines (e.g. radiologic assessment, photos for skin lesions, etc.). If a new lesion 
is detected using an objective assessment method other than radiologic assessment, then it 
should also be entered on the ‘New lesion’ RECIST CRF with appropriate method. 
Discontinuation due to disease progression or death due to study indication, without 
corresponding supportive data in the RECIST CRF (as defined above), will not be considered 
as progressive disease in the calculation of best overall response and in the analysis of PFS.
2.4.3
Change in imaging modality
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from ‘with’ to ‘without’ contrast use or 
vice-versa, regardless of the justification for the change), a major change in technique (e.g. from 
CT to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for the 
purposes of response assessment. A change in methodology will result by default in an UNK 
(unknown) overall lesion response based on the Novartis calculation. However, a response from 
the investigator or the central blinded reviewer that differs from the Novartis calculated UNK 
is acceptable, if a definitive response assessment can be justified based on the available 
information.


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Potential discrepancies between the modality used and overall lesion response (e.g. change in 
modality but response is different from ‘Unknown’) will be queried during the data validation 
process. 
2.4.4
Determination of missing adequate assessments
The term ‘missing adequate assessment’ refers to assessments that are not done or for which 
the overall lesion response is ‘Unknown’. ‘Missing adequate assessment’ will also be referred 
to as ‘missing assessment’.
As detailed in Section 5.2.5 and in section 16.2 of the Clinical Study Protocol, the PFS censoring 
and event date options depend on the presence and the number of missing tumor assessments. 
An event occurring after two or more missing assessments is censored at the last adequate tumor 
assessment. 
An exact rule to determine whether there are no, one or two missing TAs is therefore needed. 
This rule is based on the interval between the last adequate tumor assessment (LATA) date and 
the event date. The scheduled date of tumor assessments (in weeks from randomization), 
protocol specified window for tumor assessments, and the thresholds for LATA that belong to 
a visit can be found in the following table.
Table 2-2
Schedule for tumor assessment and time windows
Assessment 
schedule
Scheduled date 
– 1 week
Scheduled date 
(weeks from 
randomization)
Scheduled date 
+1 week
Threshold*
Every 8 
weeks 
for the 
first 18 
months
Baseline
0
0
0
0
C3D1
7
8
9
12
C5D1
15
16
17
20
C7D1
23
24
25
28
C9D1
31
32
33
36
C11D1
39
40
41
44
C13D1
47
48
49
52
C15D1
55
56
57
60
C17D1
63
64
65
68
C19D1
71
72
73
78
Every 
12 
weeks 
after 18 
months
C22D1
83
84
85
90
C25D1
95
96
97
102
C28D1
107
108
109
114
C31D1
119
120
121
126
* The mid-point between current and next visit (except for baseline) and the upper limit for LATA to 
be matched to a certain scheduled assessment, e.g. if LATA is at week 13, this is after threshold 
for C3D1 and before that for C5D1, so the matching scheduled assessment is C5D1.
To calculate the number of missing tumor assessments, the LATA before an event is matched 
with a scheduled tumor assessment using the time window in Table 2-2 (essentially whichever 
scheduled assessment it is closest to). Two thresholds, D1 and D2 are calculated for that 
scheduled assessment based on the protocol-specified schedule and windows


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
An event after LATA+D1 will be considered as having >=1 missing assessment

An event after LATA+D2 will be considered as having >=2 missing assessments
Since there is a change of schedule for tumor assessments at 18 months, D1 and D2 are 
defined differently depending on when LATA happens.
Rule 1: if LATA happens within 60 weeks from randomization (the matched scheduled tumor 
assessment is C15D1 or before)

D1=8+2=10 weeks

D2=2*8+2=18 weeks
Rule 2: if LATA happens after 60 weeks but within 68 weeks from randomization (the 
matched scheduled tumor assessment is C17D1)

D1=8+2=10 weeks

D2=8+12+2=22 weeks
Rule 3: if LATA happens after 68 weeks from randomization (the matched scheduled tumor 
assessment is C19D1 or later)

D1=12+2=14 weeks

D2=2*12+2=26 weeks.  
Therefore, using the D2 definition above, the censoring of an event occurring after ≥2 missing 
TAs (in the primary PFS analysis) can be refined as follows: if the distance between the last 
adequate TA date and the PFS event date is larger than D2, then the patient will be censored 
and the censoring reason will be ‘Event documented after two or more missing tumor 
assessments’.
The same definition of D2 will be used to determine the PFS censoring reason. If the distance 
between the last adequate tumor assessment date and the earliest of the following dates (analysis 
cut off, consent withdrawal etc.) is less than or equal to D2:
1. Analysis cut-off date
2. Date of consent withdrawal
3. Start date of further anti-neoplastic therapy
4. Date of loss to follow-up
then the censoring reason will be 1. ‘Ongoing without event’, 2. ‘Withdrew consent’, 3 “New 
cancer therapy added” or 4. ‘Lost to follow-up’, respectively. However, if this distance is larger 
than D2, then the censoring reason will be ‘Adequate assessment no longer available’. If an 
event is documented after two missing assessments, then the censoring reason will be ‘Event 
documented after two or more missing tumor assessments’.
2.4.5
No baseline tumor assessments
Patients with no baseline tumor assessment will be excluded from the per protocol set.
For the PFS analysis, as specified in section 16.2 of the Clinical Study Protocol, since the timing 
of disease progression cannot be determined for patients with missing baseline tumor 
assessment, these patients are censored in the PFS analysis at the date of randomization. This 
rule however only applies to the disease progression component of the PFS assessment, and not 
to the survival component. Patients without baseline tumor assessments who die within D2 


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distance (see Section 2.4.4 for definition) of randomization will be counted as having an event 
in the PFS analysis at the date of death.
2.4.6
Construction of waterfall graphs
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of all target lesions for each patient. 
Only patients with measurable disease at baseline will be included in the waterfall graphs.
Special consideration is needed for assessments where the target lesion response is CR, PR or 
SD, but the appearance of a new lesion or a worsening of non-target lesions results in an overall 
lesion response of PD. As a conservative approach, such assessments will not be considered for 
display as bars in the graph, since the percentage change in the sum of diameters of target lesions 
reflects the non-PD target lesion response, but the overall lesion response is PD. A patient with 
only such assessments will be represented by a special symbol (e.g.  ) in the waterfall graph.
Assessments with “unknown” target lesion response and assessments with unknown overall 
response will be excluded from the waterfall plots. Patients without any valid assessments will 
be completely excluded from the graphs.
The total number of patients displayed in the graph will be shown and this number will be used 
as the denominator for calculating the percentages of patients with tumor shrinkage and tumor 
growth. A footnote will explain the reason for excluding some patients (due to absence of any 
valid assessment).
All possible assessment scenarios are described in Table 2-3.
Table 2-3
Assessments considered for calculation of best percentage change 
for waterfall graphs
Case
Target response
Overall lesion 
response
Calculate % change from baseline 
in sum of diameters?
1
UNK
Any
No, exclude assessment
2
Any
UNK
No, exclude assessment
3
CR/PR/SD
PD
No, flag assessment with 
4
PD
PD
Yes
5
CR/PR/SD
CR/PR/SD
Yes
2.5
Patient disposition, demographics and other baseline 
characteristics
Demographic and other baseline data including disease characteristics/prognostic data will be 
summarized descriptively by treatment group for the FAS. Relevant medical history and current 
medical conditions at baseline will be summarized separately by system organ class and 
preferred term, by treatment group in the FAS. The summary will also be produced for the PPS 
if the FAS and PPS differ.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.


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2.5.1
Patient disposition
Patient disposition for all randomized patients will be summarized. There will be one combined 
by-treatment summary showing:
1. Number (%) of patients treated/untreated
2. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of treatment’ page)
3. Number (%) of patients who discontinued study treatment (based on the ‘End of 
Treatment’ page)
4. Reasons for study treatment discontinuation (based on ‘End of Treatment’ page)
5. Number (%) of patients who entered the post-treatment evaluations (based on ‘End of 
Treatment’ page)
6. Number (%) of patients who discontinued from the post-treatment evaluations (based 
on ‘End of post treatment follow up disposition’ page and ‘Subject status’ page)
7. Reasons for discontinuation from the post-treatment evaluations phase (based on ‘End 
of post treatment follow up disposition’ page and ‘Subject status’ page)
Enrollment by country and center will be summarized for all screened patients and the summary 
will also include number (%) of patients by treatment arm using the FAS.
In a separate summary, the reasons for patients not completing the screening phase will be 
presented based on the “Screening Phase Disposition” CRF.
2.5.2
Basic demographic and background data
Demographic and background disease characteristics data will be listed in detail. Qualitative 
data (e.g. race, ECOG performance status, etc.) will be summarized by means of contingency 
tables by treatment arm and quantitative data (e.g. age, body weight, etc.) will be summarized 
by appropriate descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) by treatment arm.
Discrepancies between randomization stratification information (obtained from the Interactive 
Response Technology (IRT) system) and stratum information based on data collected on CRFs 
will be tabulated and listed.
Unless otherwise specified, stratified analyses and analyses “by stratum” will be based on IRT 
stratification data, while data for other subgroup analyses will be based on CRF data.
2.5.3
Diagnosis and extent of cancer
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, histological grade, stage at initial diagnosis, 
time since initial diagnosis, stage at time of study entry, presence/absence of target and non-
target lesions, number and type of metastatic sites involved, HER-2 / estrogen / progesterone 
receptor status, disease-free interval (DFI) for non-de novo patients, and a categorization of 
prior (neo-) adjuvant endocrine therapy (ET) as outlined below:

De novo patients will be identified as those with “De novo” box ticked in the eCRF.

DFI for non-de novo patients will be calculated as the time from initial diagnosis to 
recurrence/progression and categorized as ≤12 months and >12 months.

Patients will be grouped as follows based on prior (neo-)adjuvant ET:


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
No prior (neo-)adjuvant endocrine therapy

Progression while on or within 12 months of end of (neo-)adjuvant ET

Progression > 12 months after end of (neo-)adjuvant ET.
Time since initial diagnosis will be summarized in months. A month is defined as 
365.25/12=30.4375 days.
2.5.4
Medical history
Medical history and ongoing conditions, including cancer-related conditions, will be 
summarized and listed. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by primary system organ class and 
preferred term. Medical history/current medical conditions are coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA) terminology available at the time of 
the analyses. The MedDRA version used for reporting will be specified in the CSR and as a 
footnote in the applicable tables/listings.
2.5.5
Prior anti-neoplastic therapy
The number and percentage of patients recording any prior anti-neoplastic medications, 
radiotherapy or surgery (biopsy and non-biopsy separately) will be summarized by treatment 
arm both separately and in a combined fashion.

Prior anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, 
hormonal therapy etc.), and also by lowest ATC class, preferred term and treatment. The 
total number of regimens along with the type (e.g. hormonal therapy), setting (e.g. 
adjuvant), and time from treatment end date of the last therapy to progression will be 
summarized by treatment arm.

Hormonal therapy (letrozole/anastrozole) for advanced breast cancer received for ≤ 14 
days with or without goserelin, or treatment with goserelin for ≤ 28 days prior to 
randomization, as permitted by the study protocol, will be summarized separately.

Hormonal therapies in (neo-)adjuvant setting will also be summarized, including time 
from last dose of (neo-)adjuvant hormonal therapy to randomization.

For radiotherapy, the setting (e.g. adjuvant, palliative) for the last therapy will be 
summarized.

For surgery (excluding biopsies), the time since last surgery will be summarized by 
treatment arm.
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.
2.5.6
Other and COVID-19 Pandemic
All data collected at baseline, including patients’ referrals, will be listed.
Recruitment in the study was ongoing during the onset of the COVID-19 pandemic. The 
baseline demographic characteristics, diagnosis and extent of cancer, and prior anti-neoplastic 
therapy will be summarized seperately for patients randomized before the COVID-19 pandemic
start  and patients randomized after the COVID-19 pandemic start. 


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The start date of the COVID-19 pandemic in each region/country is defined as the approximate 
time point at which, according to the WHO situation reports and the Johns Hopkins database, 
the number of confirmed COVID-19 infections started to increase significantly (around 100 
confirmed cases) and / or governments started to take measures (such as lockdown and stay-at-
home orders) to contain the spread of the infection, whichever occurred first. As of March 1, 
2020, given the reach of the pandemic (as documented by WHO situation report 40) and media 
coverage around the world at that point in time, it is assumed that most locations could have 
been affected by actions related to COVID-19 (e.g. restrictions of mobility at regional or local 
level, measures taken by clinical sites, etc.)  The detailed start dates are listed in Table 2-4.
Table 2-4 COVID-19 start date
Region/Country 
Start Date 
China 
01-Jan-2020 
South Korea 
20-Feb-2020 
Japan 
21-Feb-2020 
Italy 
23-Feb-2020 
Rest of the World 
01-Mar-2020 
Considering that no patients were enrolled in China, South Korea, Japan and Italy in this study, 
the start date of COVID-19 is defined as 01-Mar-2020.
2.6
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.6.1
Study treatment / compliance
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. The number of patients with dose 
reductions/interruptions and the reasons, will be summarized and listed. Details of the 
derivations and summaries are provided in the following sections.
The safety set will be used for all summaries and listings of study treatment.
2.6.1.1
Duration of study treatment exposure
The duration of exposure to study treatment will be calculated as:
Duration of exposure to study treatment (days) = (last date of exposure to any study treatment 
component) – (date of first administration of study treatment) + 1.
Duration of exposure to any single component of study treatment will be calculated as:
Duration of exposure (days) = (last date of exposure to study treatment component) – (date of 
first administration of study treatment component) + 1.
The last date of exposure is defined as follows for the study treatment components:

For ribociclib, anastrozole, and letrozole: the last date of exposure is defined as the date of 
last administration of the corresponding medication;

For goserelin, the last date of exposure is defined as the date of last administration of 
goserelin + 27 days. 


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
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 the date of lost to follow-up as 
recorded in the disposition panel, respectively.
This duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). The duration of study treatment exposure and exposure to 
each treatment component will be summarized by treatment arm. In addition, the duration of 
exposure will be categorized into time intervals (e.g. <3 months; 3-<6 months; 6-<9 months, 
etc.); frequency counts and percentages will be presented for the number of patients in each 
interval.
2.6.1.2
Cumulative dose and average daily dose
Cumulative dose for any component of study treatment is defined as the total dose of the 
medication given during the study treatment exposure.  
Average daily dose is defined as [Cumulative dose (mg) / Number of dosing days]; drug free 
day(s) are not counted as dosing days.
Cumulative dose and average daily dose will be summarized using descriptive statistics by 
treatment arm for each component of study treatment. Patients with no exposure to the study 
treatment component will be excluded from the corresponding summary.
2.6.1.3
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure to each study treatment 
component is defined as follows: 
For letrozole, and anastrozole, DI is defined as
DI (mg/day) = Cumulative dose (mg) / duration of exposure to study treatment component 
(days).
For goserelin, DI is defined as
DI (mg/28 days) = Cumulative dose (mg) / {[(date of last administration of goserelin + 27) –
(date of first administration of goserelin) + 1] / 28},
to account for the goserelin dosing schedule in the DI computation.
For ribociclib, DI is defined as
DI (mg/day) = Cumulative dose (mg) / adjusted duration of exposure to ribociclib (days),
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 as defined in Section 2.6.1.1. 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.


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Specifically, let D1 represent the duration of exposure to ribociclib as defined in Section 2.6.1.1.
Then the adjusted duration of exposure is defined as 
D=21*[D1/28]+min(21,D1-28*[D1/28]) days, 
where [x] stands for the integer part of x. In this equation [D1/28] is the number of completed 
cycles, and D1-28*[D1/28] is the additional number of days in the last, incomplete cycle (if 
any). For example, if D1=30 then [D1/28]=1, D1-28*[D1/28]=2, and D=23. If D1=7 then D=7; 
if D1=22 then D=21; if D1=28 then D=21, etc.
Planned dose intensity (PDI) is defined as the assigned dose by unit of time planned to be given 
to patients as per protocol. The PDI for each study treatment component is displayed in Table 
2-5. Note that DI will also be calculated and reported in the units displayed in Table 2-5, 
whereas duration of exposure itself will be summarized in months.
Table 2-5
Planned dose intensity
Medication
PDI (dose unit/unit of time)
Ribociclib
400 mg/day for the experimental arm
600 mg/day for the control arm
Letrozole
2.5 mg/day
Anastrozole
1 mg/day
Goserelin
3.6 mg/28 days
Relative dose intensity (RDI) is defined as:
RDI = DI (dosing unit / unit of time)  / PDI (dosing unit / unit of time).  
DI and RDI will be summarized separately for each of the study treatment components.
2.6.1.4
Dose reductions, interruptions and delays
The number and percentage of patients with dose reductions, interruptions or delays, and the 
reasons, will be summarized by treatment arm as outlined below. 
Interruption: An interruption is defined as a 0 mg dose given on one or more days during the 
period where (for ribociclib only) a patient is not on the “off” part of a treatment cycle, after 
which > 0mg dose resumes. For patients who had dose interruption checked but never resumed 
non-zero dose, the dose interruption will not be counted. For example, in the sequence of 600 
mg – 0mg (dose break) -0mg (dose interruption) – 0 mg (dose permanently discontinued) the 
0mg (dose interruption) will not be counted as a dose interruption. Interruptions will be 
summarized for each component of study treatment.
Delay: A special case of an interruption is one that, for ribociclib, occurs at the start of a new 
cycle, after a planned rest period. Such instances will be identified as a subset of the 
interruptions (specifically those occurring directly after a planned dose break) and will be 
summarized separately as dose delays.
Reduction: A dose reduction for ribociclib is defined as a decrease from the previous non-zero 
dose to another non-zero dose less than the protocol-planned dose, even if this decrease has 
been directly preceded by an interruption.  For example, in the sequence 600 mg – 0mg – 400
mg, the 400mg dose will be counted as a reduction. 


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If due to dosing error, a patient took a dose during the dosing break with a dose that is lower 
than the previous dose but resumed the correct dose subsequently, this will not be considered 
as a dose reduction. For example, a patient took 600 mg from day 1-5, then mistakenly took 
200 mg per day on day 6-8, then resumed 600 mg dosing on day 9. This will not be considered 
as a dose reduction.
As a sensitivity analysis for short duration of dose reduction arising from dosing error, summary 
of dose reduction will also be produced excluding the dose reduction episodes due to dosing 
error lasting less than 28 days.  
Missing data: If dose is recorded but frequency is missing or entered as ‘none’, it is assumed 
that the study drug was taken as per-protocol.
In this study, dose reductions for letrozole, anastrozole or goserelin are not permitted and will 
not be summarized, however all dosing data will be listed.
2.6.1.5
Discontinuation of study treatment components
The reasons for discontinuation of each study treatment component will be summarized by 
treatment arm, based on the information on the component-specific end of treatment CRFs.
2.6.2
Concomitant therapy and post treatment anti-cancer therapies
Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, coinciding with the study 
assessment period (even if started before the study assessment period). 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system. 
Concomitant medications will be summarized by lowest ATC class, preferred term and 
treatment arm. These summaries will include: 
1. medications starting on or after the start of study treatment but no later than 30 days 
after last dose of study treatment, and 
2. medications starting prior to the start of study treatment and continuing after the start 
of study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to 
the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. 
The safety set will be used for all concomitant medication tables and listings.
Concomitant medications that have the potential to impact some specific analyses (e.g. PK, 
efficacy or safety analyses) will be identified prior to database lock. Separate summaries of 
these concomitant medications will be produced using the appropriate analysis set (e.g. FAS 
for those potentially affecting efficacy).

Strong inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow 
therapeutic window, medications with a known risk of QT prolongation and other 


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prohibited medications described in Section 2.3 will be identified. They will be tabulated 
by ATC class and preferred term.

Any anti-neoplastic therapies administered concomitantly with study treatment will be 
listed based on their identification through the protocol deviation process.
Post treatment anti-cancer therapy
Anti-neoplastic therapies after discontinuation of study drug will be listed and tabulated by ATC 
class, preferred term and treatment arm by means of frequency counts and percentages using 
the FAS. 
2.7
Analysis of the primary objective
The primary objective of the study is to determine whether the dosing regimen of ribociclib 400 
mg QD 3 week-on/1 week-off in combination with NSAI (Arm 1) is non-inferior to the 
currently approved regimen of 600 mg QD 3 week-on/1 week-off in combination with NSAI 
(Arm 2) in terms of ORRs assessed by local investigators. As such, the primary efficacy 
endpoint of the study is to evaluate the non-inferiority of Arm 1 compared to Arm 2, based on 
the ratio of ORR between the two arms. The experimental arm (Arm 1) will be considered to 
be non-inferior to the control arm (Arm 2) if the lower 90% CI limit of the ratio of the ORR in 
Arm 1 to Arm 2 is greater than 0.814. The non-inferiority (NI) margin of 0.814 was chosen to 
demonstrate the retention of at least 50% of the active treatment effect in terms of ORR for 
ribociclib in combination with NSAI vs. NSAI alone.
2.7.1
Primary endpoint
The primary endpoint of the study is overall response rate (ORR), defined as the proportion of 
patients with best overall response (BOR) of confirmed complete response (CR) or partial 
response (PR) assessed by local investigators according to RECIST 1.1 (See protocol 
Section 16.2 for further details for RECIST 1.1). ORR is based on the tumor evaluations from 
patients who have been treated for at least 6 months or have discontinued treatment. The cut-
off date for the primary analysis will be established based on the description in Section 2.1. The 
primary efficacy variable, ORR, will be based on the PPS population according to the 
randomized treatment group.
The tumor endpoint derivation is based on the sequence of overall lesion responses at each 
assessment/time point. However, the overall lesion response at a given assessment/time point 
may be provided from different sources as illustrated in Table 2-6.
Table 2-6
Sources for overall lesion response
Source 1
Investigator (local radiology) reported overall lesion response
Source 2
Novartis-calculated overall lesion response based on raw (i.e. individual 
lesion) measurements from investigator (local radiology)
Source 3
Final BIRC-reported overall lesion response
The primary efficacy analysis will be based on the investigator/local radiology review. The 
investigator reported overall lesion response at each assessment/time point (Source 1 in Table 
2-6) will be used to derive the efficacy endpoints. 


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The overall response at each assessment will also be calculated using the raw lesion 
measurements (Source 2 in Table 2-6). The calculated responses will be listed along with the 
responses given by the investigator. As a sensitivity analysis, ORR based on calculated overall 
lesion response (Source 2 in Table 2-6) will also be summarized.
Tumor assessment data based on BIRC assessment (Source 3) will be used for selected 
supportive efficacy analyses. The BIRC consists of two independent radiologists and an 
adjudicator. The BIRC-reported overall lesion response data will be used to derive the BIRC-
based endpoints. Data from independent readers will be listed together with the adjudication. 
Differences in overall responses between local radiology (Source 1) and central radiology 
(Source 3) will be listed.
2.7.2
Statistical hypothesis, model, and method of analysis
2.7.2.1
Hypothesis and test statistic
The following statistical hypotheses will be tested to address the primary objective based on the 
non-inferiority decision rule:
H01: θ1 < = 0.814 vs. HA1 : θ1 > 0.814
where θ1 is the ratio of ORR in Arm 1 to ORR in Arm 2. The non-inferiority of Arm 1 to Arm 
2 will be established if the lower 90% CI limit of θ1 is greater than the pre-specified NI margin 
0.814.
The CI of ORR ratio will be constructed using Mantel-Haenszel method to include lung/liver 
metastasis as the stratification factor (strata based on IRT data).
2.7.2.2
ORR and Wald confidence intervals
ORR will be presented by treatment arm along with standard Wald asymptotic (i.e. normal 
approximation) 95% confidence intervals.
2.7.3
Handling of missing values/censoring/discontinuations
In the primary analysis, all the eligible overall responses will be considered for the evaluation 
of best overall response. Only patients with confirmed best overall response as CR or PR will 
be considered as responders for ORR calculation, and all other patients will be considered as 
non-responders including patients with best overall response (BOR) listed as unknown or 
missing.
2.7.4
Sensitivity and Supportive analyses
Sensitivity analyses
As a sensitivity analysis to assess the impact of stratification, the primary endpoint will be 
repeated in an unstratified test in the PPS.
As a sensitivity analysis, the primary analysis for ORR with and without stratification will also 
be repeated in the FAS.  


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Supportive analyses
As a supportive analysis, the primary analysis will be repeated using Blinded Independent 
Review Committee (BIRC) assessment and Novartis calculated overall lesion response in both 
the PPS and FAS.
Subgroup analyses to assess the homogeneity of overall response rate based on demographic 
and baseline disease characteristics will be performed in both arms; the subgroups to be 
included is defined in Section 2.2.5. The analysis will be conducted in both the PPS and FAS.
2.8
Analysis of the key secondary objective
ECG data will be collected via 12-lead digital ECG machines. The data will be transmitted to a 
designated CRO for centralized cardiac safety analysis. 
The key secondary objective of the study is to evaluate the QTc (with Fridericia's correction) 
profile of the experimental arm. The objective of mitigating QT prolongation will be met if the 
upper 90% CI limit of the ∆ QTcF at Cycle 1 Day 15 (2 h post-dose) compared to baseline 
(Cycle 1 Day 1 pre-dose) is less than 20 ms (FDA 2015). This analysis will be based on all 
patients in the Safety Set that have a non-missing QT assessment performed at baseline and 
Cycle 1 Day 15 (2h post-dose).
QTcF collected at all the timepoints including  Cycle 1 Day 15 (2h post-dose) will also be 
summarized by treatment arm as one of secondary objectives as specified in Section 2.10.4. 
2.9
Analysis of secondary efficacy objective(s)
2.9.1
Progression free survival (PFS) 
PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression or death due to any cause. PFS will be censored if no PFS event is observed. 
The censoring date will be the date of the last adequate tumor assessment (see protocol 
Section 16.2 for further details). Clinical deterioration without objective radiological evidence 
will not be considered as documented disease progression. PFS will be assessed via a local 
radiology assessment as well as BIRC according to RECIST 1.1.
PFS will be analyzed in the FAS population according to the randomized treatment group as 
follows:

The PFS 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.

Number of patients with a PFS event and number of patients censored for the PFS analysis 
will be summarized. In addition, a summary of reasons for PFS censoring will be provided 
by treatment arm based on the reasons defined in Section 2.4.4. These summaries on 
censoring reasons will be produced for PFS by investigator radiology and BIRC review.

Comparison of PFS event type/censor between local radiology review and BIRC review
No inferential analysis that compares progression free survival between the two treatment arms 
will be performed.


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2.9.2
Clinical benefit rate (CBR) 
CBR is defined as the proportion of patients with a best overall response of complete response 
(CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 
24 weeks. CR, PR, and SD are defined as per local review as well as BIRC according to RECIST 
1.1 (see protocol Section 16.2 for further details). 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. For BIRC assessment, NCR-
NPD might be recorded if the BIRC reviewer is not able to identify target lesion at the baseline, 
and in this case, NCR-NPD will be handled in the same way as SD in terms of CBR calculation.
CBR will be calculated based on the FAS. CBR and its 95% confidence interval will be 
presented by treatment group.
No inferential analysis that compares CBR between the two treatment arms will be performed.
2.9.3
Time to response (TTR) 
TTR is defined as the time from the date of randomization to the first documented response of 
either complete response (CR) or partial response (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 protocol Section 16.2
for further 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 arms. The distribution of time to response will 
be estimated using the Kaplan-Meier method and the median time to response will be presented 
along with 95% confidence interval only if a sufficient number of responses is observed. A 
descriptive summary of time to response for the responders will also be presented.
No inferential analysis that compares TTR between the two treatment arms will be performed.
2.9.4
Duration of response (DOR) 
DOR only applies to patients whose best overall response is complete response (CR) or partial 
response (PR) according to RECIST 1.1 based on tumor response data per local review. The 
start date is the date of first documented response of CR or PR (i.e. the start date of response, 
not the date when response was confirmed), and the end date is defined as the date of the first 
documented progression or death due to underlying cancer. Patients continuing without 
progression or death due to underlying cancer will be censored at the date of their last adequate 
tumor assessment. 
DOR will be listed and summarized by treatment group for all patients in the FAS with 
confirmed BOR of CR or PR (see protocol Section 16.2 for further details). The distribution of 
duration of response will be estimated using the Kaplan-Meier method and the median response 
duration will be presented along with 95% confidence interval only if a sufficient number of 
responses is observed.


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No inferential analysis that compares DOR between the two treatment arms will be performed.
2.9.5
ECOG performance status
The ECOG PS scale (Table 2-7) will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active):
Table 2-7
ECOG Performance Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
The following intervals will be used to group the ECOG PS data over time. Day in columns 2 
and 3 is defined as date of ECOG PS assessment date – randomization date + 1. The 
correspondence with Day in column 1 assumes that a patient is treated on the day of 
randomization; however the definition of Day in columns 2 and 3 still applies if this is not the 
case, i.e. randomization date is taken as the reference for the windows.
Table 2-8
Time windows for ECOG PS assessments
Assessment
Target day of assessment
Time Interval
Baseline
Day 1 (if not available use 
screening)
Cycle 1 Day 15
15
Day 2 to day 21 
Cycle 2 Day 1
29
Day 22 to day 42 
Cycle 3 Day 1
57
Day 43 to day 63 
Cycle 3 Day 15
71
Day 64 to day 77
Cycle 4 Day 1
85
Day 78 to day 98 
Cycle k Day 1 (k≥7)
d=(k-1)*28+1
Day d-14 to day d+13
End of Treatment
Assessment taken at the end 
of treatment visit
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. If 2 assessments within a time window are equidistant 
from the target date, then the worst of the 2 assessments will be used.
Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point. 


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2.10
Safety analyses
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 deaths, including on-treatment and 
post treatment deaths will be provided.
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:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment.
2. On-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study treatment.
3. Post-treatment period: starting at day 31 after last dose of study treatment.
2.10.1
Adverse events (AEs)
2.10.1.1 General rules for AE Reporting
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. All information obtained 
on adverse events will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment emergent adverse events may be 
summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
A patient with multiple adverse events within a primary system organ class is only counted once 
towards the total of the primary system organ class.
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. A patient with multiple grades for an AE will 
be summarized under the maximum grade recorded for the event. AE with missing CTCAE 
grade will be included in the ‘All grades’ column of the summary tables.


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In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the ribociclib arm.
The frequency of grade 3 and above AEs will be summarized separately.
Any information collected (e.g. grades, relationship to study treatment, serious, action taken 
etc.) will be summarized as appropriate. 
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
2.10.1.2 AE and deaths summaries
The following adverse event summaries will be produced: 

Summary of deaths and adverse events

AEs, irrespective of causality, by primary system organ class, preferred term and 
maximum grade

AEs with suspected relationship to study treatment by primary system organ class, 
preferred term and maximum grade

Most common grade ≥3 adverse events, irrespective of causality, by preferred term 
and maximum grade (greater than x% in either arm)

Adverse events, irrespective of causality, by primary system organ class and 
maximum grade

Adverse events, irrespective of causality, by preferred term and maximum grade

Adverse events with suspected relationship to study treatment by preferred term and 
maximum grade 

Grade 3 and above AEs, irrespective of causality, by primary system organ class, 
preferred term and maximum grade

Grade 3 and above AEs with suspected study treatment relationship by primary system 
organ class, preferred term and maximum grade

On-treatment deaths, by preferred term

All Deaths (on-treatment + post-treatment), by primary system organ class and 
preferred term

Serious AEs, irrespective of causality, by primary system organ class, preferred term 
and maximum grade

Serious AEs with suspected relationship to study treatment, by primary system organ 
class, preferred term and maximum grade

AEs leading to discontinuation, irrespective of causality, by primary system organ 
class, preferred term and maximum grade

AEs requiring dose adjustment , irrespective of causality, by primary system organ 
class, preferred term and maximum grade

AEs requiring treatment interruption, irrespective of causality, by primary system 
organ class, preferred term and maximum grade


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
AEs requiring additional therapy, irrespective of causality, by primary system organ 
class, preferred term and maximum grade

Non-serious AEs (at least x% incidence rate in either treatment arm) by primary 
system organ class and preferred term.

Serious and non-serious adverse events with number of occurrences (an occurrence is 
defined as >1 day between start and prior end date of record of same preferred term)

On-treatment deaths and SAEs with fatal outcome, by SOC and PT
2.10.1.3 Grouping of AEs of special interest (AESI)
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to ribociclib. These groupings are defined using MedDRA terms, 
SMQs (standardized MedDRA queries), HLGTs (high level group terms), HLTs (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may 
also be used. A NMQ is a customized group of search terms which defines a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 
need. It may include a combination of single terms and/or an existing SMQ, narrow or broad. 
For each specified AESI, the number and percentage of patients with at least one event of the 
AESI occurring during the on-treatment period will be summarized.
Summaries of these AESIs will be provided by treatment arm (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, etc.). 
A Case Retrieval Sheet (CRS) with the exact composition of the AE groupings is to be used to 
map reported AEs to the AESI groupings. This file may be updated (i.e. it is a living document) 
based on review of accumulating trial data, and therefore the groupings are also subject to 
potential change. Table 2-9 provides the latest groupings at the time of the finalization of the 
SAP. The most up-to-date version of the CRS will be used at the time of the analysis.
Table 2-9
AESI groupings
AESI grouping
MedDRA category
Anemia
SMQ
Diarrhea
SMQ
Hepatobiliary toxicity
SMQ
Infections
SMQ and SOC
Leukopenia
HLT
Nausea, emesis
HLT
Neutropenia
HLT and PT
Pneumonitis, interstitial lung disease 
SMQ
Pulmonary embolism
SMQ and HLT
QTc prolongation
SMQ
Renal impairment
SMQ
Reproductive toxicity
SMQ
Thrombocytopenia
SMQ


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2.10.2
Laboratory data
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected no later than 30 
days after the last administration of study treatment. All laboratory assessments will be listed 
and those collected later than 30 days after the last treatment date will be flagged in the listings
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. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. CTCAE Grade 0 will be assigned for all non-missing values not graded as 
1 or higher. The criteria to assign CTC grades are given in Appendix 1.
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients with each CTC grade as their worst post-baseline 
value (regardless of the baseline status). Each patient will be counted only for the 
worst grade observed post baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value 
will be produced for hematology and biochemistry laboratory parameters with CTC 
grades.

For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges.

Number and percentage of patients meeting categorical liver function test criteria, 
including ALT, AST and ALT/AST (>3x, 5x, 8x, 10x, 20x ULN), Total Bilirubin 
(>1x, 2x ULN), ALP (>1.5x, 2x, 3x, 5x, 8x, 10x ULN), combined categories of 
ALT/AST and total bilirubin (e.g., ALT/AST>3x ULN & total bilirubin > ULN) as 
well as potential Hy’s Law criteria (ALT or AST > 3 x ULN and TBIL > 2 x ULN and 
ALP < 2 x ULN). For the combined categories, the assessments need not be 
concurrent, i.e. patients are counted based on their most extreme value for each 
parameter (highest in the case of ALT, AST and TBIL; lowest in the case of ALP).

Box plots of laboratory values by scheduled time point and treatment arm.
The following listings will be produced for the laboratory data:

Listing of patients with CTC grade 3 or 4 laboratory abnormalities;

Listing of all laboratory data with values flagged to show the corresponding CTC 
grades and the classifications relative to the laboratory reference ranges.
Time to first occurrence of grade 2 or worse laboratory toxicity and time to first occurrence of 
grade 3 or worse laboratory toxicity will be performed for (i) neutropenia and (ii) ALT/AST.  
Median time to first occurrence and 95% CI will be provided based on the Kaplan-Meier 
method. In addition, Kaplan-Meier plots will be generated.
Time to first occurrence of grade X or worse laboratory toxicity is defined as the time from the 
start of treatment to the start date of the first incidence of grade X or worse laboratory toxicity, 


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i.e. time in days is calculated as (start date of first occurrence) – (date of first dose of study 
treatment) +1. A patient will be censored if:

The patient did not report any post-baseline grade X or worse event on or before the 
analysis cut-off date.

The patient discontinued treatment without reporting any grade X or worse event up to 30 
days after study treatment discontinuation.

The patient died without reporting any grade X or worse event.

The patient received a new anticancer therapy before reporting any grade X or worse 
event. 
The censoring date will be the earliest of the following dates: end of treatment + 30 days, 
analysis cut-off, new anti-cancer therapy start date, death date and last non-missing 
assessment for the lab parameter. Note that patients who have grade X or worse toxicity at 
baseline or missing baseline evaluation will be excluded from this analysis. 
In addition, the median time to first occurrence for the subset of patients who experienced the 
event of interest will be calculated. Simple descriptive statistics, median, min and max as well 
as 25th percentile and 75th percentile, will be presented.
Duration of grade X or worse laboratory toxicity may also be summarized. Duration of grade 
X or worse event is calculated as:
(Date when the grade of the event decreases to below X) – (date of onset of grade X or 
worse event) + 1
For patients experiencing any grade X or worse event, the duration of the first such event will 
be summarized using the Kaplan-Meier method. Median duration and 95% CI will be presented. 
In addition, Kaplan-Meier plots will be generated. 
A patient will be censored for the duration of grade X or worse event, if:

The patient dies without reporting a decrease to below grade X

The patient receives a new anticancer therapy before reporting a decrease to below grade 
X

The patient discontinues from the study treatment without reporting a decrease to below 
grade X up to 30 days after study treatment discontinuation

The patient is still ongoing at the analysis cut-off date without reporting a decrease to 
below grade X
The censoring date is the earliest of the following dates: end of treatment + 30 days, analysis 
cut-off, new anti-cancer therapy start date, death date and last non-missing assessment for the 
lab parameter.
2.10.3
ECG and cardiac imaging data
All analyses of ECG data will be based on the average of all available replicate ECGs assessed 
at each time point for each patient. For unscheduled assessments, 15-minute windows will be 
applied to group assessments for averaging.
The last available ECG assessment before the start of study treatment will be used as the 
‘baseline’ assessment. Assessments specified to be collected post-dose on the first date of 
treatment are not considered baseline values.


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Change from baseline of QTcF at time points including Cycle 1 Day 15 as specified in Section 
2.8 will also be summarized. Notable elevations of QTcF will be summarized based on all on-
treatment ECG assessments. The totality of the safety data obtained in Arms 1 and 2, generated 
from each time point as outlined in the ECG monitoring and assessment schedule including PR, 
QRS, QT, and RR intervals, will be compared as part of the overall assessment for QT 
prolongation risk mitigation.
Notable elevations of ECG summarize the number of patients meeting or exceeding predefined 
limits in terms of absolute QT/QTc interval data/PR/RR/QRS or changes from baseline as 
defined in Table 2-10, and notable elevations of ECG summary includes only newly occurring
ECG abnormality. A newly occurring ECG abnormality is defined as an abnormal post-baseline 
ECG finding that is not present at baseline. The percentage of patients having notable ECG 
interval values is based on the number of patients at risk for the change with a value at baseline 
and post-baseline.
Table 2-10
Clinically notable ECG values
ECG parameter (unit) 
Clinically notable criteria 
QT, QTcF, QTcB (ms) 
New > 450 
New > 480 
New > 500 
Increase from Baseline > 30 
Increase from Baseline > 60 
PR duration (ms)
Increase > 25% from baseline and to PR duration > 200 
New > 200
QRS duration (ms)
Increase > 25% from baseline and to QRS duration > 110
New > 110 
Heart Rate (bpm) 
< 50 and decrease from Baseline of > 25% 
> 100 and increase from Baseline of > 25% 
Time to grade 2 or worse QT prolongation will be analyzed using the Kaplan-Meier method 
and the median time to grade 2 or worse QT prolongation will be presented along with a 95% 
confidence interval if there are sufficient numbers of events for each treatment group.
In addition, the median time to event for the subset of patients who experienced grade 2 or 
worse QT prolongation will be calculated. Simple descriptive statistics, median, min and max 
as well as 25th percentile and 75th percentile, will be presented.
Note that patients who have grade 2 or worse toxicity at baseline or missing baseline evaluation 
will be excluded from these analyses.
Further analysis includes shift table summarizing the baseline to worst on-treatment result of 
QT/QTc, and table with descriptive statistics at baseline, post-baseline time points and change 
from baseline to post-baseline time points.
All ECG data will also be listed by treatment group, patient and visit/time; abnormalities will 
be flagged.


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2.10.4
Vital signs
Vital signs assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height, weight, body temperature, pulse rate, and 
systolic and diastolic blood pressure.
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline

Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline.

Body temperature:  ≥ 39.1°C

Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm
Clinically notable below normal values

Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline

Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline

Body temperature: ≤ 35°C

Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm
The following summaries will be produced for each vital sign parameter:

Summary statistic for change from baseline to the worst post-baseline value (in both 
directions, i.e. from baseline to highest post baseline and from baseline to lowest post 
baseline value).

Number and percentage of patients with at least one post-baseline vital sign 
abnormality (in both directions, i.e. both elevated and below normal values).
In addition, the following two listings will be produced by treatment arm:

Patients with clinically notable vital sign abnormalities.

All vital sign assessments will be listed by patient and vital sign parameter.
In both listings, the clinically notable values will be flagged and also assessments collected later 
than 30 days after the last treatment date will be flagged.
2.10.5
Other safety data
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate.
All assessments collected later than 30 days after the last treatment date will be flagged in the 
listings.
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration.
Subgroup analyses will be explored as described in Section 2.2.5.


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2.11
Pharmacokinetic endpoints
2.11.1
General principle
All PK analyses will be based on the PAS, unless otherwise specified. Evaluability criteria 
described below for concentrations and parameters is based on the dose of the respective drug 
for which the PK corresponds to.
Evaluable concentrations are defined as those for which all of the following apply:

samples taken within the following time windows around the scheduled time points:

Pre-dose: prior to dosing on the assessment day and collected at 24 ± 2 hours after the 
last dose

2 h post-dose: within ± 15 minutes of the scheduled time point

4 or 6 h post-dose: within ± 30 minutes of the scheduled time point

24 h post-dose: within ± 2 hours of the scheduled time point

no vomiting occurs within the first 4 hours of the last dose (pre-dose samples)

no vomiting occurs within the first 4 hours of the current dose (post-dose samples)

the concentration has not been flagged for exclusion by the pharmacokineticist

for ribociclib concentrations, assessments with at least 10 consecutive days of ribociclib 
dosing (10 doses at 600 mg or 10 doses at 400 mg or 10 doses at 200 mg) immediately 
prior to the PK collection
A PK parameter will be considered as NOT evaluable if any of the following conditions are 
satisfied: 

vomiting occurs within 4 hours of the current or last dose 

for ribociclib, the patient did not receive at least 10 consecutive days of ribociclib dosing 
(10 doses at 600 mg or 10 doses at 400 mg or 10 doses at 200 mg) prior to and on the PK 
collection day 

the parameter is flagged for exclusion by the pharmacokineticist
For ribociclib concentrations, as well as for ribociclib PK parameters, patients will be classified 
into the following dose groups at C1D15 and timepoint:

RIBO600: consists of all patients who provided evaluable concentrations/parameters after 
receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the 
PK collection (for concentrations) or prior to and on the PK collection day (for parameters) 
without a dose change or interruption.

RIBO400 consists of all patients who provided evaluable concentrations/parameters after 
receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the 
PK collection (for concentrations) or prior to and on the PK collection day (for parameters) 
without a dose change or interruption.

RIBO200 consists of all patients who provided evaluable concentrations/parameters after 
receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the 
PK collection (for concentrations) or prior to and on the PK collection day (for parameters) 
without a dose change or interruption (if any).


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At least ten consecutive doses are expected to provide adequate time to reach steady state for 
ribociclib at 600 mg, 400 mg or 200 mg.
Only evaluable PK concentrations/parameters which are not flagged for exclusion will be used 
for figures, summaries, and statistical analysis. Concentration and parameter listings will 
include all values, with flags indicating those excluded from analyses. 
Ribociclib concentration and parameter summaries, figures, and listings will be presented by 
treatment arm.
PK data collected from this study may be combined with data from other studies to support a 
population PK analysis of ribociclib using non-linear mixed effect modeling; details will be 
provided in a separate analysis plan.
PAS will be used in all pharmacokinetic data analysis and PK summary statistics.
2.11.2
PK concentrations
Ribociclib plasma concentration data will be listed by treatment, patient, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point.
Descriptive statistics of concentrations will include n, m (number of non-zero concentrations), 
mean, CV%, SD, median, geometric mean, geometric CV%, minimum and maximum. 
Coefficient of variation CV (%) is calculated as follows: 100*(SD/arithmetic mean).
Geometric CV (%) is calculated as follows from non-zero values: 


1
ˆ
exp
100
%
CV
2 



                                      
where 
2ˆ
denotes the variance of the log-transformed values.
Geometric mean and arithmetic mean (SD) concentration-time profiles on C1D15, as well as 
individual concentration-time profiles with median on C1D15 of ribociclib by treatment arm 
will be graphically presented. 
2.11.3
PK parameters
In approximately 20 patients per arm, extensive PK sampling for ribociclib will be performed 
as detailed in Section 8.5.1 of study protocol. For these patients, PK parameters (if available) 
of ribociclib, including but not limited to those listed in Table 2-11, will be calculated from the 
individual concentration-time profile. 
Pharmacokinetic parameters will be listed by treatment and patient. Descriptive summary 
statistics will include n, mean (arithmetic and geometric), SD, and CV (arithmetic and 
geometric), median, minimum, and maximum. An exception to this is Tmax where n, median, 
minimum, and maximum will be presented.
Table 2-11
Noncompartmental pharmacokinetic parameters
AUC0-24
The AUC from time zero to 24 hours (ng*h/mL)
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(ng*h/mL)
AUCinf
The AUC from time zero to infinity (ng*h/mL)


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Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (h)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (h).
CL/F
The total body clearance of drug from the plasma (L/h)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) (L)
2.11.1
Handling missing and invalid values
Plasma samples will be assayed for LEE011 concentrations by Novartis or Novartis designated 
laboratory using validated LC-MS/MS methods with a LLOQ of approximately 1.00 ng/mL for 
ribociclib. 
All concentrations below the LLOQ will be displayed in listings as zero with a flag and handled 
as zero in any calculations of summary statistics, but handled as missing for the calculation of 
the geometric means and their CV.
Any missing PK parameter data will not to be imputed.
2.12
PD and PK/PD analyses
Not applicable.
2.13
Patient-reported outcomes
Not applicable.
2.14
Biomarkers
Not applicable.
2.15
Other Exploratory analyses
Not applicable.
2.16
Interim analysis
No formal interim analysis is planned for this study. The primary analysis will be performed 
after all patients have been treated for at least 6 months or have discontinued study treatment. 
A final analysis will be performed after efficacy follow up is complete.
In order to minimize the potential impact of treatment knowledge, until the primary analysis is 
conducted, no aggregate statistical analyses shall be performed by treatment.


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3
Sample size calculation
3.1.1
Primary endpoint(s)
A total sample size of approximately 350 patients is planned for this study, randomly allocated 
in a 1:1 ratio between Arm 1 (175 patients) and Arm 2 (175 patients). Assuming an enrollment 
rate of 20 patients per month, the primary analysis cut-off would be expected to be 
approximately 24 months from the randomization of first patient. The sample size calculations 
are proposed such as to meet the non-inferiority margin of 0.814 with 80% power and one-sided 
5% level of significance under the assumptions of an ORR of 48.3% in Arm 1 (experimental 
arm) and 43.9% in Arm 2 (control arm) and that 10% patients will not be evaluable for 
ORR. The details of operating characteristics are described below (EAST 6.3).
Table 3-1
Primary endpoint: Overall Response rate (ORR)
Ratio of
ORR from Arm 1/Arm 2*
The ORR in Arm 1 based on the 
ORR ratio
Probability of lower 90% CI 
limit of the ratio of ORR Arm 
1/ Arm 2> 0.814 *
1.1
48.3%
80.0%
1.05
46.1%
66.5%
1
43.9%
50.1%
0.95
41.7%
32.5%
0.9
39.5%
18.5%
0.814
35.7%
5.1%
* ORR in the control arm (Arm 2) is set to be 43.9% based on the pooled historical data from 
CLEE011A2301 and CLEE011E2301 (NSAI only).
For the calculation of non-inferiority margin, the ORRs of ribociclib in combination with NSAI 
vs NSAI alone were estimated by combining the historical 6-month overall response rate 
observed in patients with the measurable disease from the following two studies:

Study CLEE011A2301, where ribociclib was investigated at a starting dose of 600 mg QD 
3 week-on/1 week-off in combination with letrozole in postmenopausal women; and

Study CLEE011E2301 (NSAI only) where ribociclib was investigated at a starting dose of 
600 mg QD 3 week-on/1 week-off in combination with NSAI and goserelin in 
premenopausal women.
In both studies, the patient population is similar to the one proposed for this study, as all patients 
have HR-positive, HER2-negative advanced breast cancer with no prior hormonal treatment for 
advanced disease; and the ORRs are also very similar in CLEE011A2301 and CLEE011E2301 
despite the difference in the menopausal status of the study populations. The ORR up to 6-
months was estimated to be 43.9% in ribociclib in combination with NSAI and 29.1% in NSAI 
alone by pooling patients with measurable disease from studies CLEE011A2301 and 
CLEE011E2301. As such, the NI margin is calculated based on 50% retention on the log-scale 
of the ratio of 43.9% to 29.1%, which leads to the NI margin of 0.814 (FDA 2016).
3.1.2
Secondary endpoint(s)
The key secondary endpoint of the study is to evaluate if the upper 90% confidence interval for 
the QTcF change from baseline at Cycle 1 Day 15 (2h post-dose) is less than 20 ms for the 


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experimental dosing arm (Arm 1). Assuming that the ∆QTcF standard deviation is 20 ms, the 
probability of meeting this threshold under different scenarios of ∆QTcF at the Cmax is 
presented in Table 3-2.
Table 3-2
Operating characteristics for the key secondary endpoint: ∆QTcF at 
Cycle 1 Day 15 (2 h post-dose). Probability of the upper 90% CI < 20 
ms under different value to True QTcF with a sample size of 175 
patients in Arm 1
True mean ( QTcF, ms)
Probability of upper 90% CI limit < 20 ms
15.5
90.6%
16
84.1%
17.5
50.0%
18
37.2%
18.8
19.9%
19.9
5.6%
3.1.3
Sample size considerations for PK analysis
Blood samples will be collected from all study patients for the analysis of plasma concentrations 
of ribociclib and assessment of ribociclib pharmacokinetics. In a subset of patients (~20 patients 
per arm), extensive PK blood sampling will be performed to provide approximate 12 evaluable
patients with full PK profiles per arm, and the PK collection schedule is specified in protocol 
Section 8.5.1.1.1. This sample is anticipated to represent the PK in the targeted treatment group. 
No hypothesis will be tested and therefore no specific sample size calculation has been 
performed. The choice of sample size and sampling time points were selected based on 
historical data and PK profile of ribociclib.
4
Change to protocol specified analyses
The protocol deviation, “Patient had dose reduction of ribociclib within cycle 1” is not 
considered as a protocol deviation in the analysis. Instead, it is just considered as a condition 
to exclude the patient from per protocol set in the analysis.
This protocol deviation was defined before the primary analysis to acturately capture the 
number of patients who had dose reduction within cyle 1. However, after further review, it is 
not a protocol deviaition from clinical perspective. So, it is excluded from protocol deviation 
summary tables and listings. 
5
Details of statistical analysis
5.1
Baseline comparability
Appropriate descriptive summary statistics of baseline variables (see Section 2.5) will be 
provided as in-text tables in the core CSR and also in Section 14 in the post-text tables. The 
summaries will be grouped by treatment arms, but no p-values will be provided. 


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5.2
Mantel-Haenszel estimator for the ratio of ORR
Suppose patients in experimental arm ( = 1) and control arm ( = 0) are randomized with 
strata liver/lung metastasis ( = 1,2), and let  and  denote the number of responsers (i.e. 
CR, PR) and the number of patients in arm  and stratum , respectively. Further, let  and 
denote the number of responsers (i.e. CR, PR) and the number of patients in stratum  in both 
arms, respectively.
Confidence intervals for the ratio of ORR in the experimental arm to the control arm referred 
as common relative risk is calculated using the Mentel-Haenszel estimate of the common 
relative risk over strata (Mantel and Haenszel 1959, Agresti 2002):
 =
Σ
/
Σ
/
The confidence limits for the common relative risk is then calculated using normal 
approximation after log transformation for . Therefore, the 100(1 −)% confidence 
interval for log() is given by 
log() ± / 
where / is 1 − percentile of standard normal distribution and  is given by Greenland 
and Robins (1985):
  = !"#
$ %log%&& =
Σ
( −)/

(Σ
/)(Σ
/)
The lower bound of the aforementioned confidence limit is  exp%−/ & = exp(log%& −
/ ) after exponentiation with  = 10, which then will be compared with the pre-specified 
non-inferiority margin 0.814 as the primary analysis.
The Mantel and Haenszel approach for the calculation of confidence interval of relative risk is 
implemented in PROC FREQ with CMH option in the TABLE statement. Specifically, the 
TABLE statement is in the following order TABLE STRATA*TREATMENT*RESPONDER 
with option CMH1, and this will provide the point estimate as well as the confidence interval 
for.
5.3
Time-to-event analyses
The following sections present a general methodology to be used to analyze time-to-event 
variables, e.g.:

Progression-free survival

Time to response: defined as the time between date of randomization until first 
documented response (CR or PR) according to RECIST 1.1               

Duration of response

Time to first occurrence of grade X or worse laboratory toxicity

Time to grade 2 or worse QT prolongation                                                                                               


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5.3.1
Analysis of time-to-event data with ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model. 
5.3.2
Kaplan-Meier estimates
The survival function in each treatment arm will be estimated using the Kaplan-Meier (product-
limit) method as implemented in PROC LIFETEST with METHOD=KM option. The PROC 
LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence intervals 
calculated from PROC LIFETEST output using the method of [Brookmeyer and Crowley 1982]. 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific time 
points will be summarized. Median survival for each treatment arm will be obtained along with 
95% confidence intervals calculated from PROC LIFETEST output using the method of 
[Brookmeyer and Crowley 1982].  Kaplan-Meier estimates with 95% confidence intervals at 
specific time points will be summarized. The standard error of the Kaplan-Meier estimate will 
be calculated using Greenwood’s formula [Collett 1994].
5.3.3
The event/censor date for PFS analysis
The analysis of PFS will be based on the local radiological assessments (Source 1 in Table 2-6)
as well as BIRC (Source 3 in Table 2-6). The analysis will be performed on the FAS and will 
use the default censoring and event date options from Table 16-8 of study protocol section 16.2
i.e. event/censoring rules will be based on options A(1), B(1), C1(1), C2(1), D(1), E(1), and 
F(2) (summarized in Table 5-1). In particular, PFS will be censored at the last adequate tumor 
assessment if a patient didn’t have an event or the event occurred after two or more missing 
tumor assessments (see Section 2.4.4). PFS will also be censored at the last adequate tumor 
assessment prior to the start of a new antineoplastic therapy; i.e. option F(2) in Table 16-8 of 
protocol section 16.2 will be used. 
Table 5-1
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 
assessments 
Censored
No progression (or death)
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
Treatment discontinuation due to 
‘Disease progression’ without 
Ignore clinical progression and 
follow situations above
As per above situations


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documented progression, i.e. 
clinical progression based on 
investigator claim
* The rare exception to this is if the patient dies no more than D2 days (see Section 2.4.4 for 
definition) after randomization, in which case this is a PFS event at the date of death
5.4
Duration of follow-up
Study follow-up will be summarized using the following methods: 

Summary of duration between randomization and cut-off date, and follow-up times for PFS, 
which are defined as follows:

Randomization (recruitment) period = (Date of last patient randomized - Date of first 
patient randomized + 1) / 30.4375 (months)

Duration between randomization and data cut-off date = (Cut-off date – Date of 
randomization + 1) / 30.4375 (months). This item will be summarized overall.

Follow-up time = (Date of event or censoring – Date of randomization + 1) / 30.4375 
(months) regardless of censoring. Date of censoring is defined as the last adequate 
tumor assessment date for PFS. This item will be summarized by treatment arm.
All summaries will be reported in months. The calculations for PFS will be based on local 
assessment. Date of censoring is the same as defined in the PFS analysis.
The time from PFS 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.
5.5
Confidence intervals for response rate and clinical benefit rate
Response rate and clinical benefit rate will be summarized as percentages with 95% confidence 
intervals. A standard Wald asymptotic confidence interval, i.e., normal approximation, 
(implemented using SAS procedure FREQ for one-way tables) will be calculated.
5.6
Imputation rules
The partial date imputation rule will be described in the programming datasets specification. 
5.7
AEs coding/grading
5.7.1
Coding of AEs
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
5.7.2
Grading of AEs
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.3.


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The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE v4.0.3 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death.
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will also 
be used in this project; if an AE results in death it will be documented in the outcome (“fatal”). 
Information on deaths will also be collected on the ‘Death’ CRF. 
5.8
Laboratory parameters derivations
Not applicable
6
References
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case of the binomial". Biometrika 26: 404–413
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall 
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doi:10.1093/jnci/22.4.719.


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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
Zhang JJ, Chen H, He K, Tang S, Justice R, Keegan P, Pazdur R and Sridhara R. Evaluation 
of blinded independent central review of tumor progression in oncology clinical trials: a meta-
analysis. Therapeutic innovation & regulatory science: 2012, 47(2): 167-174.
EMA (2020a) Guidance on the management of clinical trials during the COVID-19 
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FDA (2020) Guidance on conduct of clinical trials of medical products during COVID-19 
pandemic guidance for industry, investigators, and institutional review boards.  


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Appendix 1
CTC grades for laboratory values in Novartis 
Oncology


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