A Companion Sample Collection Protocol to Support the Discovery of Breast Cancer Aberrations With Treatment of CDK4/6 Therapy/LEE011/Ribociclib
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Novartis Pharmaceuticals

Clinical Development
Ribociclib (LEE011)
Protocol CLEE011AUS42 / NCT03050398
A companion sample collection protocol to support the 
discovery of breast cancer aberrations with treatment of 
CDK4/6 therapy/LEE011/Ribociclib
Author(s):
 
Document type:
Original Protocol
Version number
00 
Development phase
I/II
Document status:
Final
Release date:
15-Dec-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 02-Dec-2013

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................4
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Synopsis.............................................................................................................................11
1
Background........................................................................................................................13
1.1
Overview of current treatment...............................................................................13
2
Rationale............................................................................................................................13
2.1
Study rationale and purpose...................................................................................13
2.2
Rationale for study design .....................................................................................14
3
Objectives and endpoints...................................................................................................15
4
Study design ......................................................................................................................16
4.1
Description of study design ...................................................................................16
5
Patient population..............................................................................................................17
5.1
Inclusion criteria ....................................................................................................18
5.2
Exclusion criteria...................................................................................................18
6
Treatment...........................................................................................................................18
6.1
Study treatment......................................................................................................18
6.2
Patient numbering..................................................................................................18
6.3
Concomitant medications ......................................................................................18
7
Visit schedule and assessments .........................................................................................18
7.1
Study flow and visit schedule................................................................................18
7.1.1
Screening...............................................................................................19
7.1.2
Patient data to be collected in the central laboratory requisition 
forms .....................................................................................................19
7.1.3
Early study termination, and premature withdrawal.............................20
7.2
Assessment ............................................................................................................20
7.2.1
Assessments in tumor tissue..................................................................20
21
7.2.3
Secondary analyses in tumor tissue.......................................................21
21
21
8
Safety monitoring and reporting........................................................................................22
8.1
Serious adverse events...........................................................................................22

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8.1.1
Serious adverse event definitions..........................................................22
8.1.2
Serious adverse event reporting ............................................................22
9
Data collection and management.......................................................................................23
9.1
Data confidentiality ...............................................................................................23
9.2
Site monitoring ......................................................................................................24
9.3
Data collection.......................................................................................................24
10 Statistical methods and data analysis ................................................................................25
10.1
Analysis sets ..........................................................................................................25
10.2
Patient demographics/other baseline characteristics .............................................25
10.3
Statistical analysis plan..........................................................................................25
10.4
Safety reporting .....................................................................................................25
10.4.1
Serious adverse events (AEs)................................................................25
10.5
Sample size calculation..........................................................................................26
11 Ethical considerations and administrative procedures ......................................................26
11.1
Regulatory and ethical compliance........................................................................26
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................26
11.3
Informed consent procedures.................................................................................26
11.4
Discontinuation of the study..................................................................................27
11.5
Publication of study protocol and results...............................................................27
11.6
Study documentation, record keeping and retention of documents.......................27
11.7
Confidentiality of study documents and patient records .......................................28
11.8
Audits and inspections...........................................................................................28
11.9
Financial disclosures..............................................................................................28
12 Protocol adherence ............................................................................................................28
12.1
Amendments to the protocol..................................................................................28
13 References (available upon request)..................................................................................29

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List of tables
Table 7-1
Visit evaluation schedule ......................................................................18
Table 7-2
Biomarker collection schedule..............................................................22

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List of figures
Figure 4-1
Study design..........................................................................................17

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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BC
Breast Cancer
BCRP
Breast Cancer Resistance Protein
IRC
Independent Review Committee
BSEP
Bile Salt Export Pump
BUN
Blood Urea Nitrogen
CBR
Clinical Benefit Rate
CCND1
Cyclin D1
CDK4/6
Cyclin-Dependent Kinases 4 and 6
Cmax
Peak blood concentration
Cmin
Minimum concentration
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR 
Duration of Response
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EOT
End of Treatment
ER
Estrogen Receptor
FAS
Full Analysis Set
FFPE
Formalin-Fixed, Paraffin-Embedded
FIH
First-in-human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
HDL
High Density Lipoprotein
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HR+
Hormone Receptor Positive
IB
Investigator Brochure

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IC50
Inhibitory Concentration, where 50% inhibition is observed
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
LVEF
Left Ventricular Ejection Fraction
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MBC
Metastatic Breast Cancer
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition
NCRNPD
Non-Complete Response Non-Progressive Disease
NSAI
Nonsteroidal Aromatase Inhibitors
NSCLC
Non-Small Cell Lung Cancer
ORR 
Overall Response Rate
OS
Overall survival
PAS
Pharmacokinetic Analysis Set
Pd
Pharmacodynamics
PD
Progressive Disease
PFS
Progression free survival
P-gP
Permeability-glycoprotein
PgR
Progesterone receptor
PHI
Protected Health Information
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Partial Response
pRb
Retinoblastoma Protein
PS
Performance Status
PT
Prothrombin time
QD
Quaque Die (every day)
RAP
Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RDE
Recommended dose of expansion
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
R Value
ALT/ALP in x ULN
SAE
Serious Adverse Event

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SC
Steering Committee
SD
Stable Disease
SEC
Safety Event Categories
SERM
Selective ER Modulators
S-ICF
Study ICF
SMT
Novartis Safety Management Team
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic
concentration-time curve (time).
TBIL
Total Bilirubin
ULN
Upper Limit of Normal

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of the 
investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. treatment 
group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as number 
of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated placebo and 
active treatment controls (when applicable). This also includes approved drugs used outside 
of their indication/approved dosage, or that are tested in a fixed combination. Investigational 
treatment generally does not include other study treatments administered as concomitant 
background therapy required or allowed by the protocol when used in within approved 
indication/dosage
Medication 
number
A unique identifier on the label of each study treatment package which is linked to one of the 
treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study procedures that was not 
included in the investigational treatment
Subject Number
A unique identifying number assigned to each patient/subject/healthy volunteer who enrolls 
in the study
Randomization 
number
A unique treatment identification code assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Stage related to 
study timeline
A major subdivision of the study timeline; begins and ends with major study milestones such 
as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the original 
site to other parts of the body
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study treatment 
was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment component relationship 
relative to a study treatment combination; study treatment in this case refers to the 
investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when a patient permanently discontinues study treatment for any reason
Supportive 
treatment
Refers to any treatment required by the exposure to a study treatment, e.g. premedication of 
vitamin supplementation and corticosteroid for pemetrexed disodium.

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

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Synopsis
Title
A companion sample collection protocol to support the discovery of 
breast cancer aberrations with treatment of/LEE011/Ribociclib
Sponsor and Clinical 
Novartis – Region US
Phase
I/II
Investigation/Study Type
Interventional
Purpose and Rationale
The purpose of this US only companion sample collection protocol of 
the Global Phase IIIb trial (CLEE011A2404) is to (1).  investigate the 
aberrations of common pathways for HR+ breast cancer at baseline in 
all consented patients enrolled in this companion sample collection 
protocol (2). evaluate genetic mutations in tumor following the 
progression on ribociclib (3). assess various mutations in diverse 
patient populations at diagnosis (4). 
 
 
 
 
Primary Objective(s)
Determine the various modes of resistance to ribociclib following 
progression of disease.
Secondary Objectives
Secondary: 
-
To assess the mutational aberrations across a diverse patient 
population with newly diagnosed HR+ HER2- advanced breast 
cancer.
Study 
Design 
and 
Assessments
This is a multicenter, US specific, non-treatment based companion 
sample collection protocol. This protocol will evaluate the aberrations of 
common pathways for newly diagnosed HR+/HER2- advanced breast 
cancer tumors and responses to ribociclib in diverse patient 
populations. This companion sample collection protocol is available for 
all US patients enrolled on CLEE011A2404 (CompLEEment-1) and will 
not alter the planned treatment.  Tumor collection required for this study 
will occur at two time points: at baseline/screening and upon the 
development of progressive disease as shown in Section 7.2.  
The analyses of samples will be conducted in an on-going fashion as 
tumor tissue from patients becomes available. Sites will be provided 
with the results the genetic mutation profiles of their patients’ tumor 
upon progression.

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The baseline/screening tumor sample (metastatic site preferred) should 
be obtained during the screening process for the CLEE011A2404 study 
prior to starting the investigational drug regimen. However, a window of 
one month into study treatment will be permitted if not possible to 
obtain a fresh tumor tissue sample during the screening period so as to 
not delay study treatment. If fresh tissue is unavailable, archival tissue 
from the primary or metastatic site (metastatic site preferred) will then 
be acceptable (and may be sent in after the start of study treatment to 
allow for logistic planning of obtaining the archival sample). The second 
tumor tissue sample will be obtained at time of progression and prior to 
subsequent therapy.
Population
Patients enrolled in the United States to protocol CLEE011A2404 (a 
study that includes men and postmenopausal women with HR+, HER2-
aBC who had not received any prior hormonal agent for treatment of 
advanced disease).
Key Inclusion criteria
Patients eligible for this companion sample collection protocol sample 
collection protocol must meet all inclusion in CLEE011A2404.
Key Exclusion criteria
Patients eligible for this companion sample collection protocol must not 
meet any of the exclusion criteria in the CLEE011A2404 study, in 
addition to the following:
1. Patients without either fresh or archival tumor tissue accessible.
Investigational and reference 
therapy
Ribociclib 600mg oral daily (3 weeks on/ 1 week off) in combination 
with letrozole 2.5 mg oral once daily
Statistical methods 
Details of the analyses including primary analysis to be will be 
described in a corresponding statistical analysis plan.

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1
Background
1.1
Overview of current treatment
Breast cancer is the most common malignancy in women in the US and the leading cause of 
cancer deaths in women worldwide. Hormone receptor positive breast cancer is the most 
common form of breast cancer. In the overall patient population, it is estimated that 
246,660 women will be diagnosed with breast cancer this year and 39,620 will die from it.  
Breast cancers are heterogeneous and exist in many different subtypes, characteristics, 
responses to treatment, and patient outcomes. Breast cancer ranks second as a cause of
cancer death in women after lung cancer.1 Subtypes of breast cancer are classified by the 
presence of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth 
factor receptor 2 (HER2) antigens as well as by distinct gene expression profiles9,12 and
other features for prognostic and treatment purposes. Seventy percent of invasive breast
cancers in women >45 years of age, express ER and/or PgR, but not HER2, and are termed 
hormone receptor positive HER2 negative (HR+/HER2-).4
2
Rationale
2.1
Study rationale and purpose
Despite the advances in treatment, resistance to single agent endocrine therapy is a well-
established barrier, leading to many patients progressing within approximately 1-year of first-
line treatment.3,7,8 Patient treatment is currently guided by hormone receptor status and HER2 
expression, but accumulating evidence suggests that genetic mutations also influence drug 
responses and patient survival.10 Thus, identifying the unique gene mutation pattern in each 
breast cancer subtype will further improve personalized treatment and outcomes for breast 
cancer patients. 
Currently there is no clinical data available reporting reasons for tumor progression following 
treatment with a CDK 4/6 inhibitor, which represents an unmet need and requires further 
exploration. There are multiple potential reasons why a patient would progress on CDK 4/6 
inhibitor + endocrine combinations. These may include loss or mutation of retinoblastoma 
protein (Rb) (the direct target of CDK 4/6 inhibitors), alterations in the estrogen receptor 
pathway as a consequence of endocrine resistance, or activation of other signaling pathways 
including the PI3K/AKT/mTOR pathway. The heterogeneity of the anticipated mechanism of 
resistance requires further exploration through analysis of the tumor following progression of 
a CDK 4/6 inhibitor.6
Despite improvement in diagnosis and treatment, racial disparities are prominent. Survival is 
lower for both African American and Hispanic women at every stage of diagnosis compared 
to Caucasian women.  The 2008–2012 age-adjusted breast cancer incidence rate for Caucasian 
women in the United States was 128.1 per 100,000 women compared to 124.3 for African 
American women, 91.9 for Native American women, 91.9 for Hispanic women, and 88.3 for 
Pacific Islander women, per 100,000 women. For the same time period, the mortality rates 
were 21.9 per 100,000 women for Caucasian women compared to 31 for African American 

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women, 14.5 for Hispanic women, 15 for Native American women, and 11.4 for Pacific 
Islander women, per 100,000 women.1 Thus, while Caucasian women are more likely to be 
diagnosed with breast cancer, African American women are more likely to die from it. For all 
stages combined, the 5-year relative survival rate is 90% for Caucasian women and 79% for 
African American women. Hispanic women are about 20% more likely to die of breast cancer 
than non-Hispanic Caucasian women diagnosed at a similar age and stage.13
While the reason for this disproportionate death due to breast cancer for African American 
and Hispanic women is multi-fold and therefore being studied at many institutions, there is 
still a lack of understanding of genetic mutations and their role. Whole-exome sequencing 
data from the tumors of African American and Caucasian women diagnosed with breast 
cancer between 1988 and 2013 (a group of 105 African American and 664 Caucasian patients) 
from the National Cancer Institute's Cancer Genome Atlas showed that the same five tumor-
specific mutations were most prevalent among both groups. However, more African 
American patients' tumors were driven by the TP53 mutation, while the PIK3CA mutation 
was more common among the tumors of Caucasian patients.5
The purpose of this US only companion sample collection protocol of the Global Phase IIIb 
trial (CLEE011A2404) is to (1).  investigate the aberrations of common pathways for HR+ 
breast cancer at baseline in all consented patients enrolled (2). evaluate genetic mutations in 
tumor following the progression on ribociclib (3). assess various mutations in diverse patient 
populations at diagnosis (4). 
 
 
 
2.2
Rationale for study design
Tumor tissue samples will be collected in this trial at baseline to identify biomarkers that may 
be predictive of benefit from the combination of ribociclib and letrozole, understand the 
mutations present in newly diagnosed advanced breast cancer patients and to understand the 
heterogeneity of mutations across diverse patient populations. Tumor samples will also be 
collected at time of progression (End of Treatment). This will be done using both Nanostring 
and multiplexed approaches (Next Gen Sequencing) of but not limited to CCND1, CDKN2A, 
PIK3CA and PTEN as well as protein expression profiling of PDL-1 and CD8 using AQUA 
(Automated Quantitative Analysis), a fluorescent IHC. The biopsy collected at 
progression/end of treatment will be dedicated to understanding resistance to treatment of 
ribociclib in combination with letrozole as well as immune profiling of this patient population. 
This study also provides a unique opportunity to investigate the various mutations in a 
heterogeneous patient population with HR+/HER2- advanced breast cancer at initial diagnosis 
and following progression to CDK4/6 inhibition.

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Tumor samples will be requested at baseline and following progression. Tumor tissue samples 
will be obtained only from patients who consent to participating in this this sample tumor 
collection and will be sent to a third party central laboratory for analysis.  All sites that 
participate in this study will receive the results of the genetic mutation of their patients’ tumor 
tissue profile upon progression.
3
Objectives and endpoints
This is a non-interventional study to allow for the collection of tumor and normal tissue 
samples 
 to better understand relevant mutations and the 
mechanisms responsible for resistance to treatment.
Objective
Endpoint
Primary
Determine the various modes 
of resistance to ribociclib 
following 
progression 
of 
disease
Mutations of genes that are 
relevant to HR+ and the 
CDK4/6 pathway such as but 
not 
limited 
to 
CCND1, 
CDKN2A, 
PIK3CA 
and 
PTEN 
to 
identify 
the 
potential 
mechanisms 
of
progression.
Secondary
To assess the mutational 
aberrations across a diverse 
patient population with newly 
diagnosed HR+ HER2-
advanced breast cancer
Differences in mutations will 
be assessed based on baseline 
samples and compared across 
diverse races/ethnicities with 
HR+ HER2- advanced breast 
cancer
-
specifically 
Caucasian, African America, 
Hispanic, Native American 
and Pacific Islander.

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4
Study design
4.1
Description of study design
This is a multicenter, US specific, non-treatment based companion sample collection protocol. 
This protocol will evaluate the aberrations of common pathways for newly diagnosed 
HR+/HER2- advanced breast cancer tumors and responses to ribociclib in diverse patient 
populations. This companion sample collection protocol is available for all US patients 
enrolled on CLEE011A2404 (CompLEEment-1) and will not alter the planned treatment.  
Tumor collection required for this study will occur at two time points: at baseline/screening 
and upon the development of progressive disease as shown in Section 7.2. For each tumor 
tissue sample, three analyses will be conducted (1), using Next Generation Sequencing 
(NGS): evaluating known human cancer-related genes to assess for genetic alterations and (2) 
Gene expression analysis using nanostring technology and (3) Protein assessment of PDL-1 
and CD8 to evaluate the immune profile of this patient population pre and post-treatment to 
ribociclib.

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The analyses of samples will be conducted in an on-going fashion as tumor tissue from 
patients becomes available. Sites will be provided with the results of the genetic mutation 
profiles of their patients’ tumor upon progression.
The baseline/screening tumor sample (metastatic site preferred) should be obtained during the 
screening process for the CLEE011A2404 study prior to starting the investigational drug 
regimen. However, a window of one month into study treatment will be permitted if not 
possible to obtain a fresh tumor tissue sample during the screening period so as to not delay 
study treatment. If fresh tissue is unavailable, archival tissue from the primary or metastatic 
site (metastatic site preferred) will then be acceptable (and may be sent in after the start of 
study treatment to allow for logistic planning of obtaining the archival sample). The second 
tumor tissue sample will be obtained at time of progression and prior to subsequent therapy. 
Figure 4-1
Study design
5
Patient population
Men and postmenopausal women with hormone receptor-positive (HR+) HER2-negative 
(HER2-) advanced breast cancer (ABC) with no prior hormonal therapy for advanced disease.
This US-only companion sample collection protocol is intended to be applied to the 
CLEE011A2404 study sponsored by Novartis. The investigator or designee must ensure that 

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only patients who meet the inclusion/exclusion criteria for the CLEE011A2404 protocol can 
participate.
5.1
Inclusion criteria
Written informed consent must be obtained prior to any baseline/screening procedures.
Patients eligible for this companion sample collection protocol sample collection protocol 
must meet all inclusion in CLEE011A2404.
5.2
Exclusion criteria
Patients eligible for this companion sample collection protocol must not meet any of the 
exclusion criteria in the CLEE011A2404 study, in addition to the following:
1. Patients without either fresh or archival tumor tissue accessible.
6
Treatment
6.1
Study treatment
Patients on this companion sample collection protocol will be treated per the guidelines of the 
CLEE011A2404 study on the investigational treatment of ribociclib and letrozole.
6.2
Patient numbering
Upon signing the informed consent form, the patient will be given the same unique 
identification number that corresponds to their patient number on the CLEE011A2404 study.
6.3
Concomitant medications
Concomitant medications and significant non-drug therapies given as treatment for serious 
adverse events considered by the investigator to be possibly related to the biopsy procedures 
will be collected as defined in the treatment protocol of main study CLEE011A2404 and 
documented in the treatment eCRF for CLEE011A2404 (ensuring to document in the eCRF 
details that this is related to US Companion sample collection protocol CLEE011AUS42).
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. No central laboratory requisition form will be used as a source document. 
Table 7-1
Visit evaluation schedule
Visit Name
Protocol 
Section
Screening
Cycle 1
Cycle 6
Cycle 12
End of 
Treatment/Prog
ression of 
Disease

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Visit Name
Protocol 
Section
Screening
Cycle 1
Cycle 6
Cycle 12
End of 
Treatment/Prog
ression of 
Disease
Day of Cycle
-21 to 1
1
1
1
within 15 days 
from the last 
dose1
Obtain Informed 
Consent
7.1.1
X
Tissue collection
7.2.1 
7.2.3 
7.2.4 
X2
X
1 Tissue sample may be obtained after 15 days if not feasible within 15 days from the last dose. Must 
be collected prior to starting subsequent therapy.
2 If not collected during screening, can be collected during the first month of treatment. If fresh tissue 
sample cannot be obtained, archival sample may be sent in during the first month of treatment.
7.1.1
Screening
The IRB approved Informed Consent Form (ICF) for this companion sample collection 
protocol, CLEE011AUS42, must be signed and dated before any procedures are performed 
(procedures that are part of the clinical routine or are described in the CLEE011A2404 
protocol may be performed before signing the ICF). A copy of the ICF must be given to the 
patient or to the person signing the form (if applicable). The Investigator or designee must 
record the date when the study informed consent was signed in the medical records of the 
patient as well as on the relevant central laboratory requisition form.
Investigators must assess each patient for risk factors that affect the collection of biopsies 
according to their usual clinical practice.
7.1.1.1
Screen failures
Patients who sign an ICF but fail to undergo a biopsy (or provide archival tissue) or are 
otherwise found to be ineligible after signing the study ICF will be considered screen failures 
for this protocol. Patients identified as screen failures under the treatment protocol 
CLEE011A2404 will not be enrolled under this protocol.
7.1.2
Patient data to be collected in the central laboratory requisition forms
Data for this companion sample collection protocol will be collected via the central laboratory 
requisition forms completed for each sample. These requisition forms will document that 
informed consent has been obtained for participation in this protocol and for storage of 
biological samples, confirm that the patient met the inclusion/exclusion criteria for 
CLEE011A2404, and collect information about the lesions biopsied at baseline and upon 
progression 
. Any adverse events 
considered by the investigator to be related to the biopsy procedure, should be captured in the 
CLEE011A2404 study EDC database, with a comment that it is related to the US companion 

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sample collection protocol CLEE011AUS42. Additional data collected as part of the 
CLEE011A2404 protocol and needed for the interpretation of the results from the genomic 
analyses, will also be utilized.
7.1.3
Early study termination, and premature withdrawal
7.1.3.1
Early study termination
This study can be terminated at any time for any reason by Novartis. The investigator will be 
responsible for informing IRBs of the termination of this study
7.1.3.2
Premature withdrawal
Patients may voluntarily withdraw from either the CLEE011A2404 and/or this study 
CLEE011AUS42 or be dropped from it at the discretion of the investigator at any time.  The 
reason for discontinuation will be recorded on the applicable corresponding eCRFs in the 
CLEE011A2404 EDC database (if patient is withdrawn from the CLEE011A2404 study) and 
captured on the central laboratory requisition form for US companion sample collection 
protocol CLEE011AUS42.
If a patient withdraws consent, Novartis will continue to retain and use all research results
that have already been collected for the study evaluation. All biological samples that have
already been collected may be retained and analyzed at a later date.
If a patient withdraws from the CLEE011A2404 study, the investigator will still receive the 
output of the data collected from this study up to the time point of the patient’s withdrawal.
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. Study 
treatment must be discontinued and no further assessments conducted.
7.2
Assessment 
7.2.1
Assessments in tumor tissue
The tumor sample collections for this study are summarized in Table 7-2.
All assessments will be performed by a Novartis designated central laboratory. Instructions
for collection, preparation and shipment can be found in the laboratory manual. Required
sample collection information must be entered on the appropriate requisition forms provided 
by the central laboratory.
Tumor samples will be taken pre-treatment (during screening, with an allowed one month 
window from C1D1 if unable to obtain during screening), and following progression. Blocks 
are preferred but if not possible, 20 unstained slides (minimum 15) should be made available 
for biomarker studies. If a tumor sample is not accessible pre-treatment, an archival sample is 
allowed (metastatic site preferred). A pathology report must be submitted along with the
patient’s archival tumor block/slides. Biopsy collection will also be performed at the time of 
disease progression (and prior to the start of subsequent treatment) for identifying potential 
markers of lack of response/resistance.

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Tumor samples will be tested for genetic and proteomic alterations (e.g., gene expression,
mutations, amplifications, deletions and/or protein expression/activation etc.) that are 
involved in the D-cyclin-CDK4/6-INK4a-Rb and mTOR pathways, such as mutations of 
CCND1, PIK3CA, PTEN and CDK4, gene amplification of CCND1 and CDK4, deletion of 
CDKN2A, as well as potential resistant/escape pathways to CDK 4/ 6 inhibitors. Other cancer 
associated genes will also be investigated in the tumor tissue from all patients, with the 
intention of understanding potential mechanisms of resistance to prior CDK 4/6 inhibitors.
Biomarker analyses will be correlated with clinical outcome to determine potential predictive 
biomarkers of ribociclib/letrozole response and resistance.
When choosing lesions for biopsy after the development of resistance, a sample from the 
same lesion chosen at screening/baseline is preferred if the lesion is growing in size, can be 
identified, and remains accessible to safely biopsy. Detailed instructions for the collection, 
handling, and shipping of biomarker samples are outlined in the Laboratory Manual.
7.2.3
Secondary analyses in tumor tissue
When remaining samples are available in sufficient quantity and quality, samples may be used 
to assess the mutational aberrations across a diverse patient population with newly diagnosed 
HR+ HER2- advanced breast cancer. This will be assessed based on baseline tumor tissue 
samples and compared across diverse races/ethnicities with HR+ HER2- advanced breast 
cancer.

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Table 7-2
Biomarker collection schedule
Sample Type
Volume
Visit
Sample Collection
Baseline tumor biopsy 
(Fresh tissue from 
metastatic site 
preferred. If fresh tumor 
is not accessible, 
archival tissue will be 
accepted)
Blocks are preferred 
but if not possible, 20 
unstained slides 
(minimum 15) should
be made available.
Screening
Prior to treatment (or 
within the first month of 
study). If archival, can 
be sent in when 
obtained from sample 
storage.
Newly obtained post-
progression tumor 
samples)
Blocks are preferred 
but if not possible, 20 
unstained slides 
(minimum 15) should 
be made available.
Post- progression
Upon progression (prior 
to subsequent 
treatment) 
8
Safety monitoring and reporting
8.1
Serious adverse events
For this companion sample collection protocol sample collection protocol, only serious 
adverse events considered related to the biomarker collection procedure will be extracted from 
the AE eCRF of the CLEE011A2404 protocol. All SAEs experienced should be reported in 
the CLEE011A2404 study EDC system, with a comment that the SAE was related to this US 
Companion sample collection protocol, protocol CLEE011AUS42.
8.1.1
Serious adverse event definitions
Serious adverse events (SAEs) are defined in the CLEE011A2404 protocol.  Those serious 
adverse events considered by the investigator to be possibly related to a biomarker collection 
procedure performed as part of this protocol will be indicated as such in the AE eCRF in the 
CLEE011A2404 EDC system.
8.1.2
Serious adverse event reporting
SAEs will be collected and reported as described in the CLEE011A2404 protocol.  If the 
event is suspected to be causally related to a biomarker collection procedure, as assessed by 
the investigator, it will be identified as such. SAEs will be followed until resolution or until 
clinically relevant improvement or stabilization. SAE collection ends 14 days after the last 
biomarker collection procedure.

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Any SAEs experienced after this 14 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to a biomarker collection procedure performed as 
part of this companion sample collection protocol. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to the 
biomarker collection procedures, complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and 
Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to which the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation.
If the SAE is thought to be related to a biomarker collection procedure performed as part of 
the CLEE011AUS42 protocol, an oncology Novartis Drug Safety and Epidemiology (DS&E) 
department associate may urgently require further information from the investigator for 
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to 
inform all investigators involved in the CLEE011AUS42 study that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.

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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect follow-up safety information (e.g.
has the subject experienced any new or worsened AEs) at the end of their scheduled study
period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. Data from this study will be combined with data from 
other studies, including but not limited to the treatment study CLEE011A2404 on which the 
patient received the investigational agent(s).
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and central laboratory requisition 
forms with the investigators and their staff. During the study, the field monitor will visit the
site regularly to check the completeness of patient records, the accuracy of entries on the
requisition forms, the adherence to the protocol to Good Clinical Practice and the progress of 
enrollment. Key study personnel must be available to assist the field monitor during these 
visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
recorded on the requisition forms must be traceable to source documents in the patient's file.
The investigator must also keep the original signed informed consent form (a signed copy 
is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the completed central laboratory requisition forms. Novartis monitoring 
standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria and documentation of SAEs. Additional checks of the consistency 
of the source data with the requisition forms are performed according to the study-specific 
monitoring plan.
9.3
Data collection
Biomarker (blood and tissue) samples drawn during the course of this companion sample 
collection protocol will be collected from the Investigator sites and analyzed by a Novartis 
assigned laboratory or contracted central lab. The results will be sent electronically to 
Novartis. Designated investigational site staff will complete the information required by the 
protocol into the appropriate central laboratory requisition forms (printed on 2 or 3-part non-
carbon-required paper). Field monitors will review the central laboratory requisition forms for 
accuracy and completeness and instruct site personnel to make any required corrections or 
additions. One copy of the requisition form will be forwarded to each analytical laboratory 

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with the respective samples by the designated investigational site staff, and one copy will be 
retained at the investigational site.
The Principal Investigator is responsible for assuring that the data entered on the central 
laboratory requisition forms is complete, accurate, and that entry and updates are performed in 
a timely manner. 
10
Statistical methods and data analysis
This companion sample collection protocol seeks to explore the mechanisms of resistance to 
cancer treatment through the analysis of data from tumor samples at baseline and after 
development of disease progression,
 
 Analyses are 
considered exploratory in nature and the detailed data analysis plan(s) will be described in 
stand-alone documents or, where appropriate, in the individual Statistical Analysis Plan (SAP) 
from corresponding parent treatment studies for inclusion in the respective CSRs.
Broadly, data analyses will seek to (1). analyze mutations present at the initial diagnosis of 
HR+/HER2- advanced breast cancer across diverse ethnicities (2). characterize the mutations 
identified at progression of disease following the treatment of ribociclib + letrozole and (3). 
characterize the immune response to ribociclib + letrozole. Descriptive statistics and 
exploratory modeling will be used. Details will be described in the data analysis plans.
10.1
Analysis sets
The biomarker analysis set (BAS) includes all US subjects with evaluable biomarker 
assessment from the Full Analysis set of CLEE011A2404 study.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics and prior treatment will 
be listed and summarized descriptively for the BAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical at baseline will be summarized by system 
organ class and preferred term.
10.3
Statistical analysis plan
Details of the analyses including primary analysis to be performed will be described in a 
corresponding statistical analysis plan.
10.4
Safety reporting
10.4.1
Serious adverse events (AEs)
Summary tables for serious adverse events (AEs) have to include only AEs that are only 
suspected to be related to the biomarker collection procedures in the opinion of the 
investigator. Biomarker collection-related SAEs will be summarized by system organ class 

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and/or preferred term, severity (based on CTCAE grades) and type of serious adverse event. 
These will be reported in the CLEE011A2404 EDC system with a comment that the SAE is 
related to the companion sample collection protocol CLEE011AUS42 protocol.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
Review of these safety data will be conducted on an on-going basis by members of the study 
team.  The findings will be documented and will be made available upon request.
10.5
Sample size calculation
Not applicable. All US subjects from CLEE011A2404 will be included in this study.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the
study in accordance with these documents and all of the instructions and procedures found in
this protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis
Clinical
Quality Assurance
representatives,
designated
agents
of
Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written, IRB/IEC/REB-
approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e.
all of the procedures described in the protocol). The process of obtaining informed
consent should be documented in the patient source documents. The date when a subject’s
Informed Consent was actually obtained will be captured in the appropriate central laboratory 
requisition forms.
Novartis will provide to investigators, in a separate document, a proposed Informed Consent 
Form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guidelines and regulatory requirements. Any changes to this ICF suggested by the
investigator must be agreed to by Novartis before submission to the IRB/IEC/REB and a

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copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval.
This protocol includes only men and post-menopausal women. However, all participants 
should be informed that taking the study medication may involve unknown risks to a fetus if
pregnancy were to occur during the study and agree that in order to participate in the study 
they must adhere to the contraception requirement for the duration of the study. If there is
any question that the patient will not reliably comply, they should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in the 
clinical study agreement.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for
publication and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored
study,
each
site
will
permit
authorized
representatives
of
the
sponsor(s) and regulatory agencies to examine (and when required by applicable law, to
copy) clinical records
for
the
purposes
of
quality
assurance
reviews,
audits
and
evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy  dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The central laboratory requisition forms are the primary data
collection instrument for this companion sample collection protocol. The investigator should 
ensure the accuracy, completeness, legibility, and timeliness of the data reported in the
requisition forms and all other required reports. Data reported on the requisition forms, which 
are derived from source documents, should be consistent with the source documents or the

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discrepancies should be explained. All data requested on the requisition forms must be
recorded. Any missing data must be explained. Any change or correction to a requisition 
form should be dated, initialed, and explained (if necessary) and should not obscure
the original entry. The investigator should retain records of the changes and corrections to the 
requisition forms.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or
Health Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site, prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted.
If the investigator feels a protocol deviation would improve the conduct of the study this
must be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 

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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 but not later than 10 working days.
13
References (available upon request)
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American Cancer Society, Inc. 2015.
2. Esposito A, Bardelli A, Criscitiello C, et al (2014) Monitoring tumor-derived cell-free 
DNAin patients with solid tumors: clinical perspectives and research opportunities. 
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3. García-Becerra R. Mechanisms of resistance to endocrine therapy in breast cancer: 
Focus on signaling pathways, miRNAs and genetically based resistance. Int. J. Mol. 
Sci. 2013;14:108-145.
4. Huang H, Groth J, Sossey-Alaoui K, Hawthorn L, Beall S, Geradts J. Aberrant 
expression of novel and previously described cell membrane markers in human breast 
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Bardia A (2015) Comparison of the genomic landscape between primary breast cancer 
in African American versus white women and the association of racial differences 
with tumor recurrence. J Clin Oncol 2015(2062):2126.
6. LEE011 Investigators Brochure
7. Murphy CG, et al. Endocrine resistance in hormone-responsive breast cancer: 
mechanisms and therapeutic strategies. Endocr Relat Cancer. 2016;23:R337–R352.
8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines 
v2.2016: Breast Cancer.
9. Perou CM, Sorlie T, Eisen MB, et al (2000) Molecular portraits of human breast 
tumours. Nature; 406 (6797):747-752. 
10. Reinert T, et al. Optimal management of hormone receptor positive metastatic breast 
cancer in 2016. Ther Adv Med Oncol. 2015;7:304–320.
 
12. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 
2009;360:790–800.
13. Williams, F. & Thompson, E. J. Racial and Ethnic Health Disparities (2016) 3: 233. 
doi:10.1007/s40615-015-0132-9.