Clinical trial NCT01783444
Conditions: Breast Cancer
Keywords: Everolimus Exemestane Capecitabine locally advanced metastatic breast cancer breast cancer positive for human epidermal growth factor receptor 2 HER2 HER2 positive breast cancer progression estrogen-receptor positive breast cancer ER
Sponsor: Novartis Pharmaceuticals
Start date: 2013-02-26; Completion date: 2018-07-30
Enrollment: 309 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

Detailed description:
The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent. Patients were randomly assigned with equal allocation to one of the treatment arms:

1. Exemestane (25mg daily) in combination with everolimus (10mg daily)
2. Everolimus (10mg daily)
3. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.

Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.

Randomization and Treatment Phase:

At Visit 3 all eligible patients were randomized in 1:1:1 ratio to receive everolimus (10mg daily oral tablets) in combination with exemestane (25 mg daily oral tablets), everolimus (10mg daily oral tablets) or capecitabine monotherapy (1250mg/m2 twice daily orally for two weeks followed by a one week rest period in 3-weeks cycles). Assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites. After randomization, study treatment started and continued until progression, intolerable toxicity or consent withdrawal. Further treatment after progression and study treatment discontinuation was at the investigator's discretion. Dose adjustment (reduction, interruption) according to safety findings was allowed. Regular safety and efficacy reviews by Data Monitoring Committee (DMC) were performed. Tumor assessments were performed every 6 weeks until disease progression. Additional evaluation were performed to confirm response at 4 weeks after it was first observed. After at least 150 PFS events had been documented per RECIST 1.1 by local assessment in each of the two following groups: (i) everolimus + exemestane arm plus everolimus monotherapy arm, and (ii) everolimus + exemestane arm plus capecitabine monotherapy arm, the frequency of tumor assessments was changed to every 12 weeks or as clinically indicated.

Follow-up phase:

Patients were followed for safety for 30 days after study treatment discontinuation. If a patient did not discontinue study treatment due to disease progression, lost to follow-up or consent withdrawal, then tumor assessments continued to be performed every 6 weeks until disease progression, death, lost to follow-up or investigator decision in patient best interest.

Survival Data Collection:

All patients were followed for survival status at least every 3 months regardless of treatment discontinuation reason and up to two years after randomization of last patient. Survival information could be obtained via phone and information were documented in the source documents and eCRF. Additional survival follow-up might be performed more frequently if a survival update was required for reporting the results or to meet safety or regulatory needs.

Arms: arm 1: Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm). arm 2: Everolimus (10 mg daily) (investigational arm). arm 3: Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).
Interventions: intervention 1: Capecitabine intervention 2: Exemestane intervention 3: Everolimus
Intervention descriptions: intervention 1: Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied) intervention 2: Exemestane, tablets for oral use, 25 mg per day in (locally supplied) intervention 3: Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

Protocol documents:
Prot_001.pdf: 
Oncology Clinical Development
RAD001 (everolimus)
Clinical Trial Protocol CRAD001Y2201 (BOLERO-6) / NCT01783444
A three-arm, randomized, open label, phase II study of 
everolimus in combination with exemestane versus 
everolimus alone versus capecitabine in the treatment of 
postmenopausal women with estrogen receptor positive, 
locally advanced, recurrent, or metastatic breast cancer 
after recurrence or progression on prior letrozole or 
anastrozole
Authors
 
Document type
Amended Protocol Version
EUDRACT number
2012-003757-28
Version number
03 (Clean)
Development phase
II
Document status
Final
Release date
18-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Amendment 3 (18-Apr-2017)............................................................................................12
Amendment 2 ....................................................................................................................14
Amendment 1 ....................................................................................................................17
Protocol summary:....................................................................................................................20
1
Background........................................................................................................................24
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............24
1.1.1
Epidemiology of breast cancer..............................................................24
1.1.2
Treatment options for Hormone Receptor positive Advanced 
Breast Cancer ........................................................................................24
1.1.3
Role of Mammalian Target of Rapamycin in ER+ ABC......................26
1.2
Introduction to control arm and investigational treatments...................................26
1.2.1
Overview of Everolimus .......................................................................27
1.2.2
Overview of Exemestane ......................................................................33
1.2.3
Overview of Capecitabine.....................................................................33
2
Rationale............................................................................................................................35
2.1
Study rationale and purpose...................................................................................35
2.2
Rationale for the study design ...............................................................................36
2.3
Rationale for dose and regimen selection..............................................................36
2.4
Rationale for choice of combination therapy as a control arm..............................36
2.5
Rationale for choice of comparators drugs............................................................37
2.5.1
Rationale for choice of Everolimus.......................................................37
2.5.2
Rationale for choice of Capecitabine ....................................................37
3
Objectives and endpoints...................................................................................................37
4
Study design ......................................................................................................................39
4.1
Description of study design ...................................................................................39
4.1.1
Screening Phase ....................................................................................40
4.1.2
Randomization and treatment phase .....................................................41
4.1.3
Follow-up phase....................................................................................42
4.2
Interim analysis......................................................................................................42
4.3
Timing of final primary analysis ...........................................................................43


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4.4
Definition of end of the study................................................................................43
4.5
Early study termination..........................................................................................43
5
Population..........................................................................................................................43
5.1
Patient population..................................................................................................43
5.2
Inclusion criteria ....................................................................................................43
5.3
Exclusion criteria...................................................................................................45
6
Treatment...........................................................................................................................47
6.1
Study treatment......................................................................................................47
6.1.1
Dosing regimen.....................................................................................47
6.1.2
Study drug supply .................................................................................48
6.1.3
Treatment duration................................................................................49
6.2
Dose modifications................................................................................................49
6.2.1
Dose modifications in the management of adverse reactions ...............49
6.2.2
Follow-up for toxicities.........................................................................54
6.3
Concomitant medications ......................................................................................54
6.3.1
Prohibited concomitant therapy and concomitant therapy requiring 
caution and/or action.............................................................................54
6.3.2
Study drug compliance and accountability ...........................................57
6.3.3
Disposal and destruction .......................................................................58
7
Visit schedule and assessments .........................................................................................58
7.1
Study flow and visit schedule................................................................................58
7.1.1
Screening and baseline..........................................................................63
7.1.2
Treatment period...................................................................................66
7.1.3
End of treatment visit including study completion and premature 
withdrawal.............................................................................................66
7.1.4
Follow-up ..............................................................................................68
7.1.5
Survival follow-up ................................................................................68
7.2
Assessment types...................................................................................................68
7.2.1
Efficacy assessments.............................................................................68
7.2.2
Safety and tolerability assessments.......................................................71
77
7.2.4
Patient reported outcomes.....................................................................78
8
Safety monitoring and reporting........................................................................................78
8.1
Adverse events.......................................................................................................78
8.1.1
Definitions and reporting ......................................................................78
8.1.2
Laboratory test abnormalities................................................................80
8.1.3
Adverse events of special interest.........................................................80


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8.2
Serious adverse events...........................................................................................81
8.2.1
Definitions.............................................................................................81
8.2.2
Reporting...............................................................................................81
8.3
Emergency unblinding of treatment assignment ...................................................82
8.4
Pregnancies............................................................................................................82
8.5
Warnings and precautions......................................................................................82
8.6
Data Monitoring Committee..................................................................................83
8.7
Steering Committee ...............................................................................................83
9
Data collection and management.......................................................................................83
9.1
Data confidentiality ...............................................................................................83
9.2
Site monitoring ......................................................................................................84
9.3
Database management and quality control............................................................85
10 Statistical methods and data analysis ................................................................................85
10.1
Analysis sets ..........................................................................................................86
10.1.1
Full Analysis Set ...................................................................................86
10.1.2
Safety Set ..............................................................................................86
10.1.3
Per-protocol Set.....................................................................................86
10.1.4
Dose-determining analysis set...............................................................86
10.2
Patient demographics/other baseline characteristics .............................................86
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................86
10.3.1
Study treatment .....................................................................................86
10.3.2
Concomitant therapies...........................................................................87
10.4
Primary objective...................................................................................................87
10.4.1
Variable.................................................................................................87
10.4.2
Statistical model and method of analysis..............................................87
10.4.3
Handling of missing values/censoring/discontinuations.......................87
10.4.4
Supportive analyses...............................................................................88
10.5
Secondary objectives .............................................................................................88
10.5.1
Key secondary objective .......................................................................88
10.5.2
Other secondary objectives ...................................................................89
10.5.3
Safety objectives ...................................................................................92
10.6
Interim analysis......................................................................................................94
10.7
Sample size calculation..........................................................................................94
11 Ethical considerations and administrative procedures ......................................................95
11.1
Regulatory and ethical compliance........................................................................95
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................95


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11.3
Informed consent procedures.................................................................................96
11.4
Discontinuation of the study..................................................................................96
11.5
Publication of study protocol and results...............................................................96
11.6
Study documentation, record keeping and retention of documents.......................96
11.7
Confidentiality of study documents and patient records .......................................97
11.8
Audits and inspections...........................................................................................97
11.9
Financial disclosures..............................................................................................97
12 Protocol adherence ............................................................................................................98
12.1
Amendments to the protocol..................................................................................98
13 References (available upon request)..................................................................................99
14 Appendices ......................................................................................................................103
14.1
Appendix 1...........................................................................................................103
14.1.1
Introduction.........................................................................................105
14.1.2
Efficacy assessments...........................................................................105
14.1.3
Definitions...........................................................................................105
14.1.4
Disease measurability..........................................................................105
14.1.5
Eligibility based on measurable disease..............................................106
14.1.6
Methods of tumor measurement - general guidelines.........................106
14.1.7
Baseline documentation of target and non-target lesions ...................108
14.1.8
Follow-up evaluation of target and non-target lesions........................109
14.1.9
Follow-up and recording of lesions.....................................................109
14.1.10
Non-nodal lesions................................................................................109
14.1.11
Nodal lesions.......................................................................................110
14.1.12
Determination of target lesion response..............................................110
14.1.13
Determination of non-target lesion response ......................................112
14.1.14
New lesions .........................................................................................113
14.1.15
Evaluation of overall lesion response .................................................113
14.1.16
Efficacy definitions .............................................................................114
14.1.17
Best overall response...........................................................................114
14.1.18
Time to event variables .......................................................................116
14.1.19
Progression-free survival ....................................................................116
14.1.20
Overall survival...................................................................................116
14.1.21
Time to progression.............................................................................117
117
14.1.23
Duration of response ...........................................................................117
14.1.24
Time to response .................................................................................118


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14.1.25
Definition of start and end dates for time to event variables ..............119
14.1.26
Handling of patients with non-measurable disease only at baseline...120
14.1.27
Sensitivity analyses .............................................................................121
14.1.28
Data handling and programming rules................................................122
14.1.29
Study/project specific decisions..........................................................122
14.1.30
End of treatment phase completion.....................................................123
14.1.31
End of post-treatment follow-up (study phase completion)................123
14.1.32
Medical validation of programmed overall lesion response ...............123
14.1.33
Programming rules..............................................................................124
14.1.34
Calculation of ‘time to event’ variables..............................................124
14.1.35
Incomplete assessment dates...............................................................124
14.1.36
Incomplete dates for last known date patient alive or death ...............124
14.1.37
Non-target lesion response..................................................................125
14.1.38
Study/project specific programming...................................................125
14.1.39
Censoring reason.................................................................................125
14.1.40
References (available upon request) ...................................................126
List of appendices
Appendix 1
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
List of figures
Figure 1-1
Tumor Growth Changes in the HBCx-3 Breast Xenograft Model .......28
Figure 4-1
Study Design .........................................................................................39
List of tables
Table 1-1
BOLERO-2 Study: Most common Adverse Events (equal or 
greater than 10 percent of Patients).......................................................32
Table 3-1
Objectives and related endpoints ..........................................................38
Table 6-1
Dose and treatment schedule.................................................................47
Table 6-2
Packaging and labeling .........................................................................48
Table 6-3
Supply and storage of study drugs ........................................................48
Table 6-4
Recommendation of everolimus dose reductions .................................49
Table 6-5
Everolimus dose adjustment and management recommendation for 
adverse reactions ...................................................................................50
Table 6-6
Dose modification guidelines for hematologic toxicities......................52
Table 6-7
Recommended Dose Modifications of Capecitabine............................53
Table 6-8
Clinically relevant drug interactions: inducers and inhibitors of 
isoenzyme CYP3A................................................................................56


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Table 6-9
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors ...............................57
Table 7-1
Visit evaluation schedule ......................................................................59
Table 7-2
Imaging/RECIST Assessment Collection Plan.....................................70
Table 7-3
ECOG Performance Status Scale..........................................................73
Table 7-4
Action to be taken based on Hepatitis B Screening Results .................74
Table 7-5
Guidelines for management of hepatitis B............................................74
Table 7-6
Guidelines for management of hepatitis C flare ...................................75
Table 7-7
Clinical laboratory parameters collection plan .....................................76
Table 8-1
AEs of special interest...........................................................................81
Table 10-1
Approximate* 90 percent CI bounds for HR ........................................95
Table 14-1
Response criteria for target lesions .....................................................110
Table 14-2
Response criteria for non-target lesions..............................................112
Table 14-3
Overall lesion response at each assessment ........................................113
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................120
Table 14-5
Options for event dates used in PFS, TTP, duration of response........121


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List of abbreviations
Ab
Antibodies
(e)CRF
(electronic) Case Report / Record Form
(eIF) 4E-BP1
eukaryotic translation initiation factor (eIF) 4E-binding proteins 1
(s)VEGF(R)
(soluble) Vascular Endothelial Growth Factor (Receptor)
ABC
Locally Advanced, recurrent or metastatic Breast Cancer: Advanced Breast Cancer
ADR
Adverse Drug Reaction
AE
Adverse Event
AI
Aromatase Inhibitor
AKT / PKB
Protein Kinase B (a component of the phosphatidylinositol 3-kinase signaling pathway)
AL(A)T
Alanine Aminotransferase / Glutamic Pyruvic Transaminase / sGPT
ALP
Alkaline Phosphatase
ALT
alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AS(A)T
Aspartate Aminotransferase / Glutamic Oxaloacetic Transaminase / sGOT
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Chemical Classification
AUC
Area Under the Concentration Time Curve
b.i.d.
bis in diem/twice a day
BAL
Broncho-Alveolar Lavage
BAP
Bone Alkaline Phosphatase
BC
Breast Cancer
bFGF
Basic Fibroblast Growth Factor
BP
Blood Pressure
bpm
beats per minute
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CFR
Code of Federal Regulation
CI
Confidence Interval
CL/F
Oral Clearance
Cmax
Maximum blood concentration
CMC
Chemistry / Manufacturing / Controls
Cmin
Minimum blood concentration
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CPO
Country Pharma Organization
CR
Complete Response
CRD
Clinical Research and Development
CRF
Case Report/Record Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTA
Clinical Trials Application


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CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTX
C-terminal cross linking telopeptide of type I collagen
CV
Coefficient of Variation
CYP
Cytochrome P450
CYP3A4
Cytochrome P450 3A4 isoenzyme
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DLCO
Diffusing Capacity for Carbon Monoxide
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EDTA
ethylenediaminetetraacetic acid
EGFR
Epidermal Growth Factor Receptor
ELISA
Enzyme Linked ImmunoSorbent Assay
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EOT
End Of Treatment
ER
Estrogen Receptor
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration (USA)
FEV1
Forced Expiratory Volume in one second
FKBP12
FK506-binding protein 
GCP
Good Clinical Practice
GGT
Gamma-Glutamyltransferase
GI
Gastrointestinal
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
GTP
Guanosine Triphosphate
HBcAb
hepatitis B core antibodies
HBs Ab
hepatitis B surface antibodies
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus
HDL
High-Density Lipoprotein
Hep B
Hepatitis B
Hep C
Hepatitis C
HER2
Human Epidermal Growth Factor Receptor 2
Hgb
Hemoglobin
HIF
Hypoxia-Inducible Factor
HIV
Human Immunodeficiency Virus
HMG-CoA
3-Hydroxy-3methyl-glutaryl coenzyme A
HPLC
High Performance Liquid Chromatography
HR
Hazard Ratio
HR
Hormone Receptor


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IB
Investigator’s Brochure
IC50
Inhibitory Concentration at 50%
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMS
Integrated Medical Safety
IND
Investigational New Drug Application (USA)
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT (IWRS)
Interactive Response Technology (that includes Interactive Web Response System)
ITT
Intent-To-Treat
LDH
Lactate Dehydrogenase
LDL
Low-Density Lipoprotein
LH-RH
Luteinizing hormone-releasing hormone
LLN
Lower Limit of Normal
LLOQ
Lower Limit Of Quantification
LMWH
Low Molecular Weight Heparin
LS/MS
Liquid Chromatography / Mass Spectrometry
MBC
Metastatic Breast Cancer
MPD
Molecular Pharmacodynamics
MRI
Magnetic Resonance Imaging
MRP
Mutual Recognition Procedure (EU)
mTOR
mammalian Target of Rapamycin
NADPH
Nicotinamide Adenine Dinucleotide Phosphate
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NDA
New Drug Application (USA)
NSAI
Non-steroidal Aromatase Inhibitors
NSCLC
Non-Small Cell Lung Cancer
o.d.
omnia die/once a day
ORR
Objective Response Rate
OS
Overall Survival
p.o.
per os / by mouth / orally
PCR
Polymerase Chain Reaction 
PD
Progressive Disease
PFS
Progression Free Survival
PFT
Pulmonary Function Test
P-gp
P-glycoprotein
PgR
Progesterone Receptor
PI3K
Phosphatidylinositol 3-Kinase (upstream effector of the mTOR signaling pathway)
PINP
Procollagen type I N-terminal Propeptide
PK
Pharmacokinetics
PLGF
Placental Growth Factor
PR
Partial Response
PRO
Patient Reported Outcome
PS
Performance Status


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PTEN
Phosphatase and Tensin Homolog (deleted on chromosome 10)
QoL
Quality of Life
RAPTOR
Regulatory Associated Protein of mTOR
RBC
Red Blood Cell Count
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RIA
Radioimmunoassay
RICTOR
Rapamycin-Insensitive Companion of mTOR
RMS
Reference Member State (EU)
RNA
Ribonucleic acid
S6K1
serine / threonine kinase p70S6 kinaseS6 Kinase 1
SAE
Serious Adverse Events
SD
Stable Disease
SEC
Study Evaluation Completion
SmPC
Summary of Product Characteristics
SNPs
Single Nucleotide Polymorphisms
SOP
Standard Operating Procedure
SPA
Special Protocol Assessment
SSC
Study Steering Committee
SST
Serum Separator Tube
t1/2
Half Life
T-Bil
Total bilirubin
TKI
Tyrosine Kinase Inhibitor
tmax
Time to Maximum Concentration
TSQM
Treatment Satisfaction Questionnaire for Medication
TTP
Time to Progression
ULN
Upper Limit of Normal
UNK
Unknown
WBC
Total White Blood Cell Count
WHO
World Health Organization
Wks
Weeks


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Amendment 3 (18-Apr-2017)
Study status
At the time of this amendment, the study is fully recruited with 309 patients and 11 patients 
are still receiving treatment. The last patient was randomized on 24-Nov-2014.
Amendment rationale
This study is a post-approval commitment with the Food and Drug Administration (FDA) and 
the European Medicines Agency (EMA) and the clinical study report (CSR) must be provided 
to these Agencies. Per protocol, the final PFS analysis is to be performed after at least 150 
PFS events have been documented for each of the following comparisons: (i) everolimus + 
exemestane versus everolimus monotherapy (primary objective) and (ii) everolimus + 
exemestane versus capecitabine monotherapy (key secondary objective). Overall survival (OS) 
is a secondary objective and currently the OS analyses are to be conducted with two data cut-
off dates; 2 years after the last patient’s randomization and at the time of the final PFS 
analysis.
Based on the current number of observed PFS events, the required 150 PFS events have been 
reached in one comparison and 146 PFS events have been observed in the other comparison. 
In the latter comparison, there is a high risk of not reaching the events over extended time due 
to long lasting stable disease status in the remaining patients. From a statistical perspective, 
loss of precision in the HR estimate with ≤ 4 events short of the required 150 is considered 
minimal (details described in section 10.7). The OS analyses will be amended: only one OS 
analysis will be performed and the timing for the final OS will be changed. The final OS 
analysis will be performed at the same time as the final PFS analysis using the same data cut-
off date.
In order to meet regulatory commitment for submitting the CSR without affecting the 
scientific objective of the study, the current amendment proposes to:
1. Perform the final PFS analysis after approximately (instead of at least) 150 PFS events 
have been documented for each comparison.
2. Perform the final OS analysis at the same time as the final PFS analysis using same cut-off 
date and only one OS analysis will be completed.
This amendment is considered “non-substantial” as it does not affect patient management nor 
the statistical analyses of the study data.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
1. Section 4.1.2: Replaced “at least” with “approximately”.
2. Section 4.1.3.1: Survival follow-up data collection will be stopped at the time of the final 
PFS analysis. The final PFS and OS analyses will use the same data cut-off date.
3. Section 4.3: Replaced “at least” with “approximately”.


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4. Section 7.1.3.1: Survival follow-up data collection will be stopped at the time of the final 
PFS analysis.
5. Section 7.1.5: Survival follow-up data collection will be stopped at the time of the final 
PFS analysis. Final PFS and OS analyses will use the same data cut-off date and only one 
OS analysis will be performed.
6. Section 7.2.1.1: Replaced “at least” with “approximately”.
7. Section 10.4.3: Replaced “at least” with “approximately”.
8. Section 10.5.2.1: The final OS analysis will be conducted at the same time as the final PFS 
analysis using the same data cut-off date.
9. Section 10.7: Updated Table 10-1 to include hazard ratio (HR) estimates for 146 and 150 
PFS events. Clarifications on the analysis precision were added.
IRB/IEC
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 protocol amendment are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 2
Amendment rationale
At the time of this amendment, 10-Feb-2014, 119 patients have been randomized.
The original protocol design included one final analysis for PFS, when approximately 150 
PFS events were expected in each of the two following groups: (i) everolimus + exemestane 
arm plus everolimus monotherapy arm, and (ii) everolimus + exemestane arm plus 
capecitabine monotherapy arm. In order to allow early termination of the everolimus 
monotherapy arm, in case the efficacy in the everolimus monotherapy arm is far inferior to the 
everolimus + exemestane combination arm, Novartis plans to perform an interim PFS analysis 
when approximately 75 PFS events have been observed as per local tumor assessment, across 
the following 2 arms: everolimus monotherapy and everolimus + exemestane combination 
arm. This approach was endorsed by the DMC and Study Steering Committee.
Since Capecitabine had been approved by the regulatory authorities for breast cancer 
indication as part of Standard of Care, treatment with capecitabine for patients in this study 
will be followed per its local label. Therefore, capecitabine treatment will not be terminated 
early and no interim analysis between capecitabine monotherapy arm and everolimus + 
exemestane combination therapy is deemed necessary.
In addition, instructions for missed dosing, re-screening and some administrative updates for 
clarification and consistency have been made, across the different sections of the protocol and 
across the everolimus program level. Also typographical errors were corrected throughout the 
protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
1. Protocol summary: Interim Analysis recommendation added to study design and 
objectives adapted to match endpoints
2. Section 3 Table 3-1 objectives adapted to match endpoints
3. Section 4.1.2 Randomization ratio clarified based on the Interim Analysis
recommendation
4. Section 4.2 Addition of Interim analysis to allow for the early termination of the 
everolimus monotherapy arm
5. Section 5.2 Calculation of Creatinine clearance by the Cockroft-Gault formula was added
6. Section 6.1 Instructions on early termination of the everolimus monotherapy arm and 
possible transition onto the everolimus + exemestane combination arm were added
7. Section 6.1.1 Instructions for missed dosing were added: if the missed dose for everolimus 
or/and exemestane is within 6 hours following the scheduled dosing time point, the 
missed dose of the study medication(s) should be taken. If patients realize they missed a 
dose more than 6 hours following the scheduled dosing time point, then patients should 
skip the missed dose(s). Also clarification was added to state that Everolimus 10 mg (2 x 5 
mg) and exemestane 25 mg should be taken together at the same time every day.


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8. Section 6.2.1 Dose modifications in the management of adverse reactions have been 
clarified
9. Section 6.2.1.1 Wording for dose reductions was updated, Table 6-5 was corrected for 
typographical errors and clarification was added on the dose adjustments
10. Section 6.2.1.2 Capecitabine section updated with the reference to local product 
information and Table 6-7 clarification added to FDA USA label use according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
11. Section 6.3.1 Denosumab used for the management of bone lesions was adapted
12. Section 6.3.1.1 A note was added that provides further insight into capecitabine co-
administered with CYP2C9 substrates: co-administration of CYP2C9 substrates should be 
exercised with caution (in line with Xeloda label) and should be monitored closely
13. Section 7.1.1.1 Process and eligibility for re-screening was included: patients, who met all 
inclusion exclusion criteria, however were not able to be randomized within the screening 
window due to administrative issues, will be allowed to be re-screened for re-
randomization. This was added due to time issues and constrains within the logistics of the 
site set and vendor.
14. Section 7.1.1.2. Screening failure definition was clarified
15. Table 7-4 Typographic corrections on the timing of the HBV-DNA prophylaxis 
monitoring recommendations were synchronized
16. Section 8.6 Information on efficacy interim analysis and DMC recommendations were 
added
17. Section 10 Clarification on the use of independent statistician and independent 
programmer for the interim analysis has been added.
18. Section 10.1.2 Clarification on safety analysis for the patients who receive everolimus
monotherapy that may cross over to everolimus and exemestane upon the interim analysis 
has been added.
19. Section 10.4.4 The supportive analysis for hypothesis testing and providing p-value was 
deleted
20. Section 10.5.2.1 Clarified completion of the final OS analysis to be consistent with section 
4.1.3.1
21. Section 10.6 Interim Analysis section was added to describe early termination guideline of
the everolimus monotherapy arm
22. Section 13 Reference has been added Wei L.J. (2007)
IRB/IEC
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. In addition, if 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 amended protocol.


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Final draft version of the Protocol Amendment 2 was already reviewed and commonly 
endorsed by FDA and EMA.


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Amendment 1
Amendment rationale
At the time of this amendment, 07-Jun-2013, 4 patients were randomized, 6 patients were in 
screening and 1 subject was discontinued due to disease progression.
The rationale of this amendment is as follows:

Significant drug-drug interaction between sorivudine and 5-FU leads to increased 
fluoropyrimidine toxicity, which is potentially fatal (EU SmPC for Xeloda®). Sorivudine 
pertains to a class of antiviral drugs for the treatment of Herpes simplex infection. 
Therefore, capecitabine must not be administered concomitantly with sorivudine or its 
chemically related analogues, such as brivudine (EU SmPC for Xeloda®). Accordingly, a 
new exclusion criteria (re-numbered as #19) was added to exclude subjects who are being 
treated with sorivudine or its chemically related analogues (e.g. brivudine) or to have at 
least 4 weeks period between end of treatment with such drugs and randomization date.

Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. These events occurred within several days and up to several months after 
initiating capecitabine therapy in patients with and without liver metastases (EU SmPC 
and US PI for Xeloda®). Therefore, to be consistent with exclusion criterion #20 (re-
numbered as #18 after amendment), which excludes patients under coumarin-derivate 
anticoagulants, the exclusion criterion #15 was updated to also exclude patients under low 
dose warfarin treatment.

As everolimus is a mixed inhibitor of CYP2D6 in vitro and capecitabine is presumed to 
inhibit CYP2C9 in vitro, the original protocol had a conservative approach to limit intake 
of drugs recognized as being strong or moderate inhibitors of these isoenzymes within the 
last five days prior to randomization. However, the mean steady-state of everolimus Cmax 
with an oral dose of 10 mg daily is more than 36-fold below the Ki-values of the in vitro 
inhibition. An effect of everolimus on the metabolism of CYP2D6 substrates was 
therefore considered to be unlikely (US PI for Afinitor®). Furthermore, a drug interaction 
study of capecitabine with single-dose warfarin administration showed a significant 
increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, 
probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by 
capecitabine. Other than warfarin, no formal drug-drug interaction studies between 
capecitabine and other CYP2C9 substrates have been conducted (EU SmPC and US PI for 
Xeloda®). Therefore, the exclusion criteria #18 and 19 were removed with the amendment.

The primary and key secondary analyses aim to assess the PFS treatment effect via 
stratified Cox models. To assess the impact of stratification, a sensitivity analysis using 
unstratified Cox models will be conducted. Because significance testing is not an objective 
of these analyses, the computation of the one-sided unstratified log-rank test p-value was 
removed in the amendment. Furthermore, besides the pre-specified final OS analysis, it is 
desirable to assess the treatment effect on overall survival at the time of the pre-specified 
final PFS analysis. This supplementary OS analysis is added in the amendment. No 


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multiple testing considerations are needed because hypothesis testing is not part of either 
OS analysis.
In addition to the above, some administrative updates for clarification have been made for 
consistency across the different sections of the protocol and also across the program level. 
Also typographical errors were corrected throughout the document.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes to the protocol are as follows:
1. List of abbreviations: Typographic corrections
2. Sections 1.1.1, 1.2.3 and 2.5.2: Typographic corrections
3. Section 4.1.1: Wording for capecitabine and exemestane central supply where applicable 
was added. Clarification for monitoring patients with hepatitis C positive at baseline was 
made.
4. Sections 4.1.2 and 7.2.1.1: The wording for additional confirmatory scan after initial 
observation of tumor response was updated for clarity
5. Section 5.2:
a. Inclusion criterion #4 was updated to specify that recurrence or progression should 
occur while on or after adjuvant treatment with letrozole or anastrozole, instead of 
aromatase inhibitors in general, for clarity
b. To insure adequate renal function at study entry, creatinine clearance > 60 ml/min
was added to inclusion criterion #9
6. Section 5.3:
a. Wording “low dose warfarin” was removed from the exception scenarios in exclusion 
criterion #15
b. “e.g.” was added before the list of CYP3A modifiers in exclusion criterion #17 to 
clarify these drugs as examples
c. Exclusion criteria #18 and #19 were removed
d. A new exclusion criterion numbered as 19 was added
7. Sections 6.1.1 and 6.1.2: Wording for local supply of commercially available exemestane 
and capecitabine was removed and a note for central supply of these drugs where 
applicable was added
8. Section 6.3.1:
a. A note was added on bisphosphonate therapy, which is not allowed during the study 
for chronic prevention of bone metastases
b. Section 6.3.1.1: This section was reworded for clarity, and a note was added for 
guidance on the classification of P-glycoprotein modifiers if not found in the table 6-9. 
Tables 6-8 and 6-9 were updated according to the most recent references available.
9. Table 7-1: The word “visit” under “Treatments” for clarity and missing word “twice” for 
capecitabine dosing were added


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10. Section 7.1.1.2 and 7.1.1.3: Wording on screen failure definition was updated for clarity, 
and randomization was added to replace first drug treatment
11. Section 7.1.2: Clarification was made to include an initial dosing window upon 
randomization
12. Section 7.2.1.1: Lost to follow up was added for clarity
13. Section 7.2.2:
a. ECG added to the list of safety monitoring assessments
b. Section 7.2.2.2: Informed consent was added to replace start of study drug
c. Section 7.2.2.5: Missing hepatitis B screening results information was added, and 
typographic corrections were made in Table 7-4
d. Section 7.2.2.7.2: “(if present before treatment)” was removed
14. Section 8.6: Clarification was made to define the first DMC data review meeting
15. Section 9: Randomization codes and IRT data will be available for everolimus treatment 
only
16. Section 10:
a. Designated CRO was deleted as Novartis will perform all statistical analyses
b. Section 10.4.4: The computation of the one-sided unstratified log-rank test p-value 
was removed from the sensitivity analysis
c. Section 10.5.2.1: Additional OS analysis at the time of the pre-specified final PFS 
analysis was added
d. Section 10.5.3.5: The example list of other safety data was updated for consistency 
with the eCRFs.
IRB/IEC
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. In addition, if 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 amended protocol.


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Protocol summary:
Protocol number
CRAD001Y2201
Title
A three-arm, randomized, open label, phase II study of everolimus in 
combination with exemestane versus everolimus alone versus 
capecitabine in the treatment of postmenopausal women with estrogen 
receptor positive, locally advanced, recurrent, or metastatic breast cancer 
after recurrence or progression on prior letrozole or anastrozole
Brief title
A study of everolimus plus exemestane versus everolimus versus 
capecitabine in postmenopausal women with estrogen receptor positive, 
locally advanced, recurrent, or metastatic breast cancer after recurrence or 
progression on prior letrozole or anastrozole
Sponsor and
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study is a post-approval commitment to the FDA and EMA. It is aimed 
to estimate the hazard ratio of progression free survival for everolimus plus 
exemestane versus everolimus monotherapy versus capecitabine 
monotherapy in postmenopausal women with estrogen receptor positive
(ER+), human epidermal growth factor receptor 2 negative (HER2-), locally 
advanced, recurrent, or metastatic breast cancer (ABC) after recurrence or 
progression on non-steroidal aromatase inhibitors.
The rationale of this study is based on the following:
●
Everolimus activity in breast cancer, both as monotherapy and in 
combination with endocrine therapy
●
Positive efficacy data of everolimus in combination with exemestane in 
a similar patient population
●
Capecitabine monotherapy has shown similar efficacy results to 
everolimus plus exemestane in estrogen receptor positive patients in terms 
of median progression free survival. Taking into account a different safety 
profile of chemotherapy compared to everolimus in combination with 
endocrine treatment, the evaluation of two treatment approaches in the 
randomized setting is of interest
Primary Objective and 
Key Secondary 
Objective
Primary Objective: To estimate the hazard ratio of progression free 
survival for everolimus plus exemestane versus everolimus alone in 
postmenopausal women with ER+, HER2-, ABC after recurrence or 
progression on letrozole or anastrozole.
Key Secondary Objective: To estimate the hazard ratio of progression 
free survival for everolimus plus exemestane versus capecitabine alone in 
postmenopausal women with ER+ HER2-, ABC after recurrence or 
progression on letrozole or anastrozole.


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Secondary Objectives
To evaluate the treatment groups with respect to:
●
Overall survival
●
Overall response rate
●
Clinical benefit rate
●
Safety
●
Time to ECOG performance deterioration
●
Time to Quality of Life (QoL) deterioration
●
Treatment satisfaction using Treatment Satisfaction Questionnaire for 
Medication (TSQM)
Study design
This is a three-arm, randomized, open label, multi-center phase II study 
investigating the combination of everolimus with exemestane versus 
everolimus versus capecitabine monotherapy in patients with ER+ HER2-, 
ABC after recurrence or progression on letrozole or anastrozole.
A total of 300 patients will be randomized in 1:1:1 ratio to one of the three 
arms. Treatment assignment will be stratified by the presence of visceral 
disease (yes vs. no). Based on the interim analysis results, the everolimus 
monotherapy arm might be stopped early. Under this scenario no 
additional patients will be randomized into everolimus monotherapy arm.
Population
Postmenopausal women with ER+ HER2-, ABC, recurrent or metastatic 
breast cancer after recurrence or progression on prior letrozole or 
anastrozole.
Inclusion criteria
1. Women with locally advanced, recurrent, or metastatic breast cancer. 
Locally advanced breast cancer is not amenable to curative treatment by
surgery or radiotherapy.
2. Histological or cytological confirmation of ER+ breast cancer
3. Postmenopausal women. Postmenopausal status is defined either by:
●
Age ≥ 18 with prior bilateral oophorectomy
●
Age ≥ 60 years
●
Age <60 years with amenorrhea for at least 12 months and both 
follicle-stimulating hormone (FSH) and estradiol levels are in 
postmenopausal range (according to the local laboratory)
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing 
hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) does not 
satisfy this inclusion criterion.
4. Recurrence or progression on prior NSAIs is defined as:
●
Recurrence while on, or within one year (365 days) of end of 
adjuvant treatment with letrozole or anastrozole
OR
●
Progression while on, or within one month (30 days) of the end of, 
prior treatment with letrozole or anastrozole for ABC
Notes:
●
Letrozole or anastrozole do not have to be the last treatment prior 
to randomization
●
Patients must have recovered to grade 1 or better from any 
adverse events (except alopecia) related to previous therapy prior to 
randomization


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5. Radiological or objective evidence of recurrence or progression on or 
after the last systemic therapy prior to randomization
6. Patients must have either:
●
Measurable disease defined as at least one lesion ≥ 10 mm by CT 
or MRI that can be accurately measured in at least one dimension (CT 
scan slice thickness ≤ 5 mm)
OR
●
Bone lesions: lytic or mixed (lytic + blastic) in the absence of 
measurable disease as defined above
Notes:
●
Lymph nodes have to be 15 mm in short axis to be considered 
measurable
●
If bone lesions have been previously irradiated, at least one lesion 
must have clearly progressed since the radiotherapy by CT, MRI or x-
ray for trial entry (in absence of measurable disease)
Exclusion criteria
1. HER2-overexpressing patients by local laboratory testing (IHC 3+ 
staining or in situ hybridization positive), based on the most recent test. 
Note: Patients with IHC 2+ must have a negative in situ hybridization test
2. Patients who received more than one chemotherapy line for ABC
Note: A chemotherapy line in advanced disease is an anticancer regimen 
that contains at least one chemotherapy agent and is given for 21 days or 
longer. If a cytotoxic chemotherapy regimen was discontinued for a reason 
other than disease progression and lasted less than 21 days, then this 
regimen does not count as a "prior line of chemotherapy". Chemotherapy 
regimens composed of more than one drug are considered as one line of 
therapy.
3. Patients with only non-measurable lesions other than lytic or mixed 
(lytic and blastic) bone metastasis (e.g. pleural effusion, ascites etc.)
4. Patients being treated with drugs recognized as being strong inhibitors 
or inducers of the isoenzyme CYP3A (e.g. Rifabutin, Rifampicin, 
Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, 
Telithromycin) continuously for at least 7 days during any time period in 
the last 2 weeks prior to randomization
5. Patients under treatment with sorivudine or its chemically related 
analogues, such as brivudine, or those who discontinue this treatment less 
than 4 weeks prior to randomization.
Investigational and 
reference therapy
Study treatment is defined as everolimus plus exemestane (10 mg/day + 
25 mg/day), everolimus monotherapy (10 mg/day) and capecitabine 
monotherapy (1250 mg/m2 twice daily for 2 weeks followed by one week 
rest).
Efficacy assessments
Efficacy assessments (overall tumor response and progression) will be 
evaluated every 6 weeks.
Tumor response will be based on radiological tumor measurements. The 
evaluation of overall tumor response will be performed according to 
RECIST 1.1.


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Safety assessments
The assessment of safety will be based mainly on the frequency of 
adverse events and on the number of laboratory values that fall outside of 
pre-determined ranges.
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 medication
2. on-treatment period: from day of first dose of study medication to 30 
days after last dose of study medication
3. post-treatment period: starting on day 31 after last dose of study 
medication.
Other assessments
Assessment of overall survival (OS), overall response rate (ORR), clinical 
benefit rate (CBR), deterioration in the ECOG performance status, 
changes in quality of life scores over time and patient satisfaction are 
planned in the trial.
Data analysis
The Full Analysis Set (FAS) comprises all patients to whom study 
treatment has been assigned by randomization. All primary analyses will 
be conducted using data from this population according to the intent-to-
treat (ITT) principle, i.e., patients will be analyzed according to the 
treatment and stratum they have been assigned to during the 
randomization procedure.
For the comparison of everolimus + exemestane versus everolimus alone 
(primary objective) as well as the comparison of everolimus + exemestane 
versus capecitabine alone (key secondary objective), stratified Cox 
regression models will be used to estimate the hazard ratios of a PFS 
event, along with associated 90% confidence intervals, where the 
stratification information will be obtained through IRT. For each of the three 
treatment arms, distribution of PFS will be assessed using the Kaplan-
Meier estimation method. The estimated median PFS and probability of 
not experiencing a PFS event by 2, 4, 6, and 9 months, along with 90% 
confidence intervals, will be presented.
Keywords
Postmenopausal woman, Advanced breast cancer, Endocrine therapy, 
Aromatase inhibitors


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Epidemiology of breast cancer
Breast cancer is the most frequently diagnosed cancer in women accounting for 23% (1.38 
million) of all new cancer cases and is the leading cause of cancer related deaths in females 
worldwide causing more than 400,000 deaths yearly (Jemal et al 2011). The presence of 
hormone receptor (HR) (estrogen receptor (ER) and/or progesterone receptor (PgR)) is one of 
the most important prognostic factors detected in approximately 70% of all invasive breast 
cancers. Endocrine therapy is the core treatment modality in patients with HR+ advanced 
breast cancer (ABC).
1.1.2
Treatment options for Hormone Receptor positive Advanced Breast 
Cancer
Endocrine therapy options for postmenopausal women with ER+ ABC include selective 
nonsteroidal aromatase inhibitors (NSAI; anastrozole and letrozole), steroidal aromatase 
inhibitors (exemestane), estrogen receptor antagonist (fulvestrant), and selective estrogen 
receptor modulator (SERM; tamoxifen). Blocking of estrogenic signaling with tamoxifen has 
been the main approach in treatment for ER positive breast cancer for over 30 years. 
Tamoxifen is indicated for the treatment across the whole continuum of breast cancer, ranging 
from risk reduction in women with high risk of developing breast cancer to treatment in 
multiple lines of metastatic disease. Aromatase inhibitors (AI) reduce peripheral estrogen 
synthesis by blocking the conversion of androgens to estrogens, which is the primary way 
estrogens are produced in postmenopausal women. Aromatase inhibitors are generally 
prescribed as the first line of therapy for the treatment of postmenopausal women with ER+ 
breast cancer (Beslija et al 2009, Cardoso et al 2011, NCCN 2011.2).
Despite broad spectrum of available options of endocrine therapy for the patients with ER+ 
ABC, all patients will eventually develop resistance to initial treatment.
An emerging mechanism of
endocrine resistance is aberrant signaling via the 
phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling 
pathway (Burstein 2011, Johnston 2006, Schiff et al 2004). Also, hyperactivation of the 
PI3K/mTOR pathway is observed in endocrine-resistant breast cancer cells, and treatment 
with mTOR inhibitors, including rapamycin analogs, reverses this resistance (Miller 2010). In 
addition, growing evidence supports a close interaction of the mTOR pathway with ER 
signaling. A substrate of mTOR Complex 1 (mTORC1), S6 kinase-1 (S6K1), phosphorylates 
the activation domain AF-1 of the ER, responsible for ligand-independent receptor activation 
(Yamnik et al 2009; Yamnik and Holz 2010).
Everolimus is a rapamycin derivative that inhibits mTOR through allosteric binding to 
mTORC1 but not mTORC2 (Efeyan and Sabatini 2010). Everolimus combined with AIs in 
preclinical models of ER-positive (ER+), hormone-sensitive and hormone-resistant breast 


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cancer, results in G1 arrest and enhanced apoptosis (Boulay et al 2005). In the clinic, 
everolimus monotherapy demonstrated clinical activity in patients with advanced breast 
cancer who had mostly ER+ tumors and had received previous endocrine therapy (Ellard et al 
2009). In this trial, 19 of the 49 patients enrolled were ER+/human epidermal growth factor 
receptor 2 negative (HER2-); one complete response, 2 partial responses, 3 stable disease for 
longer than 6 months, and 6 stable diseases for less than 6 months were reported in this 
subgroup. Median progression-free survival (PFS) in this subset of 19 patients was 3.5 months 
(95% C.I.: 1.9 – 5.5 months, data source: NCI-Canada). An additional partial response was 
reported in a patient with ER-positive HER2-unknown tumor (Ellard et al 2009).
More recently, the combination of everolimus with exemestane showed significant 
improvement in efficacy, in terms of PFS, response rate, and clinical benefit rate, relative to 
exemestane monotherapy (Baselga et al 2011). The median progression-free survival (PFS) by 
local assessment was 7.8 months for everolimus + exemestane versus 3.2 months for 
exemestane (HR = 0.45; 95% CI: 0.38-0.54; P<.0001). Overall response rate (12.6 % vs 1.7%; 
P<.0001) and clinical benefit rate (51.3% vs 26.4%; P<.0001) were superior in the everolimus 
+ exemestane arm versus exemestane + placebo. Analyses by central assessment showed a 
median progression-free survival of 11 months with everolimus versus 4.1 months with 
placebo (HR = 0.38; 95% CI: 0.31 – 0.48; P <.0001) confirming the results of the primary 
PFS analysis (Piccart et al 2012, Baselga et al 2012). The combination of everolimus and 
exemestane has received a marketing authorization in the USA, EU and many other countries 
based on the results of this study.
In patients with a significant tumor burden and symptomatic visceral disease, the indication of 
chemotherapy is supported by the perception of a more rapid and higher response rate. 
Endocrine responsive patients with liver or lung metastasis and no or few clinical symptoms 
do have both chemotherapy and endocrine therapy as therapeutic alternatives (Barrios et al 
2009).
The evolution of clinical practice in early breast cancer in the last decade has resulted in 
extensive use of anthracyclines and taxanes as adjuvant treatment. Capecitabine monotherapy
has become an important and frequently used option for the first-line cytotoxic treatment. 
Capecitabine is also the choice for the patients without previous exposure to taxanes or 
anthracyclines based on its generally mild safety profile and convenience of oral 
administration. Several clinical studies investigated capecitabine monotherapy in this setting 
and showed PFS between 4.1 and 7.9 months, and OS between 18.6 and 29.4 months 
(O’Shaughnessy et al 2012, Stocker et al 2007, Jaeger et al 2010, Kaufmann et al 2010, 
Robert et al 2011). Single agent capecitabine is therefore included in the NCCN and other 
national guidelines as a reasonable option for a first line treatment in patients with advanced 
BC (ABC: locally advanced, recurrent, or metastatic BC). The use of capecitabine 
monotherapy in this patient population is estimated to be up to 20% in the EU (Verma et al 
2011) and 8-16% in the US (market research data).


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1.1.3
Role of Mammalian Target of Rapamycin in ER+ ABC
The mammalian target of rapamycin (mTOR), a key protein kinase, acts as a nutrient sensor 
and monitor of the cellular metabolic state regulating protein synthesis and ultimately cell 
growth, proliferation, and survival. mTOR serves a key role in normal mammalian cell 
physiology, and is centrally involved in tumor-cell physiology, (for example, facilitating cell-
cycle progression from G1-S phase) and consequently inhibition of this target has received 
considerable attention as an anti-cancer approach, as reviewed by (Bjornsti and Houghton 
2004; Abraham and Gibbons 2007). mTOR regulates global mRNA translation (Beuvink 
2005). Indeed, downstream from mTOR is the serine / threonine kinase p70S6 kinase (S6K). 
S6K phosphorylates key residues on the ribosomal protein S6, permitting its activation and 
full function as a protein involved in ribosomal biogenesis. The mTOR kinase also modulates 
phosphorylation of 4E-BP1, releasing its inhibition of eIF-4E and consequently permitting 
efficient cap-dependent translation (Bjornsti and Houghton 2004).
Activation of the mTOR pathway is a key adaptive change driving endocrine resistance. 
Research into the mechanisms of resistance has shown that various signal transduction 
pathways are activated to escape the effect of endocrine therapy. For example, the PI3 
kinase/Akt/mTOR pathway is constitutively activated in aromatase inhibitor resistant and 
long-term estrogen deprivation BC cells (Tokunaga et al 2006; Santen et al 2005; Campbell et 
al 2001). Selective inhibitor of mTOR, sirolimus or rapamycin, demonstrated a significant 
growth inhibition particularly in long-term estrogen deprivation BC cells (Yue et al 2007). 
Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1 
but not mTORC2 (Efeyan and Sabatini 2010). However, prolonged exposure to rapamycin 
also results in mTORC2 inhibition (Sarbassov et al 2006).
In addition, there is a growing evidence supports a close interaction between the mTOR 
pathway and ER signaling. A substrate of mTOR complex 1 (mTORC1), called S6 kinase 1, 
phosphorylates the activation function domain 1 of the ER, which is responsible for ligand-
independent receptor activation (Yamnik et al 2009; Yamnik and Holz 2010)
1.2
Introduction to control arm and investigational treatments
In the context of this clinical trial, the combination arm of everolimus and exemestane is the 
considered control arm and the everolimus monotherapy and capecitabine monotherapy arms 
are considered investigational treatments.
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation. Everolimus is approved in Europe and other global markets (trade name: 
Certican®) for cardiac and renal transplantation, and in the United States (trade name: 
Zortress®) for the prevention of organ rejection of kidney transplantation.
Everolimus was also developed in oncology as Afinitor®. Afinitor was approved for advanced 
renal cell carcinoma (RCC) in 2009. In 2010, Afinitor received US approval for patients with 
subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex 
(TSC). Everolimus is also available as Votubia® in the EU for patients with SEGA associated 
with TS. Afinitor was approved for advanced PNET in 2011 in various countries, including 
the US, Canada and the EU. In April 2012, Afinitor was approved for the treatment of patients 


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with TSC who have angiomyolipoma and subsequently in the EU in November 2012 and 
various other countries. In July 2012, Afinitor in combination with exemestane was approved 
for the treatment of postmenopausal women with ER+, HER2-, advanced breast cancer after 
failure of treatment with letrozole or anastrozole in the US and EU as well as in various
countries.
The following is a brief summary of the main characteristics of everolimus. More detailed 
information can be obtained from the everolimus [Investigator’s Brochure].
1.2.1
Overview of Everolimus
Everolimus (Afinitor®; RAD001) is a derivative of rapamycin. It is a selective mTOR 
inhibitor drug class, specifically targeting the mTOR-raptor (regulatory-associated protein of 
mTOR, Raptor) signal transduction complex 1 (mTORC1). Both rapamycin and everolimus 
potently inhibit proliferation of endothelial cells (Yu and Sato 1999, Lane et al 2009) and 
have antiangiogenic activity in vivo (Guba et al 2002, Tsutsumi et al 2004, Mabuchi et al 
2007, Lane et al 2009).
Everolimus exerts its activity through high affinity interaction with the intracellular receptor 
protein FKBP12. The FKBP12/everolimus complex binds to mTORC1, inhibiting its 
signaling capacity. mTORC1 signaling is effected through modulation of the phosphorylation 
of downstream effectors, the best characterized of which are the translational regulators S6 
ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP). 
Disruption of S6K1 and 4E-BP1 function, as a consequence of mTORC1 inhibition, interferes 
with the translation of mRNAs encoding pivotal proteins involved in cell cycle regulation, 
glycolysis and adaptation to low oxygen conditions (hypoxia). This inhibits tumor growth and 
expression of Hypoxia-induced factors (e.g. HIF-1 transcription factors); the latter resulting in 
reduced expression of factors involved in the potentiation of tumor angiogenic processes (e.g. 
the vascular endothelial growth factor VEGF). Everolimus is a potent inhibitor of the growth 
and proliferation of tumor cells, endothelial cells, fibroblasts and blood vessel-associated 
smooth muscle cells. Consistent with the central regulatory role of mTORC1, everolimus has 
been shown to reduce tumor cell proliferation, glycolysis and angiogenesis in solid tumors in 
vivo, and thus provides two independent mechanisms for inhibiting tumor growth: direct 
antitumor cell activity and inhibition of the tumor stromal compartment.
1.2.1.1
Non-clinical experience
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including 
lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range 
from sub/low nM to μM. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The 
antiangiogenic activity of everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and 
metastatic tumors treated with everolimus showed a significant reduction in blood vessel 
density when compared to controls.
The potential of everolimus as an anti-cancer agent was shown in rodent models. Everolimus 
is orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse 


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xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. 
The pharmacokinetic profile of everolimus indicates sufficient tumor penetration, above that 
needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
everolimus in vitro.
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung 
and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). 
These models included tumor lines considered sensitive and “relatively resistant” in vitro. In 
general, everolimus was better tolerated in mouse xenograft models than standard cytotoxic 
agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity.
In breast cancer antitumor efficacy of everolimus was compared to other compounds in a 
panel of six breast cancer xenograft models established after direct transplantation of patients’ 
tumors onto nude mice [Report RD-2011-50492]. including an ER+ model, HBCx-3 (XTS-
181), (Marangoni et al 2007). Everolimus given daily by oral gavage for 21 to 35 days at 20 
mg/kg was well tolerated with no significant mean body weight loss. In all breast cancer 
models tested, tumor growth was significantly inhibited, while in HBCx-3 (XTS-181) this 
effect was particularly evident (Figure 1-1) with 9/10 partial tumor regressions (-13.5% mean 
tumor volume regression, p<0.001).
Figure 1-1
Tumor Growth Changes in the HBCx-3 Breast Xenograft Model
Significant tumor growth delay with everolimus administered daily p.o. at 10mg/kg was also 
documented in other four estrogen-dependent breast cancer models: ZR75-1 (ER+, PTENmut), 
UACC812 (ER+, HER2+), MDA361 (ER+, HER2+) and KPL-1 (ER+, PTENwt) [Report 
RD-2011-50447].


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It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and 
the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with 
PTEN status.
In preclinical models, the administration of everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) 
and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein upstream 
of mTOR signaling pathway.
All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes. Further details can be found in the everolimus [Investigator’s Brochure].
1.2.1.2
Clinical experience
1.2.1.2.1 Everolimus pharmacokinetics
Everolimus is rapidly absorbed with a median tmax of one to two hours. The steady-state 
AUC0-τ is dose-proportional over the dose range between 5 to 70 mg in the weekly regimen 
and 5 and 10 mg in the daily regimen. Steady-state was achieved within two weeks with the 
daily dosing regimen. Cmax is dose-proportional between 5 and 10 mg for both the weekly and 
daily regimens. At doses of 20 mg/week and higher, the increase in Cmax is less than dose-
proportional (amended Study C2102 CP report).
In healthy patients, high fat meals reduced systemic exposure to everolimus 10 mg (as 
measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals 
reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post 
absorption phase concentration-time profile (Study C2120).
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 
5 to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is 
approximately 20% at blood concentrations observed in cancer patients given everolimus 10 
mg/day (Study 303-044). Plasma protein binding is approximately 74% both in healthy 
patients and in patients with moderate hepatic impairment (Study A2303).
The major and nearly exclusive enzyme responsible for the metabolism of everolimus in man 
was CYP3A4 (DMPK(US)1998/005; DMPK(CH) R99-2448), (Kuhn et al 2001). Other CYP 
isoenzymes either do not metabolize everolimus or do so at very low rates. Everolimus is also 
a moderate inhibitor of P-glycoprotein-like mediated efflux systems, although the compound 
has a high intrinsic permeability when P-glycoprotein is inhibited (Crowe and Lemaire 1998, 
Laplante et al 2002, [DMPK(CH) 1997/417]). Following oral administration, everolimus is 
the main circulating component in human blood and is considered to contribute the majority 
of the overall pharmacologic activity (Study W107).
No specific excretion studies have been undertaken in cancer patients; however, data available 
from the transplantation setting found the drug to be mainly eliminated through the feces.


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1.2.1.2.2 Clinical experience of Everolimus in hormone receptor positive breast 
cancer (HR+ BC)
Several randomized trials evaluated everolimus in HR+ breast cancer and showed evidence of 
efficacy of everolimus in this patient population.
Everolimus monotherapy
In a multicenter, randomized phase II study, a daily dose of everolimus (10 mg) was evaluated 
in patients with mostly HR + ABC who had received prior endocrine therapy. In this trial, 19 
of the 49 patients enrolled were ER-positive/human epidermal growth factor receptor 2 
(HER2)-negative; one complete response, 2 partial responses, 3 stable disease for longer than 
6 months, and 6 stable diseases for less than 6 months were reported in this subgroup. Median 
progression-free survival (PFS) in this subset of 19 patients was 3.5 months (95% C.I.: 1.9 –
5.5 months, data source: NCI-Canada). An additional partial response was reported in a 
patient with ER-positive HER2-unknown tumor (Ellard et al 2009).
Everolimus in combination with endocrine therapy
The combination of everolimus with endocrine therapy has been assessed in different disease 
settings.
In newly diagnosed patients with HR+ early BC, a neoadjuvant randomized 270-patient phase 
II study compared the combination of everolimus and letrozole to letrozole alone. The overall 
response rate in the everolimus arm was higher than that with letrozole alone arm (68% vs. 
59% (palpation, p = 0.062) and 58% vs. 47% (ultrasound, p= 0.021) respectively. 
Additionally, there was a greater antiproliferative response, with a decrease of the Ki67 
proliferation index to <1 in 57% of patients in the everolimus arm and in 30% of patients in 
the placebo arm (P<0.01). This reduction in Ki67 was observed only two weeks after 
initiation of trial therapy (Baselga et al 2009).
In a randomized phase III, double-blind, placebo-controlled study (BOLERO-2 Study), 
everolimus in combination with exemestane was compared with exemestane alone in 724 
postmenopausal women with HR+ ABC who had a recurrence or progression on letrozole or 
anastrozole. The median duration of the follow-up of the patients was 18 months. Median PFS 
was 7.8 months for everolimus plus exemestane versus 3.2 months for placebo plus 
exemestane (HR, 0.45; 95% CI, 0.38 to 0.54; P < .0001). Centrally assessed PFS analyses 
showed a median PFS duration of 11.0 months for the everolimus plus exemestane arm versus 
4.1 months for the placebo plus exemestane arm (HR, 0.38; 95% CI, 0.31 to 0.48; P < .0001). 
Subgroup analyses showed consistent PFS benefit with combination therapy across all patient 
subsets. By local assessment, three complete responses (CRs, 0.6%) and 58 partial responses 
(PRs, 12%) were reported for the everolimus plus exemestane arm, versus only four PRs 
(1.7%) for the placebo plus exemestane arm. The CBR also was increased with everolimus 
plus exemestane therapy versus placebo plus exemestane (51.3% vs 26.4%; P < .0001). These 
differences in ORR and CBR were also supported by central radiology review (Piccart et al 
2012).


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In a 111-patient randomized phase II study in postmenopausal women with ER+ ABC 
previously pretreated with aromatase inhibitors, the combination of everolimus and tamoxifen 
showed a significant improvement in progression-free survival (8.6 months vs. 4.5 months, 
p=0.0021) and overall survival (median not reached vs. 24.4 months, p=0.0137) relative to 
tamoxifen alone (Bachelot et al 2012). Although the results of the phase II trial are 
encouraging, the small sample size may limit the impact of these results on clinical practice.
Safety profile of everolimus
The following adverse events are considered to be the class-effects of the mTOR inhibitors: 
stomatitis/oral mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, 
hemorrhages, non-infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal 
events, and thromboembolism. The more common metabolic side effects reported with mTOR 
inhibitors result from inhibitory effects on mTOR-regulated lipid and glucose pathways, while 
infections stem from the immunosuppressive properties of these agents. Virtually all of the 
side effects associated with mTOR inhibitors can be managed effectively with dose 
modification and/or supportive intervention.
The safety profile of everolimus observed in the phase III study (BOLERO-2) is consistent 
with prior experience in the oncology setting; events continue to be predominantly low grade 
(grade 1 or 2). An increased risk of non-infectious pneumonitis, infection, and stomatitis in 
the everolimus plus exemestane arm relative to the control arm [exemestane + placebo] was 
observed, although each of these events can be effectively managed in this setting.
The most common adverse events (AEs) suspected to be related to treatment, with an 
incidence ≥10%, reported in association with everolimus plus exemestane therapy were 
consistent with what was previously reported: stomatitis, rash, fatigue, decreased appetite, 
diarrhea, dysgeusia, nausea, pneumonitis, weight decreased, anemia, epistaxis, hyperglycemia, 
thrombocytopenia, and pruritus. The most common grade 3-4 AEs suspected to be related to 
treatment with an incidence of ≥2% were: stomatitis, hyperglycemia, anemia, pneumonitis,
fatigue, elevated alanine and aspartate transaminase concentrations, elevated γ-
glutamyltransferase concentrations, dyspnea, neutropenia, and thrombocytopenia. No new 
safety concerns have emerged compared to previous experience with everolimus monotherapy
or combination therapy.


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Table 1-1
BOLERO-2 Study: Most common Adverse Events (equal or greater 
than 10 percent of Patients)
AE (preferred term)
EVE + EXE
(n = 482), %
PBO + EXE
(n = 238), %
Grade
Grade
All
1
2
3
4
All
1
2
3
4
Stomatitis
59
29
22
8
0
12
9
2
1
0
Rash
39
29
9
1
0
7
5
2
0
0
Fatigue
37
18
14
4
<1
27
16
10
1
0
Diarrhea
34
26
6
2
<1
19
14
4
1
0
Nausea
31
21
9
<1
<1
29
21
7
1
0
Decreased appetite
31
19
10
2
0
13
8
4
1
0
Weight decreased
28
10
16
2
0
7
3
5
0
0
Cough
26
21
4
1
0
12
8
3
0
0
Dysgeusia
22
18
4
0
0
6
6
0
0
0
Dyspnea
22
10
6
5
<1
11
8
2
1
<1
Headache
23
17
6
<1
0
15
13
2
0
0
Arthralgia
21
15
5
1
0
17
11
6
<1
0
Peripheral edema
21
14
6
1
0
6
5
1
<1
0
Anemia
21
4
10
7
1
5
2
2
<1
<1
Back pain
15
10
5
<1
0
11
6
3
2
0
Epistaxis
17
16
2
0
0
1
1
0
0
0
Vomiting
17
11
6
1
<1
13
9
3
1
0
Pyrexia
16
13
3
<1
0
7
6
1
<1
0
Pneumonitis
16
7
6
3
0
0
0
0
0
0
Constipation
15
11
3
1
0
13
8
5
<1
0
Back pain
15
10
5
<1
0
11
6
3
2
0
Pruritus
14
11
3
<1
0
7
5
2
0
0
Insomnia
14
10
4
<1
0
8
6
3
0
0
Asthenia
14
7
6
2
<1
4
3
1
<1
0
AST increased
14
6
5
3
<1
6
2
2
1
0
Hyperglycemia
14
4
5
5
<1
2
1
1
<1
0
ALT increased
12
5
4
3
<1
5
1
2
2
0
Dry mouth
11
10
1
0
0
7
7
<1
0
0
Alopecia
11
9
1
0
0
12
12
0
0
0
Nasopharyngitis
10
9
1
0
0
9
7
2
0
0
Pain in extremity
10
6
3
<1
0
12
5
5
2
0
Urinary tract infection
10
3
7
<1
0
2
<1
2
0
0
GGT increase
10
2
2
5
2
9
1
1
5
2
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; EVE, 
everolimus; EXE, exemestane; GGT, gamma glutamyltransferase; PBO, placebo.
Further details related to everolimus safety can be found in the everolimus [Investigator’s 
Brochure].


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1.2.2
Overview of Exemestane
Exemestane is an irreversible steroidal aromatase inactivator that has demonstrated efficacy in 
the treatment of postmenopausal patients with ABC. It is indicated for adjuvant treatment of 
postmenopausal women with estrogen receptor positive (ER+) early BC who have received 
two to three years of tamoxifen and are switched to exemestane for completion of a total of 
five consecutive years of adjuvant endocrine therapy. It is also indicated for the treatment of 
ABC in postmenopausal women whose disease has progressed following tamoxifen therapy 
(in the USA) or following anti-oestrogen therapy (in Europe).
Exemestane is initially recognized by the aromatase enzyme as a false substrate and then 
transformed through an NADPH-dependent mechanism to an intermediate that binds 
irreversibly to the enzyme causing inactivation. Exemestane significantly lowers circulating 
estrogen concentrations (estradiol, estrone and estrone sulfate) but has no detectable effect on 
adrenal biosynthesis of corticosteroids or aldosterone (Aromasin prescribing information, 
Pfizer-Pharmacia, 2005).
The recommended daily dose of exemestane is 25 mg via oral administration. Exemestane is 
rapidly absorbed from the gastrointestinal tract. Its bioavailability is limited by first-pass 
metabolism, but is increased when taken with food. Exemestane is widely distributed, and is 
extensively bound to plasma proteins. It appears to be more rapidly absorbed in women with 
breast cancer (tmax of 1.2 hours) than in healthy women (tmax of 2.9 hours). The terminal half-
life for exemestane is 18-24 hours. The time needed to reach maximal E2 suppression is 7 
days (Demers et al 1993, Plourde et al 1995, Buzdar 2003). Exemestane is metabolized by 
CYP3A4 and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, 
including CYP 1A2, 2C9, 2D6, 2E1 and 3A4. Although no formal drug-drug interaction 
studies have been conducted, significant effects on exemestane clearance by CYP isoenzyme 
inhibitors appear unlikely (Aromasin prescribing information, Pfizer-Pharmacia, 2011, 
Hutson et al 2005, Buzdar 2003).
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, 
hot flushes, arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects 
include headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and 
peripheral and leg edema. Thrombocytopenia and leucopenia have been reported occasionally. 
Reductions in bone mineral density can occur with long-term use of exemestane. A total of 
1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. 
Exemestane was generally well tolerated, and adverse events were usually mild to moderate. 
Adverse events occurring in greater than 10% of patients include hot flushes (14%), nausea 
(11.9%), insomnia, headache, increased sweating, joint and musculoskeletal pain, and fatigue 
(USPI; Aromasin SmPC August 2008 (UK as RMS for EU MRP)). Androgenic effects were 
reported in a limited number of patients (4.3%) (Buzdar 2003).
Refer to the package insert of the local supply of exemestane for more details.
1.2.3
Overview of Capecitabine
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity, which functions as 
an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine 
is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, 


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thymidine phosphorylase (ThyPase), is found in tumor tissues, but also in normal tissues, 
albeit usually at lower levels (US PI for Xeloda®)
Capecitabine is indicated in combination with docetaxel for the treatment of patients with 
locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy that 
included an antracycline. Capecitabine is also indicated as monotherapy for the treatment of 
patients with locally advanced or metastatic breast cancer after failure of taxanes and an 
anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is 
not indicated. The dose of capecitabine approved by the U.S. Food and Drug Administration 
(FDA) for patients with locally advanced or metastatic breast cancer is 1,250 mg/m2 twice 
daily (bid), given intermittently for 14 days on a 21-day cycle. Capecitabine has a favorable 
safety profile, with adverse events (AEs) readily managed by dose modification, and it offers 
the additional benefit of convenient oral dosing. Capecitabine is suitable for long-term 
administration and generally lacks cumulative toxicity with prolonged use. (O’Shaughnessy et 
al 2012)
As a monotherapy, capecitabine was extensively evaluated in the first line metastatic breast 
cancer in phase II and phase III clinical trials. The ORR shown in these studies was in a range 
of 21 to 30% and PFS between 2.8 to 7.1 months in patients with metastatic breast cancer 
unselected for ER status (O’Shaughnessy et al 2012). The two phase III studies were 
conducted in unselected by ER status patients with metastatic breast cancer. Stocker et al
reported (ANZBCTG0001) study where patients with first-line mBC unsuited for more 
intensive chemotherapy were randomized to receive capecitabine monotherapy or 
cyclophosphamide, methotrexate and 5-fluorouracil (CMF). 323 patients were enrolled in this 
study. All patients had to have a relapse-free survival interval for at least 6 months following 
adjuvant chemotherapy and 80% of patients had received adjuvant endocrine therapy. The 
primary endpoint PFS was similar between two treatment arms HR= 0.86; (95%CI 0.67–1.10). 
Patients enrolled in the capecitabine arm had a median PFS of 7 months and median OS of 22 
months, compared to median PFS of 6 months and OS of 18 months in patients randomized to 
CMF arm. The OS difference was statistically significant in favor of capecitabine arm 
(HR=0.72; 95% CI, 0.55– 0.94; log-rank p=0.02). Another randomized Phase III study 
compared the efficacy and safety of first-line capecitabine with pegylated liposomal 
doxorubicin (PLD) in patients with mBC (Jäger et al 2010).The primary endpoint of time to 
progression (TTP) was similar with capecitabine and PLD (median TTP, 7.1 months versus 
6.2 months, respectively; HR, 1.21; 95% CI, 0.84 –1.75; p=0.31). Capecitabine also had 
efficacy similar to that of PLD in terms of OS (median OS time, 29.4 months versus 22.4 
months, respectively; HR=1.17; 95% CI, 0.79 –1.74; p=0.44).
Robert et al, reported a PFS of 6.2 months in ER-positive HER2 –negative breast cancer 
patients receiving capecitabine monotherapy (Robert et al 2011).
Diarrhea, hand-foot syndrome (HFS), nausea, vomiting and stomatitis are common adverse 
reaction attributed to capecitabine treatment. Across the phase II/III breast cancer trials, HFS 
and diarrhea were the most frequently reported grade 3 or 4 AEs; alopecia and 
myelosuppression were rare (O’Shaughnessy et al 2012). Refer to US PI for Xeloda® for more 
details.


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2
Rationale
2.1
Study rationale and purpose
This study aims at estimating the hazard ratios of PFS for everolimus plus exemestane versus 
everolimus alone and versus capecitabine alone, in postmenopausal women with ER+ ABC 
after recurrence or progression on aromatase inhibitors. The study is a post-approval 
commitment to the FDA and EMA.
The rationale of this study is based on the following:

Everolimus activity in breast cancer, both as monotherapy (Ellard et al 2009) and in 
combination with endocrine therapy (Baselga et al 2009; Bachelot et al 2012)

Positive efficacy data of everolimus in combination with exemestane in a similar patient 
population (Piccart et al 2012)

Capecitabine monotherapy has shown similar efficacy results to everolimus plus 
exemestane in ER+ patients in terms of median PFS (Robert et al 2011). Taking into 
account different safety profile of chemotherapy compared to everolimus in combination 
with endocrine treatment, the evaluation of two treatment approaches in the randomized 
setting is of interest
In preclinical models of ER-positive hormone-sensitive and hormone-resistant breast cancer, 
everolimus combined with AIs results in G1 arrest and enhanced apoptosis (Bouly et al 2005). 
The combination of everolimus with endocrine therapy for the treatment of ER+ ABC after 
progression on an AI has been supported in phase II trials (Baselga et al 2009; Bachelot et al 
2012). Exemestane is commonly used after failure of prior therapy with letrozole or 
anastrozole. In a Phase-II clinical setting, exemestane 25 mg once daily has been 
demonstrated to be both safe and effective in postmenopausal patients with metastatic breast 
cancer following progression on treatment with a NSAI (Lønning et al 2000). In this 
particular study, exemestane was associated with a 24.3% clinical benefit rate (defined as 
CR+PR+SD ≥ 24 weeks) in a population who received exemestane as a third- or fourth-line 
endocrine therapy. Results from a double-blind, placebo-controlled Phase-III trial comparing 
exemestane to fulvestrant in 693 postmenopausal women with ER-positive breast cancer after 
recurrence or progression on a NSAI demonstrated no difference between treatment arms in 
terms of TTP/PFS (median 3.7 months in both arms), ORR (7.4% versus 6.7%, respectively), 
or clinical benefit rate (32.2% versus 31.5%, respectively) (Chia et al 2008). Exemestane was 
therefore considered to be an appropriate combination strategy for the phase III clinical trial. 
In the trial the combination of everolimus and exemestane has shown superiority in terms of 
PFS compared to exemestane alone (Baselga et al 2011; Piccart 2012).
Everolimus monotherapy demonstrated clinical activity in patients with advanced breast 
cancer who had mostly ER+ tumors and had received previous endocrine therapy (Ellard et al 
2009).
In metastatic setting combinations of cytotoxic agents might provide a greater objective 
response rate and longer PFS compared to single agent therapy. However, the increase in side 
effects and overlapping toxicity are limiting wide use of these approaches. Therefore, 
sequential single agent cytotoxic therapy remains a frequent strategy in the first line treatment 
of metastatic or locally recurrent breast cancer (Sledge 2003). Capecitabine monotherapy is 


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used successfully as the first line therapy in patients with ER+ HER-2 negative breast cancer 
with median PFS of 6.2 months (Robert et al 2011).
2.2
Rationale for the study design
This is a phase II randomized, open label, international multicenter study. This study design is 
well-established for the estimation of the efficacy and tolerability of everolimus and 
capecitabine monotherapies compared to everolimus/exemestane combination.
2.3
Rationale for dose and regimen selection
The selection of the 10-mg continuous daily dose for everolimus is based on a 
pharmacodynamic model (Tanaka et al 2008), which was supported by results from a clinical 
pharmacodynamic study in patients with solid tumors (Tabernero et al 2008). These results 
showed that the 10-mg daily dose produced a more profound, sustained suppression of mTOR 
activity than could be achieved with weekly dosing. Also, the 10 mg daily dose of everolimus 
was favored over a 5 mg daily dose in Study C2108, a Phase 1 study combining everolimus 
with letrozole in postmenopausal patients with advanced breast cancer (Awada et al 2008). 
This was further corroborated by results from a randomized Phase 2 study conducted by the 
National Cancer Institute of Canada, where a daily regimen of 10 mg everolimus was more 
efficacious than a 70 mg weekly regimen (Ellard et al 2009). The same 10-mg dose was used 
effectively in the BOLERO-2 study (Piccart et al 2012).
The approved dose of everolimus in combination with exemestane in the treatment of 
postmenopausal women with HR+ HER2- and ABC is 10 mg daily via oral administration.
The recommended daily dose of exemestane is 25 mg via oral administration and this dose 
will be used in this study.
The approved dose of capecitabine for patients with LABC or MBC is 1250 mg/m2 twice 
daily (bid), given intermittently for 14 days on a 21-day cycle. This dose will be used in the 
study.
2.4
Rationale for choice of combination therapy as a control arm
The rationale for assigning the combination of everolimus with exemestane as the control arm 
in this trial is based on significant improvement in efficacy, in terms of PFS, response rate, 
and clinical benefit rate, relative to exemestane monotherapy in patients resistant to NSAI 
(Baselga et al 2011; Piccart et al 2012). Everolimus in combination with exemestane as the 
control arm in the trial is also based on the approval by FDA and EMA in July 2012 for the 
combination therapy in the treatment of postmenopausal women with HR+ HER2- and ABC. 
In addition, there is a regulatory requirement to compare efficacy and safety of the approved 
therapy with everolimus and capecitabine monotherapy.


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2.5
Rationale for choice of comparators drugs
2.5.1
Rationale for choice of Everolimus
Everolimus monotherapy demonstrated clinical activity in patients with advanced breast 
cancer who had mostly ER+ tumors and had received previous endocrine therapy (Ellard et al 
2009). In this trial, 19 of the 49 patients enrolled were ER-positive/human epidermal growth 
factor receptor 2 (HER2)-negative; one complete response, 2 partial responses, 3 stable 
disease for longer than 6 months, and 6 stable diseases for less than 6 months were reported in 
this subgroup. Median progression-free survival (PFS) in this subset of 19 patients was 3.5 
months (95% C.I.: 1.9 – 5.5 months, data source: NCI-Canada). An additional partial response 
was reported in a patient with ER-positive HER2-unknown tumor (Ellard et al 2009).
2.5.2
Rationale for choice of Capecitabine
Capecitabine monotherapy has become an important and frequently used option for the first-
line chemotherapy treatment particularly in patients with residual toxicity after adjuvant 
therapy or high cumulative dose of anthracyclines. Capecitabine is also the choice for the 
patients without previous exposure to taxanes or anthracyclines based on its generally mild 
safety profile and convenience of oral administration. Capecitabine monotherapy as first line 
treatment demonstrated efficacy in phase III studies in unselected patients and in patients with 
ER+ ABC (Stocker et al 2007; Jäger et al 2010; Robert et al 2011). Single agent capecitabine 
is therefore included in the NCCN and other national guidelines as a reasonable option for a 
first line treatment in patients with ABC.
Capecitabine is indicated as monotherapy for the treatment of patients with locally advanced 
breast cancer (LABC) or MBC after failure of taxanes and an anthracycline-containing 
regimen and in patients for whom further anthracycline therapy is not indicated (US PI for 
Xeloda®)
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To estimate the hazard ratio of PFS for everolimus 
plus exemestane versus everolimus alone in 
postmenopausal women with ER positive, HER2 
negative, advanced breast cancer after recurrence or 
progression on letrozole or anastrozole.
Progression free survival (PFS) based on the local 
radiologist/investigator’s tumor assessment (RECIST 
1.1)
Key secondary
Refer to Section 10.5.1
To estimate the hazard ratio of PFS for everolimus 
plus exemestane versus capecitabine in 
postmenopausal women with ER positive, HER2 
negative, advanced breast cancer after recurrence or 
progression on letrozole or anastrozole
Progression free survival (PFS) based on the local 
radiologist/investigator’s tumor assessment (RECIST 
1.1)
Other secondary
Refer to Section 10.5.2
To evaluate the treatment groups with respect to:
- Overall survival
Overall survival (OS)
- Overall response rate
Overall response rate (ORR) ) based on the local 
radiologist/investigator’s tumor assessment (RECIST 
1.1)
- Clinical benefit rate
Clinical benefit rate (CBR)
- Safety
Safety: Incidence of adverse events, serious adverse 
events, changes from baseline in vital signs and 
laboratory results (hematology, blood chemistry)
- Time to ECOG performance deterioration
Time to ECOG performance deterioration
- Time to Quality Of Life (QoL) deterioration
Time to Quality Of Life (QoL) deterioration
- Treatment satisfaction using Treatment Satisfaction 
Questionnaire for Medication (TSQM) version 1.4
TSQM score


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4
Study design
4.1
Description of study design
This is a three-arm, randomized, open label, multi-center phase II study investigating the 
combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus 
(10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in 
patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after 
recurrence or progression on letrozole or anastrozole.
The reference therapy (control arm) used in the course of this trial is the combination arm of 
everolimus plus exemestane. The investigational therapies in the context of this study are 
everolimus monotherapy and capecitabine monotherapy. All treatments will be taken orally 
until disease progression, intolerable toxicity or withdrawal of patient’s informed consent.
Patients will be randomly assigned with equal allocation to one of the treatment arms:
a. Exemestane (25mg daily) in combination with everolimus (10mg daily)
b. Everolimus (10mg daily)
c. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest 
period in 3-weeks cycles.
Treatment assignment will be stratified by the presence of visceral disease (yes vs. no). 
Visceral refers to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or 
pericardial effusion or malignant ascites.
Figure 4-1
Study Design


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4.1.1
Screening Phase
Written informed consent must be obtained before any study specific medical procedures are 
performed. The investigator or his/her authorized designee will assign a unique number to 
patients being considered for the study. Each patient is uniquely identified by a 9-digit patient
identifier (consisting of a 4-digit center number and 5-digit patient number). Once assigned, 
the patient numbers for patients will not be reused.
The study will use Interactive Response Technology (IRT), a central patient screening/
randomization system for screening, randomization and for management of everolimus drug 
supply. Other study medications (capecitabine and exemestane) will be supplied locally in 
accordance with local regulations in participating countries, or centrally supplied by Novartis 
where applicable.
After the patient signs the informed consent and prior to randomization, a patient’s pre-
randomization form, which includes key eligibility criteria, will be completed by the site and 
sent to Novartis for review and approval. Patients who do not meet the eligibility criteria will 
not be randomized. All screening assessments to confirm eligibility must be performed within 
maximum 28 days prior to the first dose of study drug (Table 7-1 and Section 7.1.1).
Screening for hepatitis B
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation 
and associated HBV morbidity and mortality (Loomba et al. 2008).
Prior to randomization, the following three categories of patients should be tested for hepatitis 
B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab:
1. All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal, and Greece. 
[.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849 ]
2. Patients with any of the following risk factors:

known or suspected past hepatitis B infection,

blood transfusion(s) prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact with hepatitis B infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,

mother known to have hepatitis B,

history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain.
3. Additional patients at the discretion of the investigator
The management guidelines, in Section 7.2.2.5, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B.


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Screening for hepatitis C
Patients with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR

known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),

blood transfusions prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact of hepatitis C infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,
At the discretion of the investigator, additional patients may also be tested for hepatitis C.
The management guidelines, in Section 7.2.2.5, are provided according to the results of the 
baseline assessment of hepatitis C viral load.
All screening evaluations will be performed within 28 days prior to Treatment Day 1. Patients 
with positive baseline hepatitis B results have to start prophylactic treatment of 1 to 2 weeks 
prior to randomization. Patients with detectable HCV-RNA results should be monitored every 
6 weeks.
4.1.2
Randomization and treatment phase
At Visit 3 all eligible patients will be randomized via IRT to one of the treatment arms. 
Randomization will be performed using a randomization list produced by the IRT vendor. A 
randomization number will be assigned to the patient, which will be used to link the patient to 
a treatment arm.
A total of 300 patients will be randomized in 1:1:1 ratio to receive everolimus (10mg daily 
oral tablets) in combination with exemestane (25 mg daily oral tablets), everolimus (10mg 
daily oral tablets) or capecitabine monotherapy (1250mg/m2 twice daily orally for two weeks 
followed by a one week rest period in 3-weeks cycles). Assignment will be stratified by the 
presence of visceral disease (yes vs. no). Visceral refers to lung, liver, heart, ovary, spleen, 
kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.
After randomization, study treatment will start and continue until progression, intolerable 
toxicity or consent withdrawal. Further treatment after progression and study treatment 
discontinuation will be at the investigator’s discretion. Dose adjustment (reduction, 
interruption) according to safety findings will be allowed. Regular safety and efficacy reviews 
by Data Monitoring Committee (DMC) will be performed.
Tumor assessments will be performed every 6 weeks until disease progression. If an initial 
observation of response is made, a confirmation scan (or photography for measurable skin 
lesions) should be obtained at least 4 weeks after the initial observation. After approximately 
150 PFS events have been documented per RECIST 1.1 by local assessment in each of the 
two following groups: (i) everolimus + exemestane arm plus everolimus monotherapy arm, 


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and (ii) everolimus + exemestane arm plus capecitabine monotherapy arm, the frequency of 
tumor assessments will be changed to every 12 weeks or as clinically indicated.
Based on the interim analysis results and DMC recommendation, the everolimus monotherapy 
arm might be stopped early. If this scenario happens before all patients are randomized, the 
ratio of 1:1:1 randomization will no longer be kept. The remaining patients will be 
randomized in 1:1 ratio to receive everolimus in combination with exemestane or capecitabine 
monotherapy.
4.1.3
Follow-up phase
Patients will be followed for safety for 30 days after study treatment discontinuation. If a 
patient did not discontinue study treatment due to disease progression, lost to follow-up or 
consent withdrawal, then tumor assessments should continue to be performed every 6 weeks 
until disease progression, death, lost to follow-up or investigator decision in patient best 
interest.
4.1.3.1
Survival data collection
All patients will be followed for survival status at least every 3 months regardless of treatment 
discontinuation reason. Survival follow-up data collection will be stopped at the time of the 
final PFS analysis. The final PFS and OS analyses will use the same data cut-off date. 
Survival information can be obtained via phone and information will be documented in the 
source documents and eCRF. Additional survival follow-up may be performed more 
frequently if a survival update is required for reporting the results or to meet safety or 
regulatory needs.
4.2
Interim analysis
One efficacy interim analysis will be conducted, which will allow early termination of the 
everolimus monotherapy arm, in case of far inferior efficacy as compared to the everolimus + 
exemestane combination treatment arm. A general guidance is to stop everolimus 
monotherapy arm if the observed hazard ratio is less than 0.20. The efficacy interim analysis 
is planned after 75 PFS events have been observed as per local tumor assessment, across the 
following 2 arms: everolimus monotherapy and everolimus + exemestane combination arm.
Please refer to Section 10 for more details. Capecitabine has been approved by the regulatory 
authorities for breast cancer indication as part of Standard of Care, and treatment with 
capecitabine for patients in this study will be followed per its local label. Therefore, 
capecitabine treatment will not be terminated early and no interim analysis between 
capecitabine monotherapy arm and everolimus + exemestane combination therapy is 
warranted. Following review of the efficacy results at the interim analysis, DMC might 
recommend to stop the monotherapy everolimus arm early. In that case, patients on the 
everolimus arm will have the option to receive everolimus + exemestane combination 
treatment at investigator’s discretion in patient best interest. No further efficacy assessments 
will be required for those patients. However, safety, end of treatment, and safety follow up 
visits will be conducted, as per protocol.


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4.3
Timing of final primary analysis
The study will be analyzed for PFS related objectives when approximately 150 PFS events per 
local tumor assessment have been documented in each of the two following groups:
a. the everolimus + exemestane arm combination arm plus the everolimus monotherapy arm, 
and
b. the everolimus + exemestane arm combination arm plus the capecitabine monotherapy 
arm.
The expected time to observing 150 PFS events in each of the two groups (a. and b.) is about 
28 months after randomization of the first patient (see Section 10 for further details).
4.4
Definition of end of the study
The definition of the end of the study will be the date of the last visit of the last patient.
4.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible (for 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 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast 
cancer after recurrence or progression on prior letrozole or anastrozole.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who have discontinued this study may not be 
re-enrolled.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Women with locally advanced, recurrent, or metastatic breast cancer. Locally advanced 
breast cancer is not amenable to curative treatment by surgery or radiotherapy.
2. Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer


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3. Postmenopausal women. Postmenopausal status is defined either by:

Age ≥ 18 with prior bilateral oophorectomy

Age ≥ 60 years

Age <60 years with amenorrhea for at least 12 months and both follicle-stimulating 
hormone (FSH) and estradiol levels are in postmenopausal range (according to the 
local laboratory)
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone 
(LHRH) agonist (goserelin acetate or leuprolide acetate) does not satisfy this 
inclusion criterion.
4. Recurrence or progression on prior NSAIs is defined as:

Recurrence while on, or within one year (365 days) of end of adjuvant treatment with 
letrozole or anastrozole
OR

Progression while on, or within one month (30 days) of the end of, prior treatment 
with letrozole or anastrozole for ABC
Notes:

Letrozole or anastrozole do not have to be the last treatment prior to randomization

Patients must have recovered to grade 1 or better from any adverse events (except 
alopecia) related to previous therapy prior to randomization
5. Radiological or objective evidence of recurrence or progression on or after the last 
systemic therapy prior to randomization
6. Patients must have either:

Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be 
accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm)
OR

Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as 
defined above
Notes:

Lymph nodes have to be 15 mm in short axis to be considered measurable

If bone lesions have been previously irradiated, at least one lesion must have clearly 
progressed since the radiotherapy by CT, MRI or x-ray for trial entry (in absence of 
measurable disease)
7. Adequate bone marrow and coagulation function as shown by:

Absolute neutrophil count (ANC) ≥ 1.5 109/L

Platelets ≥ 100 ×109/L

Hemoglobin (Hgb) ≥ 9.0 g/dL

INR ≤ 2


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8. Adequate liver function as shown by:

Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 
ULN (or ≤ 5 if hepatic metastases are present).

Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert
Syndrome)
9. Adequate renal function as shown by serum creatinine ≤ 1.5 × ULN and creatinine 
clearance > 60 ml/min. Creatinine clearance will be calculated using the Cockroft-Gault 
formula.
10. Fasting serum cholesterol ≤ 300 mg/dl and fasting triglycerides ≤ 2.5 x ULN
11. ECOG Performance Status ≤ 2
12. Left ventricular ejection fraction assessment (echocardiogram or MUGA scan) performed 
within 4 weeks prior to randomization, showing a LVEF value ≥ LLN
13. Signed written informed consent must be obtained before any screening procedure or 
study related activities are performed and according to local guidelines.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ 
hybridization positive), based on the most recent test. Note: Patients with IHC 2+ must 
have a negative in situ hybridization test
2. Patients who received more than one chemotherapy line for ABC
Note: A chemotherapy line in advanced disease is an anticancer regimen that contains at 
least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic 
chemotherapy regimen was discontinued for a reason other than disease progression and 
lasted less than 21 days, then this regimen does not count as a "prior line of 
chemotherapy". Chemotherapy regimens composed of more than one drug are considered 
as one line of therapy.
3. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) 
bone metastasis (e.g. pleural effusion, ascites etc.)
4. Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors.
5. Patients who received a fluoropyrimidine-containing regimen as a prior chemotherapy 
treatment within 24 weeks prior to randomization
6. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin) or known
hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil
7. Patients with known rare hereditary problems of galactose intolerance, the lapp lactase 
deficiency, glucose-galactose malabsorption or dihydropyrimidine dehydrogenase (DPD) 
deficiency.
8. Another malignancy within 5 years prior to randomization, with the exception of 
adequately treated: in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma, 
non-melanomatous cancer of skin or history of stage IA melanoma that has been cured.
9. Radiotherapy within four weeks prior to randomization except in case of localized 
palliative radiotherapy (for analgesic purpose) or for lytic lesions at risk of fracture which 


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was completed at least two weeks prior to randomization. Patients must have recovered 
from radiotherapy toxicities.
Note: Lesions in previously irradiated areas should not be considered measurable, unless 
they have clearly progressed since the radiotherapy. If lesions in previously irradiated 
areas have not progressed since the radiotherapy, they should be considered non-
measurable and followed as non-target lesions
10. Currently receiving any hormone replacement therapy, unless discontinued prior to 
randomization.
11. Current or history of CNS metastases. Patients with symptoms suggestive of CNS 
metastases should have a CT/MRI to rule out CNS metastasis prior to randomization to be 
eligible.
12. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use 
at the time of study entry except topical applications, inhaled sprays, eye drops or local 
injections.
13. Bilateral diffuse lymphangitic carcinomatosis
14. Patients with a known history of HIV seropositivity. Screening for HIV infection at 
baseline is not required.
15. Active, bleeding diathesis, or on oral anti-vitamin K medication (except LMWH and 
acetylsalicylic acid or equivalent, as long as the INR is ≤2).
16. Any severe and / or uncontrolled medical conditions.
17. Patients being treated with drugs recognized as being strong inhibitors or inducers of the 
isoenzyme CYP3A (e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, 
Itraconazole, Voriconazole, Ritonavir, Telithromycin) continuously for at least 7 days 
during any time period in the last 2 weeks prior to randomization
18. Patients being treated with coumarin-derivate anticoagulants such as warfarin and 
phenprocoumon
19. Patients under treatment with sorivudine or its chemically related analogues, such as 
brivudine, or those who discontinue this treatment less than 4 weeks prior to 
randomization
20. History of noncompliance to medical regimens
21. Patients unwilling to or unable to comply with the protocol


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6
Treatment
6.1
Study treatment
The investigational therapies in the context of this study are everolimus monotherapy and 
capecitabine monotherapy. The control therapy is everolimus + exemestane combination 
therapy.
Study treatment is defined as everolimus + exemestane, everolimus monotherapy or 
capecitabine monotherapy. All study drugs are open label and defined as everolimus, 
exemestane and capecitabine.
Patients who terminated everolimus monotherapy early, per DMC recommendation based on 
the efficacy interim analysis results (if applicable), will be provided with an option to receive 
the everolimus + exemestane combination treatment at investigator’s discretion in patient best 
interest. No further efficacy assessments will be required for those patients. However, safety, 
end of treatment, and safety follow up visits will be conducted, as per protocol.
6.1.1
Dosing regimen
Patients will be randomly assigned with equal allocation to one of the treatment arms below:
a. Everolimus in combination with exemestane
b. Everolimus monotherapy
c. Capecitabine monotherapy
Table 6-1
Dose and treatment schedule
Study drugs
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
Everolimus
Tablets for oral use
10 mg (2 × 5 mg)
Daily
Exemestane
Tablets for oral use 
25 mg
Daily
Capecitabine
Tablets for oral use
1250 mg/m2
Twice daily for 2 weeks 
followed by one week rest (3-
week cycle)
Everolimus (RAD001) will be self-administered by continuous oral daily dosing of 2 × 5 mg 
tablets. Everolimus should be taken at the same time every day. Everolimus tablets should be 
swallowed whole with a glass of water once daily, either consistently with food or 
consistently without food. Tablets should not be chewed or crushed.
Capecitabine and exemestane will be self-administered as described in Table 6-1 in 
accordance with the local label in participating countries.
Everolimus 10 mg (2 x 5 mg) and exemestane 25 mg should be taken together at the same 
time every day.
If patients realize they missed a dose of study medications (everolimus, exemestane) within 6 
hours following the scheduled dosing time point, they should take the missed dose of the 
study medication(s). If patients realize they missed a dose more than 6 hours following the 


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scheduled dosing time point, then patients should skip the missed dose(s). For missing dose of 
capecitabine, please refer to the local product information.
6.1.2
Study drug supply
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the study medication specific Dosage Administration Record CRF.
Everolimus is formulated as tablets of 5 mg strength and will be provided centrally by 
Novartis. Medication label for everolimus will comply with the legal requirements of each 
country and be printed in local language. The storage conditions for study drug will be 
described on the medication label.
Commercially available exemestane and capecitabine will be supplied locally in accordance 
with local regulations in participating countries, or centrally supplied by Novartis where 
applicable.
Table 6-2
Packaging and labeling
Study drug
Packaging
Labeling (and dosing frequency)
Everolimus
Tablets in blister packs
Labeled as Everolimus; 2× 5 mg
tablets to be taken orally
Exemestane
Refer to local product information1
25 mg tablets to be taken orally. 
Refer to local product information
Capecitabine
Refer to local product information1
1250 mg/m2 tablet to be taken 
orally. Refer to local product 
information1
1 Commercially available exemestane and capecitabine may be centrally supplied by Novartis in case the product 
is not available locally.
Study drugs must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and
designated site personnel have access. Upon receipt, the study treatment should be stored
according to the instructions specified on the drug labels.
Table 6-3
Supply and storage of study drugs
Study drug
Supply
Storage
Everolimus
Centrally supplied by Novartis
Refer to the study drug label
Exemestane 
Locally supplied 
Refer to local product information
Capecitabine
Locally supplied 
Refer to local product information1
1 Commercially available exemestane and capecitabine may be centrally supplied by Novartis in case the product 
is not available locally.


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6.1.3
Treatment duration
Eligible patients will receive either: everolimus monotherapy, capecitabine monotherapy or 
everolimus in combination with exemestane. All treatments will be open label. Patients will 
start taking their first dose of medication at Day1, and continue to receive study treatment 
until disease progression, intolerable toxicity, withdrawal of consent or investigator decision 
in patient’s best interest.
6.2
Dose modifications
6.2.1
Dose modifications in the management of adverse reactions
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment, refer to the Section 
6.2.1.1, Section 6.2.1.2, and Section 6.2.1.3.
Note: If the study medication in either everolimus or capecitabine monotherapy arm is
discontinued for more than 4 consecutive weeks due to treatment related toxicities, the patient 
will permanently discontinue that study medication. If either one of the study medications in
the everolimus + exemestane arm is discontinued for more than 4 consecutive weeks due to 
treatment related toxicities, the patient will permanently discontinue that study medication, 
and should continue with the another one until disease progression, intolerable toxicity or 
withdrawal of patient consent.
6.2.1.1
Everolimus
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption of everolimus therapy. If dose reduction is required, the suggested dose is 
approximately 50% lower than the daily dose previously administered.
If a patient already had 2 levels of dose reduction, no further dose reduction is permitted.
Patients who interrupt study treatment for more than 4 weeks must discontinue from the study
or the study medication (in combination arm if applicable).
Recommendations for dose reduction, interruption or discontinuation of everolimus in the 
management of adverse reactions are summarized in Table 6-4, Table 6-5 and Table 6-6.
Table 6-4
Recommendation of everolimus dose reductions
Dose level
Dose and schedule
0 = starting dose 10 mg
10 mg daily (2 × 5 mg daily)
-1 dose level
5 mg daily
-2 dose level
5 mg every other day


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Table 6-5
Everolimus dose adjustment and management recommendation for 
adverse reactions
Adverse Drug 
Reaction
Severitya
Everolimus Dose Adjustmentb and Management 
Recommendations
Non-infectious 
pneumonitis
Grade 1
Asymptomatic,
radiographic findings only
No dose adjustment required.
Initiate appropriate monitoring.
Grade 2
Symptomatic,
not interfering with ADLc
Consider interruption of therapy, rule out infection and 
consider treatment with corticosteroids until symptoms 
improve to grade 1.
Re-initiate everolimus at a lower dose.
Discontinue treatment if failure to recover within 4 wks.
Grade 3
Symptomatic,
interfering with ADLc;
O2 indicated
Interrupt everolimus until symptoms resolve to grade1.
Rule out infection, and consider treatment with corticosteroids.
Consider re-initiating everolimus at a lower dose. If toxicity 
recurs at grade 3, consider discontinuation.
Grade 4
Life-threatening,
ventilatory support 
indicated
Discontinue everolimus, rule out infection, and consider 
treatment with corticosteroids.
Stomatitis
Grade 1
Minimal symptoms,
normal diet
No dose adjustment required.
Manage with non-alcoholic or salt water (0.9%) mouth wash 
several times a day.
Grade 2
Symptomatic but can eat 
and swallow modified diet
Temporary dose interruption until recovery to grade 1.
Re-initiate everolimus at the same dose.
If stomatitis recurs at grade 2, interrupt dose until recovery to 
grade 1. Re-initiate everolimus at a lower dose.
Manage with topical analgesic mouth treatments (e.g. 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol or phenol) with or without topical corticosteroids (i.e. 
triamcinolone oral paste).d
Grade 3
Symptomatic and unable 
to adequately eat or 
hydrate orally
Temporary dose interruption until recovery to grade 1.
Re-initiate everolimus at a lower dose.
Manage with topical analgesic mouth treatments (i.e. 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol or phenol) with or without topical corticosteroids (i.e. 
triamcinolone oral paste).d
Grade 4
Symptoms associated 
with life-threatening 
consequences
Discontinue everolimus and treat with appropriate medical 
therapy.


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Adverse Drug 
Reaction
Severitya
Everolimus Dose Adjustmentb and Management 
Recommendations
Other non-
hematologic 
toxicities
(excluding 
metabolic events)
Grade 1
If toxicity is tolerable, no dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2
If toxicity is tolerable, no dose adjustment required.
Initiate appropriate medical therapy and monitor.
If toxicity becomes intolerable, temporary dose interruption 
until recovery to grade 1. Re-initiate everolimus at the same 
dose.
If toxicity recurs at grade 2, interrupt everolimus until recovery 
to grade 1. Re-initiate everolimus at a lower dose.
Grade 3
Temporary dose interruption until recovery to grade 1.
Initiate appropriate medical therapy and monitor.
Consider re-initiating everolimus at a lower dose. If toxicity 
recurs at grade 3, consider discontinuation.
Grade 4
Discontinue everolimus and treat with appropriate medical 
therapy.
Metabolic events
(e.g. 
hyperglycemia, 
dyslipidemia)
Grade 1
No dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2
No dose adjustment required.
Manage with appropriate medical therapy and monitor.
Grade 3
Temporary dose interruption.
Re-initiate Afinitor at a lower dose.
Manage with appropriate medical therapy and monitor.
Grade 4
Discontinue everolimus and treat with appropriate medical 
therapy.
a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-
threatening symptoms.
b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously 
administered.
c Activities of daily living (ADL)
d Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.


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Table 6-6
Dose modification guidelines for hematologic toxicities
Toxicity
Actions
Thrombocytopenia
Platelet count
≥ 75000/mm3: No change
50000/ mm3 to 75000/ mm3
Hold everolimus treatment until recovery to ≥
75000/mm3
Reintroduce everolimus at the same dose level
< 50000/ mm3
Hold everolimus treatment until recovery to ≥
75000/mm3
Reintroduce everolimus at the next lower dose level, if available.
Absolute Neutrophil count (ANC)
≥ 1000/ mm3:
No change
500/ mm3 to 1000/ mm3
Hold everolimus treatment until recovery to ≥ 1000/ mm3
Reintroduce everolimus at the same dose level
< 500/ mm3
Hold until recovery to ≥ 1000/ mm3.
Reintroduce everolimus at the next lowest dose level, if available.
Febrile neutropenia
Hold further dosing until ANC ≥ 1250/mm3 and no fever.
Then resume dosing at the next lower dose level if available.
Toxicity requiring interruption for > 4 weeks
Permanently discontinue everolimus treatment
Physicians should always manage patients according to their medical judgment based on the particular clinical 
circumstances.
Management of skin toxicity
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenphydramine, oral prednisolone (short course) topical corticosteroids or pimecrolimus.
6.2.1.2
Capecitabine
Local label should be used for capecitabine dose modifications for the management of adverse 
reactions or as described in Table 6-7.


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Table 6-7
Recommended Dose Modifications of Capecitabine
Toxicity*
During a course of therapy
Dose adjustment for next
treatment (% of starting 
dose)
Grade 1
Maintain dose level.
Maintain dose level.
Grade 2
1st appearance
Interrupt until resolved to grade 0-1.
100%
2nd appearance
75%
3rd appearance
50%
4th appearance
Discontinue treatment permanently.
-
Grade 3
1st appearance
Interrupt until resolved to grade 0-1.
75%
2nd appearance
50%
3rd appearance
Discontinue permanently.
-
Grade 4
1st appearance
Discontinue permanently 
OR
If physician deems it to be in the patient's best 
interest to continue, interrupt until resolved to 
grade 0-1.
50%
* Common Terminology Criteria for adverse events v4.0 or toxicity management per local label was used, except 
for the hand-and-foot syndrome 
6.2.1.2.1 Adjustment of Starting Dose in Special Populations
Renal Impairment
No adjustment to the starting dose of capecitabine is recommended in patients with mild renal 
impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). 
Dose reduction should be made if grade 2 to 4 adverse events occurred, Table 6-7.
Cockroft and Gault Equation:
(140 - age [yrs]) (body wt [kg])
Creatinine clearance for males =
—————————————
(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 × male value
Elderly
For capecitabine monotherapy, no adjustment in starting dose is needed. However, sever 
Grade 3 or 4 treatment-related adverse events were more frequent in patients ≥ 60 years old 
compared to younger patients. Careful monitoring of elderly patients is advisable.
Hepatic Impairment due to Liver metastasis
Patients with mild or moderate hepatic impairment due to liver metastasis should be 
monitored carefully while administered capecitabine. No starting dose reduction is necessary.


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6.2.1.3
Exemestane
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, 
hot flushes, arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects 
include headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and 
peripheral and leg edema. Thrombocytopenia and leucopenia have been reported occasionally. 
Reductions in bone mineral density can occur with long-term use of exemestane.
Exemestane was generally well tolerated, and adverse events were usually mild to moderate. 
Adverse events occurring in greater than 10% of patients include hot flushes (14%), nausea 
(11.9%), insomnia, headache, increased sweating, joint and musculoskeletal pain, and fatigue 
(USPI; Aromasin SmPC August 2008 (UK as RMS for EU MRP)). Androgenic effects were 
reported in a limited number of patients (4.3%) (Buzdar 2003).
Refer to the package insert of the local supply of exemestane for more details.
6.2.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event. All patients will 
be followed for onset of any new serious adverse events for 30 days following the last dose of 
study treatment.
6.3
Concomitant medications
All medications and non-drug therapies taken within 30 days prior to starting study treatment 
should be reported on the Concomitant Medication/Significant Non-drug Therapy eCRF. The 
investigator should instruct the patient to notify the study site about any new medications 
(including over-the-counter drugs and herbal/alternative medications) he/she takes after the 
start of study treatment. Patients must be instructed not to take any additional medications 
(including over-the-counter products and herbal/alternative medications) during the trial 
without prior consultation with the investigator. All medications (other than study treatments) 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts study treatment must be listed on the Concomitant 
medications/Significant non-drug therapy eCRF.
6.3.1
Prohibited concomitant therapy and concomitant therapy requiring 
caution and/or action
The following concomitant treatments are not allowed during the study:

Investigational or commercial anticancer agents, such as chemotherapy, immunotherapy, 
targeted therapy, biological response modifiers, or endocrine therapy other than 
exemestane (including steroids) should not be given to patients.

Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (e.g. raloxifene) are 
prohibited.


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
Prolonged systemic corticosteroid treatment, except for topical applications (e.g. rash), 
inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-
articular) should not be given. A short duration (<2 weeks) of systemic corticosteroids is 
allowed (e.g. chronic obstructive pulmonary disease, anti-emetic).

Hematopoietic growth factors (e.g. erythropoietins, G-CSF and GM-CSF) are not to be 
administered prophylactically. Use of these should be reserved to cases of severe 
neutropenia and anemia as per the labeling of these agents.

Oral coumarin-derivate anticoagulants such as warfarin and phenprocoumon should be 
avoided in patients receiving capecitabine as study treatment. If patient needs to take 
coumarin-derivate anticoagulants anticoagulant response (INR or protrombin time) should 
be monitored frequently in order to adjust the anticoagulant dose based on Xeloda 
prescribing information. Altered coagulation parameters and / or bleeding, including 
deaths have been reported during concomitant use.

Aluminium hydroxide- and magnesium hydroxide-containing antacid (such as Maalox) 
should not be administrated immediately after capecitabine because of their effect on the 
pharmacokinetics of capecitabine.
It is to be noted that:

Use of bisphosphonate or denosumab for osteoporosis and management of bone 
metastases are allowed for approved indications as per local label. Chronic concomitant 
bisphosphonate therapy for the prevention of bone metastases are not permitted during the 
study.
Please refer to prescribing information for details of administration. If 
bisphosphonate therapy is initiated after randomization, the reason for its use must be 
clearly documented.

Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required. Whenever possible, these patients should have a tumor assessment 
of the lesion(s) before they actually receive the radiotherapy. No dose modification of 
study treatment is needed during radiotherapy.

Everolimus may affect the response to vaccinations making it less effective. Live vaccines 
should be avoided while a patient is treated with everolimus.

The level of phenytoin should be carefully monitored in patients receiving capecitabine 
and phenytoin dose may need to be reduced based on Xeloda prescribing information.
6.3.1.1
CYP3A4, CYP2C9 and P-glycoprotein inhibitors/inducers/substrates
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Capecitabine and its metabolites do not inhibit the metabolism of CYP3A4 substrates but 
capecitabine and/or its metabolites may inhibit the metabolism of CYP2C9 substrates.
Therefore:

Co-administration of CYP2C9 substrates (e.g. Irbesartan, Losartan, Phenytoin, 
Cyclophosphamide) should be exercised with caution and monitored closely per 
capecitabine local label.

Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or should be avoided.


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
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution.

Seville orange, star fruit, grapefruit and their juices affect CYP3A4 and PgP activity. 
Concomitant use should be avoided.

Avoid the use of strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, 
rifabutin, phenobarbital, St. John’s wort), Please refer to Table 6-8 listing relevant
inducers and inhibitors of CYP3A and to Table 6-9 for a list of relevant substrates, 
inducers, and inhibitors of PgP.
Note: Most of PgP inhibitors/inducers are also inhibitors/inducers of CYP3A4. In case the 
drug is not listed on Table 6-9 below, refer to the list of CYP3A modifiers (Table 6-8) and 
apply the same classification specified therein to the concerned PgP inhibitor/inducer. In the
rare case the PgP inhibitor/inducer cannot be found in either Table 6-8 or Table 6-9, then 
consider the drug as a strong PgP inhibitor and follow the guidance as per the stated above.
Table 6-8
Clinically relevant drug interactions: inducers and inhibitors of 
isoenzyme CYP3A
Inducers
Strong inducers:
avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s wort 
(Hypericum perforatum)
Moderate inducers:
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, talviraline, thioridazine,
tipranavir
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole (Krishna et al 2009), ritonavir, saquinavir, 
saquinavir, telaprevir, telithromycin, tipranavir, troleandamycin, voriconazole
Moderate inhibitors:
amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (Citrus parasidi fruit 
juice), imatinib, Schisandra sphenanthera, tofisopam, verapamil
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct 2, 2011, 
which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the University of Washington’s Drug Interaction Database, and Indiana University 
School of Medicine's Drug Interaction Table.


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Table 6-9
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A dual inhibitors
Substrates
colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, vincristine
Inducers
rifampin, St John’s wort
PgP Inhibitors and PgP/CYP3A Dual Inhibitors
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (Ginkgo biloba), indinavir, 
itraconazole, lopinavir, mibefradil, milk thistle (Silybum marianum), nelfinavir, nifedipine, nitrendipine, 
paroxetine, quercetin, quinidine, ranolazine, ritonavir, saquinavir, Schisandra chinensis, St John’s wort 
(Hypericum perforatum), talinolol, telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, 
verapamil
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, 
which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the University of Washington’s Drug Interaction Database, and Indiana University 
School of Medicine's Drug Interaction Table.
6.3.2
Study drug compliance and accountability
6.3.2.1
Study drug compliance
Records of study drug administration will be kept at the study and recorded in the Dosage 
Administration Record eCRF(s).
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient or caregiver. This information should be 
captured in the source document at each visit for study drugs (everolimus, exemestane and 
capecitabine).
To accurately record the administration of study treatments, the following information must 
be recorded in the Dosage Administration Record eCRF page throughout the study:

Planned dose administration

Actual total dose administered

Regimen

Start/End date of drug administration

Dose change/delay and reason for such
6.3.2.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.


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At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.3.3
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which data are entered into the database (D) or remain in 
source documents only (S). Assessments that generate data for database entry and which are 
recorded on eCRFs are listed using the eCRF name. Assessments that are transferred to the 
database electronically (e.g., laboratory data) are listed by test name.
No CRF will be used as a source document.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section
Screening
Baseline
Day 1 3 wks 6 wks 12 wks Every 6 
wks
End of treatment 
(EOT)
Post-treatment 
Evaluation
Study 
Evaluation 
Completion 
(SEC)
Survival 
follow up
Every 3 
months
EOT+30 
days
FU
Visit Window
±7 Days
+14 days after 
ending study drug
Visit no.
1
2
3
4
5
6
7, 8, etc 777
501
502, 
503
etc
778
Treatment days
-28 to -1 -7 to -1 1
21
42
84
Screening
Obtain Informed Consent
D
7.1.1,
11.3
X
IRT Registration (after ICF 
signed)
7.1.1
X
Patient history
Demography
D
7.1.1.3
X
Inclusion/exclusion criteria
D,S
5.2 / 5.3
X
Relevant Medical 
history/current medical 
conditions
D
7.1.1.3
X
ECG
D
7.2.2.7.1
X
Only performed if clinically indicated
Cardiac Imaging 
(MUGA/ECHO)
D
7.2.2.7.2
X
Only performed if clinically indicated
Diagnosis and extent of cancer D
7.1.1.3
X
HER2 and HR status
D
5.2
X
Smoking history
D
7.1.1.3
X


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Category
Protocol 
Section
Screening
Baseline
Day 1 3 wks 6 wks 12 wks Every 6 
wks
End of treatment 
(EOT)
Post-treatment 
Evaluation
Study 
Evaluation 
Completion 
(SEC)
Survival 
follow up
Every 3 
months
EOT+30 
days
FU
Visit Window
±7 Days
+14 days after 
ending study drug
Visit no.
1
2
3
4
5
6
7, 8, etc 777
501
502, 
503
etc
778
Treatment days
-28 to -1 -7 to -1 1
21
42
84
Prior antineoplastic therapy 
(surgery, radiotherapy, 
medications)
D
7.1.1.3
X
Prior/concomitant medications D
7.1.1.3
X
X
X
X
X
X
X
X
X
Screening log
D
7.1.1.2
7.1.1.3
X
Pre-randomization Form
S
7.1.1.1
X
Randomization
IRT - Randomization
7.1.1.4
X
Physical examination
S
7.2.2.2
X
X
X
X
X
X
X
Weight
D
7.2.2.2
X
X
X
X
X
X
X
Height
D
7.2.2.2
X
Vital signs
D
7.2.2.3
X
X
X
X
X
X
X
ECOG Performance status
D
7.2.2.4
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.6
X
X
X
X
X
X
Chemistry
D
7.2.2.6
X
X
X
X
X
X
Lipid Panel
D
7.2.2.6
X
X
X
X
X
Coagulation
D
7.2.2.6
X


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Category
Protocol 
Section
Screening
Baseline
Day 1 3 wks 6 wks 12 wks Every 6 
wks
End of treatment 
(EOT)
Post-treatment 
Evaluation
Study 
Evaluation 
Completion 
(SEC)
Survival 
follow up
Every 3 
months
EOT+30 
days
FU
Visit Window
±7 Days
+14 days after 
ending study drug
Visit no.
1
2
3
4
5
6
7, 8, etc 777
501
502, 
503
etc
778
Treatment days
-28 to -1 -7 to -1 1
21
42
84
Urinalysis
D
7.2.2.6
X
Hepatitis B and C 
screening/monitoring (if 
applicable)
D
4.1.1
7.2.2.5
X
X
X
X
X
Tumor assessments
D
7.2.1
X
X
X
X
X
X
Safety
Adverse events
D
7.2.2.1
X
X
X
X
X
X
X
X
X
Pulmonary Function Tests 
(PFTs)
D
7.2.2.8
Not mandatory - can be performed at screening or baseline (prior to 
administration of first dose), during the trial if clinically indicated, and if 
warranted to exclude or manage non-infection pneumonitis
Patient Reported Outcome (PRO)
EORTC (QLQ-C30)
D
7.2.4
X
X
X
X
X
X
EORTC module (BR23)
D
7.2.4
X
X
X
X
X
X
TSQM
D
7.2.4
X
X
X
X


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Category
Protocol 
Section
Screening
Baseline
Day 1 3 wks 6 wks 12 wks Every 6 
wks
End of treatment 
(EOT)
Post-treatment 
Evaluation
Study 
Evaluation 
Completion 
(SEC)
Survival 
follow up
Every 3 
months
EOT+30 
days
FU
Visit Window
±7 Days
+14 days after 
ending study drug
Visit no.
1
2
3
4
5
6
7, 8, etc 777
501
502, 
503
etc
778
Treatment days
-28 to -1 -7 to -1 1
21
42
84
Treatments (First dose within 7 days after baseline visit)
Everolimus + Exemestane
OR
Everolimus
OR
Capecitabine
D
6.1.1
10 mg daily + 25 mg daily
D
6.1.1
10 mg 
D
6.1.1
1250 mg/m2 twice daily for 2 weeks 
and 1 week rest
Discontinuation
IRT - Progression/ 
discontinuation/ Death
7.1.3
X
Antineoplastic therapies since 
discontinuation of study
treatment
D
7.1.4
X
Survival Follow-up - At least 
every 3 months (may be via 
phone contact)
D
7.1.5
X


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7.1.1
Screening and baseline
Written informed consent must be obtained before any study specific medical procedures are
performed.
The investigator is obliged to give the patient thorough information about the study and the 
study related assessments and she should be given ample time to consider her participation. If 
a patient is unable to read, an impartial witness should present during the entire informed 
consent discussion. The original signed informed consent should be kept in the patient’s 
source records and a photocopy of the signed consent should be provided to the patient.
For details on the screening assessments please refer to Table 7-1.
Patient Number:
Each patient in the study is uniquely identified by a 9 digit patient number which is a 
combination of his/her 4-digit center number and 5-digit subject number. The center 
number is assigned by Novartis to the investigative site.
Upon signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 
2; the third patient is assigned patient number 3). The investigator or his/her staff will access 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. Once assigned to a patient, the patient number will not be reused. If the patient fails 
to be randomized, the IRT must be notified within 2 days why the patient was not randomized.
To enter a patient into study:

Obtain written consent and complete all the screening and baseline evaluations

Pre-randomization form must be completed by site and sent to Novartis for approval prior 
to randomizing patient via IRT.

Assign a 9-digit patient identifier (consisting of a 4-digit center number and 5-digit patient 
number).

Contact and provide the IRT with the patient information for registration purposes.
7.1.1.1
Eligibility screening
Patient eligibility will be checked by the Sponsor once all screening and baseline procedures 
are completed. The Patient Pre-randomization Form will be sent from the site to the Sponsor 
via email for evaluation. Upon confirmation of eligibility, the Sponsor will return the signed 
form to the site via email. The investigator site will then be allowed to randomize the patient 
to the study via IRT.
Re-screening is allowed, only, for patients who meet all of the inclusion/exclusion criteria, but
were not randomized due to one of the following administrative reasons:


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
CT /MRI results have expired (>28 days prior to randomization) due to unexpected 
administrative issues

Delays in sample processing, damage to the shipped samples and other administrative lab 
related issues.

Unexpected drug supply issues.
Procedure for re-screening is as follows:

Site must register the patient as a screen failure in IWRS

Site is to send a re-screening request to the CRA within 7 days of the screen failure date

Patient number will be the same as the initial screening

Informed consent doesn’t need to be resigned.

Lab assessments needs to be to performed -7 or -1 days before randomization

Adverse events that begin or worsen after informed consent should be recorded in the 
Adverse Events CRF. Conditions that were already present at the time of informed 
consent should be recorded in the Relevant Medical History/Current Medical Conditions 
CRF.

CRA is to review and confirm patient’s eligibility for re-screening with the site.

CRA will forward the request to the global study team using the BOLERO-6 email 
address 
for review/approval

CTH/CM will assess the request and provide an approval for randomization, if all 
eligibility criteria are met, by providing a rescreening-code (4 numbers) to the site.
Patients may be re-screened only once and must be randomized within 28 days after the 
recorded rescreening date. All evaluations including original assessments and repeated 
assessments must be collected on the eCRF.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but are not randomized for any reason will be 
considered a screen failure. The reason for not being randomized will be entered into the 
Screening Log. The demographic information must also be completed for screen failure 
patients.
If the patient fails to be randomized, the IRT must be notified within 2 days that the patient 
was not randomized.
7.1.1.3
Patient demographics and other baseline characteristics
Screening assessments to confirm eligibility must be performed within 28 days prior to 
randomization. The following patient demographic and baseline characteristics will be 
collected on the eCRF:

Demographic information (age, sex, race etc.);

Medical history/current active conditions;

Smoking history


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
History and current disease status (including staging, diagnosis information, previous 
anticancer treatments and sites of disease). The following information must be collected 
for all previous anticancer therapy: Date start, date end, setting (neoadjuvant vs. adjuvant 
vs. therapeutic), best response, reason for treatment discontinuation;

Prior/concomitant medications;

Additionally, the following assessments will be performed:
a. Tumor assessment (Table 7-2);
b. ECG;
c. Left ventricular ejection fraction (LVEF) via ECHO or MUGA
d. Laboratory assessments: HBV and HCV test to be performed by central laboratory.
e. At screening visit, patients listed in Section 4.1.1 should be tested for hepatitis B 
(HBV DNA HBsAg, HBc Ab, and HBs Ab) and HCV RNA-PCR. If the patient is 
already known to have a chronic infection with HBV or HCV and is taking anti-HBV 
medication, the site does not have to wait for the screening HBV or HCV results from 
the central laboratory prior to randomization.
HBV and HCV monitoring should be done as listed in Table 7-4, Table 7-5 and Table 7-6.
Baseline assessments to confirm eligibility must be performed within 7 days prior to the first 
dose of study treatment. Baseline assessments in the study include:

Complete physical examination/neurological exam, vital signs;

ECOG performance status;

Laboratory assessments will be performed by either central or local laboratory : 
hematology, blood chemistries, coagulation, fasting serum lipid profile, urinalysis;

Patient reported outcome (PRO): EORTC QLQ-C30 and QLQ-BR23
In addition, the Screening Log should be completed after screening/baseline assessments are 
performed.
7.1.1.4
Randomization
At Visit 3 (Day 1 visit), all eligible patients will be randomized via IRT to one of the 
treatment arms prior to the first dose of study treatment.
The investigator or his/her delegate will log on to the IRT System 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 everolimus to be dispensed to the 
patient. The randomization number will not be communicated to the caller.
Assignment will be stratified by:

the presence of visceral disease (yes vs. no)
A patient randomization list, produced by Novartis, will be provided 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 
groups, which in turn are linked to the study medication numbers. A separate medication 


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randomization listing will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of the study 
medication numbers to each of the study drugs. The randomization scheme for patients will be 
reviewed and approved by a member of the Biostatistics Quality Assurance Group.
Specific website information and instructions for IRT will be provided separately to each 
study site.
 All assessment 
required at Day 1 must be performed prior to dispending the study medication(s) instructed by 
the IRT to the patient. The first dose of study treatment should be administered on the same 
day as randomization.
7.1.2
Treatment period
Patients will start the study treatment as soon as possible, but not later than 7 days after being 
randomized, and continue to be treated per protocol until documentation of disease 
progression, intolerable toxicity or withdrawal of consent. However, study treatment may 
prematurely be discontinued for other reasons as well. Please refer to Section 7.1.3.2.
For details of assessments required for the treatment period, refer to Table 7-1.
During study treatment, the site personnel must assess study drug (everolimus, exemestane 
and capecitabine) compliance using pill counts at each visit. This information should be 
captured in the source documents. All doses taken by the patient and all dose changes during 
the study must be recorded on the Dosage Administration Record eCRF.
7.1.3
End of treatment visit including study completion and premature 
withdrawal
At the time patients discontinue the study treatment, a visit should be scheduled as soon as 
possible, but not later than 14 days from the last day of study medication, at which time all of 
the assessments listed for the End of Treatment (EOT) visit will be performed. An End of 
Treatment CRF page should be completed, giving the date and reason for stopping the study 
treatment.
7.1.3.1
Study drug discontinuation
The term “discontinuation” refers to a patient’s withdrawal from study treatment (everolimus 
plus exemestane, everolimus or capecitabine).
Patients who receive treatment with everolimus plus exemestane and discontinue everolimus
for any reason other than progression may continue exemestane as part of the trial therapy and 
should follow the protocol safety and efficacy assessments as scheduled in Section 7.1. In rare 
cases, patients who discontinue exemestane for any reason other than progression may 
continue everolimus as part of the trial therapy and should follow the protocol safety and 
efficacy assessments as scheduled.
The patient may discontinue the study treatment for any of the following reasons:


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
Adverse event(s)

Disease progression, defined in Section 7.2.1

Protocol deviation

Subject withdrew consent

Lost to follow-up

Administrative problems

Death

Investigator decision in patient best interest
Patients who discontinue study treatment regardless of the reason must have end of treatment 
evaluation (Refer to Table 7-1, EOT) on the day or within 14 days after the last day of study 
treatment discontinuation. The investigator or his/her designee will proceed as outlined below:

Complete the end of treatment evaluations (additional details are provided in Table 7-1) 
and complete the End of Treatment eCRF page indicating the date and reason for stopping 
the study drug.

Update IRT immediately with everolimus discontinuation and report disease progression 
and/or deaths accordingly.
After the end of treatment visit, there will be additional follow-up on the patient. See Section 
7.1.4 and Section 7.1.5 for further details.

Post-treatment safety follow-up (for 30 days after last dose of study treatment);

Patients who have discontinued study treatment and have not progressed will be followed 
for tumor assessments, ECOG and PRO QLQ-C30 and BR23 every 6 weeks until disease 
progression.

Patients will be followed for overall survival every 3 months Survival follow-up data 
collection will be stopped at the time of the final PFS analysis.If patients who discontinue 
treatment due to “Subject withdrew consent” agree to be followed for progression and/or 
survival, additional data will be collected.
7.1.3.2
Premature withdrawal and study evaluation completion
Patients may voluntarily withdraw from the study treatment or be taken off study treatment at 
the discretion of the investigator at any time.
As a general rule, if a patient discontinues from the study treatment and later is withdrawn 
from the study, the reasons for study evaluation completion may include the following:

Subject withdrew consent

Lost to follow-up

Death

New cancer therapy

Disease progression


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For patients who are lost to follow-up, the investigator 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 investigator must determine the primary reason for 
a patient’s premature withdrawal from the study and record this information on the Study 
Evaluation Completion eCRF.
7.1.4
Follow-up
All patients should be followed up to and including 30 days for safety after study treatment 
discontinuation. Adverse events and SAE information will be collected and recorded in the 
appropriate eCRFs. Record all concomitant medications or therapies used/taken to treat the 
SAEs.
If patients discontinue study treatment for any reason other than progression, lost to follow-up 
or consent withdrawal, the tumor assessments, ECOG performance status and EORTC QLQ 
C30 and BR23 will continue to be performed every 6 weeks until progression, lost to follow-
up, consent withdrawal or investigator decision in patient best interest.
The first antineoplastic medications/therapies given to a patient after the last dose of study 
treatment must be recorded on the eCRF.
7.1.5
Survival follow-up
All patients will be followed for survival status (i.e., phone contacts, visit) at least every 3 
months regardless of treatment discontinuation reason. Survival follow-up data collection will 
be stopped at the time of the final PFS analysis. Final PFS and OS analyses will use the same 
data cut-off date and only one OS analysis will be performed. Survival information will be 
documented in the source documents and eCRF. Additional survival follow up may be 
performed more frequently if a survival update is required for reporting the results or to meet 
safety or regulatory needs.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Tumor assessments
Tumor response will be based on radiological tumor measurements and evaluated locally 
using RECIST Criteria (refer to RECIST 1.1) as described in Appendix 1.
Tumor assessments will occur every 6 weeks after randomization until disease progression 
with a visit window of ±7 days. All patients who discontinue from study drug(s) for any 
reason other than disease progression, lost to follow up and withdrawal of consent from the 
study will continue to have tumor assessments every 6 weeks and until the patient has 
documented disease progression determined by the local radiologist and/or the investigator. 
After approximately 150 PFS events have been documented per RECIST 1.1 by local 
assessment in the combination of the everolimus + exemestane and everolimus alone arms as 
well as in the combination of the everolimus + exemestane and capecitabine alone arms, the 
frequency of tumor assessments will be changed to every 12 weeks or as clinically indicated.


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Patients must meet the following RECIST 1.1 conditions at study entry:

The minimum size of measurable lesions at baseline should be twice the slice thickness of 
the baseline scans

Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be 
accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm)
OR

Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as 
defined above
Notes:

Lymph nodes have to be 15 mm in short axis to be considered measurable

If bone lesions have been previously irradiated, at least one lesion must have clearly 
progressed since the radiotherapy by CT, MRI or x-ray for trial entry (in absence of 
measurable disease)
Clinical lesions (i.e., skin nodules and palpable lymph nodes) will only be considered 
measurable when they are superficial. For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
should not be considered as a measurable lesion in this trial. Blastic bone lesions are non-
measurable. These lesions should be captured as non-target lesions on the appropriate eCRF 
page(s).
In the absence of measurable disease at baseline, patients with bone only lesions (lytic + 
blastic) will be allowed to enter the study and the following will be considered disease 
progression among these patients:

the appearance of one or more new lytic lesions in bone

the appearance of one or more new lesions outside of bone

unequivocal progression of existing bone lesions.
Please refer to Appendix 1 for details regarding the evaluation of response criteria.
Note: If an initial observation of response is made, a confirmation scan (or photography for 
measurable skin lesions) should be obtained at least 4 weeks after the initial observation.


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Table 7-2
Imaging/RECIST Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment/Follow-up
CT or MRI
(Chest, Abdomen, Pelvis)
Mandated
Mandated, every 6 weeks (+/- 7
days).
Whole body bone scan or 
skeletal survey
Mandated
If clinically indicated
Brain CT or MRI (e.g. Brain)
Mandated if symptoms suggestive of 
CNS metastases present
If clinically indicated
Bone X-ray (or CT / MRI)
Mandated during screening period for 
any hot spot or positive finding 
identified by bone scan/skeletal survey 
to confirm bone lesion(s)
Mandated for any confirmed bone 
lesion at screening every 6 weeks 
(+/- 7 days). The same method used 
at screening (for confirmation) 
should be used at each evaluation.
Mandated for any hotspot or positive 
finding identified by bone 
scan/skeletal survey during 
treatment/follow up.
Color photography (with a ruler)
Mandated for any skin lesions at 
screening
Mandated for any skin lesions 
identified at screening every 6 
weeks
7.2.1.2
Radiology procedure
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedure must be implemented at the study center:

All lesions identified at screening (target and non-target) will be reassessed using the same 
method (CT scan with contrast or MRI with contrast etc.) and technique (i.e. for scans, the 
use of contrast, slice thickness etc.) throughout the course of the study so that the basis of 
measurement remains consistent for accurate comparison and determination of disease 
status.

Regarding the use of contrast, at screening (≤ 4 weeks prior to randomization), all patients 
should have a CT scan with contrast or MRI with contrast of the chest, abdominal and 
pelvic area. CT scan without contrast or MRI without contrast may be used for patients 
who are allergic/sensitive to the radiographic contrast media used in CT scans or MRI. 
Ultrasound scans cannot be used to measure tumor lesions.

All CT scans and MRIs obtained on all patients enrolled at the center should be reviewed 
by the local radiologist who together with the investigator will determine the local 
assessment of response and progression. The same radiologist/physician should perform 
the evaluation for the entire duration of the study if possible. All radiology evaluations 
will be performed by the local radiologist. All bone scans and bone imaging (X-ray, CT or 
MRI) obtained from the patient with bone metastases at baseline also should be reviewed 
similarly.


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7.2.2
Safety and tolerability assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs), 
including serious adverse events (SAEs), the regular monitoring of hematology, serum 
chemistry, coagulation, urinalysis, routine monitoring of vital signs (heart rate, blood pressure, 
and body temperature), weight, ECOG performance status, CT scans of the chest, abdominal, 
and pelvic area, physical examinations, cardiac assessments (MUGA scan/ECHO), ECG and 
pulmonary function tests (PFTs) if clinically indicated.
These assessments should be performed ± 7 days of the scheduled day of assessment 
(Table 7-1) except for adverse events and concomitant medications that will be evaluated and 
recorded continuously throughout the study.
Significant findings of any safety evaluation must be recorded either on the Relevant Medical 
History/Current Medical Conditions eCRF (if present before signing informed consent) or on 
the Adverse Events eCRF (if newly occurring or worsening since signing informed consent).
7.2.2.1
Adverse events
An adverse event for the purposes of this protocol is the appearance of (or worsening of any 
pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing 
the informed consent even if the event is not considered to be related to the study drug(s). 
Please refer to Section 6.1 for the protocol-specific definitions of study drug and study 
treatment.
Adverse events will be assessed according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, 
the severity of mild, moderate, severe, and life-threatening, or grades 1 - 4, will be used. 
CTCAE grade 5 (death) will not be used in this study; rather, death information will be 
collected on a separate eCRF page. Adverse event monitoring should be continued for at least 
30 days following the last dose of study treatment.
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Abnormal laboratory values or test 
results constitute adverse events only if they induce clinical signs or symptoms, or require 
therapy (e.g., any hematologic abnormality that requires transfusion or cytokine treatment); 
and should be recorded on the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them. In addition, isolated abnormal laboratory values that cause study 
discontinuation or constitutes in and of itself a Serious Adverse Event should be recorded on 
the Adverse Events eCRF
The occurrence of adverse events should 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, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine:


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1. The severity grade CTCAE grade 1-4
2. Its relationship to each study drug (suspected/not suspected)
3. Its duration (start and end dates or if continuing at final exam)
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization)
5. Whether it is serious, where a serious adverse event (SAE) is defined as one which:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (specify what this includes)

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

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

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
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1.
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, an assessment should be made at each visit (or more frequently, 
if necessary) of any changes in its severity, its suspected relationship to the study drug(s), any
of the interventions required to treat it, and its outcome.
Information about common side effects already known about the investigational drug can be 
found in the [Investigator’s Brochure] or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
7.2.2.2
Physical examination, weight and height
Physical examination must include a total body examination (i.e., general appearance, skin, 
neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes 
and extremities) and a clinical neurological examination.


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Physical examination and weight check will be performed at the following visits:

Baseline (≤ 7 days prior to administration of the study drugs)

Day 1 (prior to administration of the study drugs);

Week 3, week 6 and then every 6 weeks

End of Treatment
Height is measured only at Baseline visit.
Significant findings that are present prior to informed consent must be included in the 
Relevant Medical History / Current Medical Conditions eCRF. Significant findings made after 
the start of study drug which meet the definition of an adverse event must be recorded on the 
Adverse Event eCRF.
7.2.2.3
Vital signs
Body temperature, respiration rate, sitting pulse rate and sitting blood pressure will be 
routinely measured.

Baseline (≤ 7 days prior to administration of the study drugs)

Day 1 (prior to administration of the study drugs)

Week 3, week 6, and every 6 weeks

End of Treatment
7.2.2.4
Performance status
The ECOG performance status Scale Index allows patients to be classified as to their 
functional impairment, the definition of scores in relation to the PS is given in Table 7-2.
ECOG PS will be evaluated at the following visits:

Baseline (≤7 days prior to administration of the study drugs)

Day 1 (prior to administration of the study drugs)

Every 6 weeks

End of treatment
Table 7-3
ECOG Performance Status Scale
Score
Performance 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 housework, 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


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7.2.2.5
Management of Hepatitis reactivation/flare
Monitoring and prophylactic treatment for hepatitis B reactivation
Table 7-4 provides details of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing. If the patient is already known to have a 
chronic infection with HBV and is taking anti-HBV medication, the site does not have to wait
for the screening HBV results from the central laboratory prior to randomization.
Table 7-4
Action to be taken based on Hepatitis B Screening Results
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HBsAg
+ or -
+
-
-
-
HBs Ab
+ or -
+ or -
+
and no prior
HBV vaccination
+ or -
-
or + with prior 
HBV vaccination
HBc Ab
+ or -
+ or -
+ or -
+
-
Recommendation
Prophylaxis treatment should be 
started 1-2 weeks prior to first dose of 
study drug.
Monitor HBV-DNA approximately every 
6 weeks
(from Visit 3 and onwards)
No prophylaxis
Monitor HBV-DNA 
approximately every 6 weeks
(from Visit 3 and onwards)
No specific 
action
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug.
For hepatitis B reactivation, definition and management guidelines see Table 7-5.
Table 7-5
Guidelines for management of hepatitis B
HBV reactivation (with or without clinical signs and symptoms)*
For patients with baseline
results:
Positive HBV-DNA
OR
Positive HBsAg
--------------------------------------
Reactivation is defined as:
[Increase of 1 log in HBV-DNA
relative to baseline HBV-DNA
value OR new appearance of
measurable HBV-DNA]
Treat: Start a second antiviral
AND
Interrupt study drug administration until resolution:
-
≤ baseline HBV-DNA levels
If resolution occurs within 28 days, study drug should be re-started at one 
dose lower, if available. (see Table 6-4- Study drug dose reductions) If the 
patient is already receiving the lowest dose of study drug according to the 
protocol, the patient should restart at the same dose after resolution. Both 
antiviral therapies should continue at least 4 weeks after last dose of study 
drug.
If resolution occurs > 28 days, patients should discontinue study drug but 
continue both antiviral therapies at least 4 weeks after last dose of study 
drug.


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HBV reactivation (with or without clinical signs and symptoms)*
For patients with baseline results:
Negative HBV-DNA and HBsAg
AND
[Positive HBs Ab (with no prior
history of vaccination against
HBV), OR positive HBc Ab]
-------------------------------------
reactivation is defined as:
New appearance of
measurable HBV-DNA
Treat: Start first antiviral medication
AND
Interrupt study drug administration until resolution:
≤ undetectable (negative) HBV-DNA levels
If resolution occurs within 28 days, study drug should be re-started at one 
dose lower, if available. (see Table 6-7 - Study drug dose reductions) If the 
patient is already receiving the lowest dose of study drug according to the 
protocol, the patient should restart at the same dose after resolution. 
Antiviral therapy should continue at least 4 weeks after last dose of study 
drug.
If resolution occurs > 28 days, patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug.
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v4.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in which case they should be recorded as grade 
4 (CTCAE v4.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on which the 
rise or reappearance of HBV- DNA was recorded.
Monitoring for hepatitis C flare
The following two categories of patients should be monitored every 6 weeks for HCV flare:

Patients with detectable HCV RNA-PCR test at screening.

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening(including those that were treated and are considered ‘cured’)
For definition of HCV flare and the management guidelines, see Table 7-6 Guidelines for 
management of hepatitis C. If the patient is already known to have a chronic infection with 
HCV, the site does not have to wait for the screening HCV results from the central laboratory 
prior to randomization.
Table 7-6
Guidelines for management of hepatitis C flare
HCV flare *
For patients with baseline results:
Detectable HCV-RNA,
HCV flare is defined as:
> 2 log10IU/mL increase in HCV-RNA
AND
ALT elevation > 5 x ULN OR 3 x baseline level,
whichever is higher
Discontinue study drug
For patients with baseline results:
Knowledge of past hepatitis C infection with no
detectable HCV-RNA,
HCV flare is defined as:
New appearance of detectable HCV-RNA
AND
ALT elevation > 5 x ULN OR 3 x baseline level,
whichever is higher
Discontinue study drug
*All flares of hepatitis C are to be recorded as grade 3 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Flare),
unless considered life threatening by the investigator; in which case they should be recorded as grade 4 (CTCAE 
v 4.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral flare is the date on which both the clinical 
criteria described above were met (e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 2011 and 
whose ALT reached > 5 x ULN on 22 JAN 2011), the date of viral flare is 22 JAN 2011.


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7.2.2.6
Laboratory evaluations
The standard clinical laboratory analyses described below are to be performed by a central 
laboratory according to the Visit Schedule, outlined in Table 7-1.
Local laboratories may be used during the screening period to determine the eligibility criteria 
for a patient or during study treatment if necessary, although the use of the central laboratory 
is recommended. If local laboratories are used, the following items must be completed:

Local laboratory data must be entered on the appropriate eCRF

The lab normal ranges for each parameter analyzed must be provided to Novartis via the 
lab normal range (LNR) form

A copy of the local laboratory certificate must be provided to Novartis
In addition, 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 for that laboratory.
Abnormal laboratory parameters which are clinically relevant (e.g., require dose modification 
and/or interruption of study drug, lead to clinical symptoms or signs or require therapeutic 
intervention), whether specifically requested in the protocol or not, must be recorded in the 
eCRF. When abnormal laboratory values or test results constitute an adverse event (Section 
7.2.2) it must be recorded on the eCRF Adverse Events page.
The frequency of the assessments is indicated in Table 7-1 and repeated if clinically indicated. 
Dose modifications for abnormal laboratory values are found in Table 6-4, Table 6-5, Table 6-
6 and Table 6-7.
Table 7-7
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells with Differential 
(including Neutrophil count., Basophils count, Eosinophils, Lymphocytes, Monocytes)
Chemistry
Fasting Glucose, Albumin, Total protein, Alkaline phosphatase, ALT (SGPT), AST 
(SGOT), GGT, Sodium, Potassium, Calcium, Creatinine, , Uric Acid, Total Bilirubin, Lipid 
profile: Total Cholesterol, LDL, HDL, Triglycerides, Blood Urea Nitrogen (BUN) or Urea
Urinalysis
Dipstick test: Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, Protein.
Coagulation
International normalized ratio [INR])
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12-lead ECG is to be performed at screening and if clinically indicated during the 
study. Tracings must be dated and signed by the investigator (or his/her designee) and filed 
with the subject’s source documentation. Results from 12-lead ECG should be captured on the 
ECG Evaluation eCRF. Significant findings must be recorded as Relevant Medical History 
/Current Medical Conditions (if present before signing informed consent). ECG may be 
repeated at the discretion of the investigator at any time during the study and as clinically 
indicated, any clinically relevant findings should be added to the Adverse Event eCRF.


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7.2.2.7.2 Cardiac Imaging – MUGA (multiple gated acquisition) scan or 
echocardiogram
MUGA scan or echocardiogram (ECHO) to assess LVEF will be performed at screening. 
Significant findings must be recorded as Relevant Medical History / Current Medical 
Conditions.
If clinically indicated, a post-baseline LVEF assessment may be performed at the discretion of 
the investigator. Any clinically relevant findings should be added to the Adverse Event eCRF. 
The same method (MUGA or ECHO) should be used throughout the course of the study so 
that the basis of assessment remains consistent for accurate comparison.
7.2.2.8
Monitoring for pneumonitis (pulmonary function tests)
Pulmonary function tests can be performed only if clinically indicated. During study treatment, 
all pulmonary function tests (Spirometry, Room air O2 saturation at rest, DLCO) must be 
performed if the patient develops non-infectious pneumonitis according to the management 
guidelines addressed in Table 6-5.
When needed, PFTs must be performed under supervision of trained personnel. Potential lung 
radiological changes can be detected by the Chest CT scans that are performed on all patients 
every 6 weeks for tumor assessment according to the schedule of events (Table 7-1). A 
bronchoscopy with biopsy and/or a bronchoalveolar lavage (BAL) will be performed only 
when medically necessary for ensuring patient care. When non-infectious pneumonitis is 
diagnosed, consultation with a pulmonologist should be considered.
Further details are provided in Section 6.2.1 and Table 6-5.


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7.2.4
Patient reported outcomes
Patient reported outcomes (PRO) will be evaluated using the EORTC QLQ-C30, the breast 
module BR23 questionnaire and Treatment Satisfaction Questionnaire for Medication (TSQM)
version 1.4. The EORTC QLQ-C30 and the module BR23 were developed to assess the 
quality of life of breast cancer patients, while TSQM is to assess patient’s satisfaction with the 
study treatment. Completion of the PRO questionnaires will be dependent on the availability 
of EORTC QLQ-C30, BR23 and TSQM in the local language.
EORTC QLQ-C30 and BR29 will be performed at the following visits:

Baseline

Every 6 weeks during the study treatment

EOT

Every 6 weeks during post-treatment follow-up
TSQM will be performed at the following visits:

Week 3

Week 6

Week 12

EOT
Samples of these questionnaires can be found on the website of the EORTC and PROQOLID 
groups for research into Quality of Lifethe PRO:
http://groups.eortc.be/qol/downloads/modules/specimen_20qlq_c30.pdf (version present as of 
January 2009)
http://groups.eortc.be/qol/downloads/modules/specimen_20qlq_br23.pdf (version present as 
of January 2009)
proqolid.org/instruments/treatment_satisfaction_questionnaire_for_medication_tsqm (version 
present as of May 2012)
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 


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require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Except screening failures, adverse events that begin or worsen after informed consent should 
be recorded in the Adverse Events CRF. Conditions that were already present at the time of 
informed consent should be recorded in the Relevant Medical History/Current Medical 
Conditions CRF. Adverse event monitoring should be continued for at least 30 days following 
the last dose of study treatment. Adverse events (including lab abnormalities that constitute 
AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected on the Death form
or EOT/SEC/Survival information.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates, or ongoing at End of Study)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
or
Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken (none, study drug dosage adjusted/temporarily interrupted, study drug 
permanently discontinued due to this adverse event, hospitalization/prolonged 
hospitalization, unknown)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.


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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
8.1.3.1
Definition
The adverse events of special interest associated with mTOR inhibition include:

Stomatitis

Infections & Infestations

Rash

Non-infectious pneumonitis

Hyperglycemia
In the BOLERO-2 study of postmenopausal women with estrogen receptor positive, locally 
advanced or metastatic breast cancer who were refractory to letrozole or anastrazole, patients 
experienced the following adverse events of special interest in the everolimus + exemestane 
arm of the study:


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Table 8-1
AEs of special interest
Adverse Event
Everolimus + Exemestane (n=482), %
All Grades
Grade 3
Grade 4
Stomatitis
67
8
0
Infections & Infestations 
50
4
2
Rash
44
2
<1
Non-infectious pneumonitis
19
4
<1
Hyperglycemia
15
5
<1
Source: Summary of Clinical Safety (cut-off date: 08-Jul-2011)
For details for the management of the AEs of special interest, please refer to Section 6.2.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 


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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 each 
specific study treatment (if there is more than one study treatment), 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 whom 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, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis 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 any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
This is an open label study.
8.4
Pregnancies
Not applicable.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.


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8.6
Data Monitoring Committee
Data Monitoring Committee (DMC) will be constituted. The DMC will be responsible for the 
overall risk/benefit assessment of the study by reviewing the efficacy results from the interim 
analysis as well as accumulating safety data at regular intervals and being provided access to 
additional efficacy data as requested.
The DMC will consist of at least two oncologists and one biostatistician and will be formed 
prior to randomization of the first patient. Detailed recruitment status and interim safety 
reports will be provided to the DMC on a regular basis. The first DMC meeting will be held 
prior to randomization of the first patient. The first data review will be held when at least one 
month data are available for the first 30 randomized patients. Subsequent data reviews will 
occur every six months unless otherwise requested by the Chairman of the DMC. The DMC 
role will continue until the final analysis of PFS is performed.
The DMC will provide recommendations to the Head of Oncology Global Development at 
Novartis.
The DMC recommendations will include, but not limited to:

No safety or efficacy issues, ethical to continue the trial as planned

Ethical to continue the study but recommend an amendment to the protocol (e.g.,
incorporate an additional safety interim analysis before the next scheduled analysis)

Serious safety concerns precluding further study treatment, regardless of efficacy
In case the DMC recommends continuing the study as planned with the everolimus 
monotherapy arm based on the efficacy interim analysis, the results of this efficacy interim 
analysis will not be revealed until the final analysis.
Further information detailing the membership and operational aspects of the DMC are 
provided in the DMC charter.
8.7
Steering Committee
A Study Steering Committee (SSC) will also be constituted for overseeing the conduct of the 
study and making any necessary recommendations as needed. The SSC will include at least 
four main investigators. Other members may be added after consultation with the SSC 
members. The SSC will also include two Novartis physicians, a statistician and the clinical 
trial head. The details of the role of the Steering Committee will be defined in a Steering 
Committee charter.
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:


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
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.
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.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.


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The study sites will collect the protocol required laboratory samples and will send these 
samples to a Central Laboratory for analysis. Laboratory samples will be processed centrally 
and the results will be transmitted to the investigative staff, to Novartis (or to the designated 
CRO). As needed, blood work done at local laboratories will be collected as unscheduled 
assessments. Documentation (such as certifications and normal ranges) for all local 
laboratories used must be collected for data management. Please refer to the [Central 
Laboratory Manual] for detailed instructions on central laboratory sample collection and 
analysis.
9.3
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff is required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about everolimus treatment dispensed to the patient will be 
tracked using an Interactive Response Technology. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the Global Head of Biostatistics and Data Management and the 
Global Head of Clinical Development.
Since this is EDC study, the investigator will receive a CD-ROM or paper copies of the 
patient data after the database lock for archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from all centers participating in the trial will be combined, so that an 
adequate number of patients is available for analysis. Novartis will perform all the analyses.
The efficacy interim analysis and safety analyses for the DMC meetings will be performed by 
the independent statistician and independent programmer. Any data analyses performed 
independently by any investigator should be submitted to Novartis before publication or 
presentation.


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10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. All primary analyses will be conducted using data from this 
population according to the intent-to-treat (ITT) principle, i.e., patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication and 
have at least one post-baseline safety evaluation. Patients will be analyzed according to the 
study treatment (regimen) they actually received.
Note: the statement that a patient had no adverse events (on the adverse event eCRF) 
constitutes a safety assessment.
The safety analysis for patients who received everolimus monotherapy arm that cross over to 
everolimus + exemestane combination arm (second line medication) will be performed on the 
subset of Safety set patients receiving at least one dose of second line medication. This subset 
will be referred to as Safety set 2nd line (Safety-2L).
10.1.3
Per-protocol Set
Not Applicable
10.1.4
Dose-determining analysis set
Not Applicable
10.2
Patient demographics/other baseline characteristics
Baseline demographic and disease characteristics data will be listed and summarized by 
treatment group using the FAS. Qualitative data such as sex, race, etc. will be presented using 
frequency tables (counts and proportions by category). Relevant descriptive statistics (mean, 
median, minimum, maximum and standard deviation in most cases) will be used to present 
quantitative data.
10.3
Treatments (study treatment, concomitant therapies, compliance)
10.3.1
Study treatment
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
by treatment group. The number of patients with dose changes/interruptions will be presented 
by treatment group, along with reasons for the dose change.


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10.3.2
Concomitant therapies
Concomitant medications and relevant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized by Anatomical Therapeutic Chemical Classification 
System (ATC) term, preferred term and treatment arm by means of frequency counts and 
proportions. 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 relevant non-drug therapies starting and ending prior to 
the start of study treatment will be listed.
The safety set will be used for all aforementioned concomitant medication tables and listings.
10.4
Primary objective
The primary objective of this study is to estimate the hazard ratio of a progression-free 
survival event comparing the everolimus + exemestane combination therapy with the 
everolimus monotherapy in postmenopausal women with ER-positive, HER2-negative, 
advanced breast cancer (ABC) after recurrence or progression on letrozole or anastrozole.
10.4.1
Variable
The primary endpoint in this study is progression-free survival (PFS), defined as the time 
from the date of randomization to the date of first documented progression or death due to any 
cause. If a patient has not had an event, PFS will be censored at the date of the last adequate 
tumor assessment (see RECIST 1.1 in Appendix 1). Disease progression for primary endpoint 
derivation will be assessed using the local (treating center’s) investigator’s/radiologist’s tumor 
assessment.
10.4.2
Statistical model and method of analysis
The primary endpoint, PFS, as determined based on the local tumor assessment, will be 
analyzed using data from the FAS following the ITT principle, i.e., patients will be analyzed 
according to the treatment group they were randomized and the stratum they were assigned to 
at the baseline. Distribution of PFS will be assessed using the Kaplan-Meier estimation 
method. The estimated median PFS and probability of not experiencing a PFS event by 2, 4, 6 
and 9 months, along with 90% confidence intervals, will be presented by the two treatment 
groups. The stratified Cox regression model will be used to estimate the hazard ratio (HR) of 
a PFS event, along with the associated 90% confidence interval, comparing the everolimus + 
exemestane combination therapy with everolimus monotherapy where the stratification 
information will be obtained through IRT.
10.4.3
Handling of missing values/censoring/discontinuations
This is an event-driven trial and the final PFS analysis will be performed after approximately 
150 PFS events have been documented in each of the two following groups: (i) the everolimus 
+ exemestane plus the everolimus monotherapy arm, and (ii) the everolimus + exemestane 
arm plus the capecitabine monotherapy arm. A database cut-off date will be established after 
approximately 150 PFS events have been documented in both (i) and (ii) defined above. For 


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the final analysis, PFS will be censored on the cut-off date if no PFS event is observed before 
or on the cut-off date, or on the date a new anti-neoplastic therapy, whichever occurs earlier. 
The censoring date will be the date of the last adequate tumor assessment before either of 
those two dates. If a PFS event is observed after two or more missing or non-adequate tumor 
assessments, then the date of progression will be censored at the date of the last adequate 
tumor assessment. If a PFS event is observed after a single missing or non-adequate tumor 
assessment, the actual date of event will be used.
10.4.4
Supportive analyses
A sensitivity analysis will be performed to assess the PFS treatment effect using the 
unstratified Cox regression model yielding the hazard ratio estimate of a PFS event along with 
the 90% confidence interval.
Other sensitivity analyses will be performed that will additionally include PFS events 
recorded after two or more missed or non-adequate tumor assessments with the PFS event 
date defined as (i) the actual event date [actual event PFS analysis], and (ii) the date of the 
next scheduled tumor assessment [backdating PFS analysis].
Descriptive analyses within subgroups defined by the single stratification factor will be 
performed: the analyses will include Kaplan-Meier PFS summaries, hazard ratio point and 
interval estimates from unstratified Cox regression models.
A Cox regression model will be used to evaluate the effect of baseline demographic and 
disease characteristics on PFS. The robustness of the PFS hazard ratio estimate to the 
adjustment for various prognostic factors in the Cox model including prior chemotherapy (yes 
vs. no), performance status (0 vs. 1 or 2), patients with bone lesions only at baseline (yes vs. 
no), time since first diagnosis of metastasis/recurrence to randomization (<= 6 months vs. > 6 
months), non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) use (adjuvant vs. 
metastatic setting), number of organs involved (1 vs. 2 vs. ≥ 3), and PgR status (positive vs. 
negative) will be assessed. The strata will be based on stratification information obtained 
through IRT.
10.5
Secondary objectives
10.5.1
Key secondary objective
The key secondary objective of this study is to estimate the hazard ratio of a PFS using local 
investigator’s/radiologist’s tumor assessments comparing the everolimus + exemestane 
combination therapy with the capecitabine therapy in postmenopausal women with ER-
positive, HER2-negative, advanced breast cancer after recurrence or progression on letrozole 
or anastrozole.
Distribution of PFS will be assessed using the Kaplan-Meier estimation method. The 
estimated median PFS and probability of not experiencing a PFS event by 2, 4, 6 and 9 
months, along with 90% confidence intervals, will be presented by the two treatment groups. 
The stratified Cox regression model will be used to estimate the hazard ratio (HR) of a PFS
event, along with the associated 90% confidence interval, comparing the everolimus + 
exemestane combination therapy with the capecitabine therapy where the stratification 


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information will be obtained through IRT. The confidence interval for the HR will not be 
adjusted for multiple comparisons. The same missing value/censoring rules as in Section 
10.4.3 will apply.
10.5.2
Other secondary objectives
Other secondary objectives of this study are to evaluate each of everolimus + exemestane 
versus everolimus monotherapy and everolimus + exemestane versus capecitabine 
monotherapy with respect to overall survival (OS), overall response rate (ORR), clinical 
benefit rate (CBR), deterioration in the ECOG performance status, changes in quality of life 
scores over time, and safety.
10.5.2.1 Overall Survival (OS)
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death due to any cause. The final OS analysis will be conducted at the same time as the final 
PFS analysis using the same data cut-off date. If death has not been observed by the analysis 
cut-off date, then OS will be censored at the date of last contact.
The OS analysis will be based on data from the FAS on the ITT basis, i.e., according to the 
treatment group patients are randomized to at baseline. Distribution of OS in each of the three 
treatment arms will be assessed using the Kaplan-Meier estimation method. The estimated 
median OS and probability of surviving at the estimated median OS, along with 90% 
confidence intervals, will be presented for the three treatment arms. Stratified Cox regression 
models will be used to estimate the hazard ratio (HR) of death from any cause, along with the 
associated 90% confidence interval, comparing (i) the everolimus + exemestane combination 
therapy with everolimus monotherapy, and (ii) the everolimus + exemestane combination 
therapy with capecitabine monotherapy where the stratification information will be obtained 
through IRT.
10.5.2.2 Overall Response Rate (ORR)
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.1 (Appendix 1). 
ORR will be calculated based on the FAS according to the ITT principle, using local 
radiologist’s/investigator’s tumor assessment. Patients with bone lesions only at baseline will 
be included in the numerator if they achieve a complete response. ORR estimates will be 
presented by treatment group along with exact 90% confidence intervals (Clopper and 
Pearson 1934). The estimation procedure will be repeated based on data for a subset of 
patients in the FAS with measurable disease only at baseline.
10.5.2.3 Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR) is defined as the proportion of patients with best overall response 
of CR, PR or stable disease (SD) with duration of 24 weeks or longer. A patient will be
considered to have a SD for 24 weeks or longer if SD is recorded at 24 weeks or later after 
randomization. Taking into account the allowed time window for tumor assessment visits, the 
SD response has to be recorded at 23 weeks or later after randomization to be included in the 
CBR calculation. CR, PR and SD are defined according to RECIST 1.1 (see Appendix 1). 


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CBR will be calculated based on the FAS according to the ITT principle, using local 
radiologist’s/investigator’s tumor assessment. Patients with non-measurable disease only at 
baseline will be included in the numerator if they achieve a complete response. CBR will be 
summarized for the three treatment groups using descriptive statistics.
10.5.2.4 ECOG Performance Status
ECOG performance status (PS) scale as described in Table 7-3 will be used to assess physical 
health of patients. An analysis of the time to definitive deterioration of the ECOG PS by at 
least one category of the score from baseline will be performed. A deterioration is considered 
definitive if no improvements in the ECOG PS are observed at subsequent measurement times 
during the treatment period following the time point at which the deterioration is observed.
Death will be considered as worsening of the ECOG PS if it occurs close to the last available 
assessment, where “close” is defined as being within twice the planned period between two 
assessments. Patients who die after more than twice the planned period between two 
assessments will be censored at the date of their last assessment before the cut-off.
Patients receiving any further anti-neoplastic therapy prior to definitive worsening will be 
censored at their date of last assessment prior to the start of therapy. Patients that have not 
worsened at the data cut-off point will be censored at the date of last assessment prior to the 
cutoff.
The Kaplan-Meier estimation method will be used to assess the distribution of time to 
definitive worsening in the ECOG PS score, stratified by treatment. The estimated treatment-
specific median times to definitive worsening will be presented along with 90% confidence 
intervals.
10.5.2.5 Patient-reported outcomes (PRO)
The FAS will be used for all PRO summaries and listings.
Quality of life questionnaire (QLQ)
The EORTC QLQ-C30 questionnaire along with the breast module (BR23) will be used to 
collect patients’ quality of life (QoL) data. Raw QoL data will be scored according to the 
EORTC scoring manual. The global health status/QoL scale score is identified as the primary 
QoL variable of interest. Physical functioning, emotional functioning and social functioning 
scale scores are identified as secondary QoL variables of interest.
The number of patients providing QoL data and the number of patients missing/expected to 
have QoL assessments will be summarized by each treatment group for scheduled assessment 
time points.
Descriptive statistics (count, mean, median, standard deviation, first and third quartile) will be 
used to summarize individual item and multi-item scale scores at each scheduled assessment 
time. Patients will be included if they completed at least one questionnaire item. Additionally, 
change from baseline in the scale scores at the time of each assessment will be summarized.
Time to definitive 10% deterioration in the global health status / QoL, and in each of the three 
secondary scales, will be examined for the three treatment arms. In addition, time to definitive 


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5-point deterioration in the global health status / QoL score will be explored for each 
treatment arm. The assessed distributions will be presented descriptively using Kaplan-Meier 
curves. Summary statistics based on Kaplan-Meier distributions will be presented, including 
the estimated median time to definitive 10% (5-point) deterioration and the probability of not 
experiencing definitive 10% (5-point) deterioration by 12 and 24 weeks. Both point estimates 
and 90% confidence intervals will be presented.
Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-
points) compared to baseline, with no later increase above this threshold observed during the 
course of the study. A single-item measure reporting a decrease of at least 10% (5-point) is 
considered definitive only if it is the last one available for the patient. Baseline is defined as 
the latest available assessment made on or before the date of randomization. Time to 
definitive deterioration is the number of days between the date of randomization and the date 
of the assessment at which definitive deterioration is seen.
Death will be considered as deterioration of symptoms/QoL if it occurs close to the last 
available assessment where “close” is defined as twice the planned period between two 
assessments. This avoids overestimating the time to definitive worsening in patients dying 
after an irregular assessment scheme. Patients who die after more than twice the planned 
period between two assessments since the last assessment will be censored at the date of their 
last available questionnaire.
Patients receiving any further anti-neoplastic therapy before definitive worsening will be 
censored at the date of their last assessment before starting this therapy. Patients that have not 
worsened as of the cut-off date for the analysis will be censored at the date of their last 
assessment (questionnaire) before the cut-off.
Treatment satisfaction questionnaire for medication (TSQM)
Patients’ self-reported satisfaction or dissatisfaction with the study treatment will be measured 
using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Patients 
will provide assessments of treatment satisfaction at week 3, 6, 12, and the end-of-treatment 
(EOT)visit. The questionnaire will be administered in the patients’ local language in a quiet 
setting.
TSQM items will be divided into four scales: side effects, effectiveness, convenience, and 
global satisfaction. Raw TSQM data will be scored according to the scoring manual
Descriptive statistics (count, mean, median, standard deviation, first and third quartile) will be 
used to summarize individual item and multi-item scale scores by treatment group and 
assessment time point (week 3, week 12, and EOT). For weeks 3 and 12, differences in mean
scale scores along with 90% confidence intervals comparing treatment satisfaction with 
everolimus + exemestane versus everolimus alone, and everolimus + exemestane versus 
capecitabine alone will be reported (no significance testing will be performed).


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10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. The assessment of safety will be based 
mainly on the frequency of adverse events and on the number of laboratory values that fall 
outside of pre-determined ranges. All safety data will be listed.
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 medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting on day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent AEs, i.e., AEs that started or worsened during the on-treatment period, will be 
summarized by system organ class, preferred term, severity (based on CTCAE grades), type 
of adverse event and relation to the study drug by treatment group. Deaths reportable as 
severe adverse events (SAEs) and non-fatal SAEs will be listed by patient and tabulated by 
type of adverse event and treatment group. All AEs (including those from the pre- and post-
treatment periods) will be listed and those collected during the pre- and post-treatment period 
will be flagged.
Adverse events will be summarized by presenting the number and percentage of patients 
having any adverse event in each body system and having each individual adverse event. Any 
other information collected (e.g., severity or relatedness to study medication) will be listed as 
appropriate.
In addition, adverse events of related nature and/or for which there is a specific clinical 
interest in connection with the study treatments may be analyzed by categories regrouping the 
relevant preferred terms, as appropriate. For each such category, the number and percentage 
of patients with at least one AE belonging to the category will be reported.
10.5.3.3 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTCAE).
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
group. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by parameter and treatment group.
Laboratory data will be classified into CTC grades according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0. A severity grade of 0 will be 
assigned when the value is within normal limits. In the unlikely case when a laboratory 


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normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory value will still 
be taken as within normal limits and assigned a CTC grade of zero.
Besides listings, the following summaries will be produced for the laboratory data (by 
laboratory parameter and treatment):

Number and percentage of patients with worst post-baseline CTC grade (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.
10.5.3.4 Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters expected to be collected include: height (cm), weight (kg), body temperature (°C), 
heart rate (beats per minute), systolic and diastolic blood pressure (mmHg), and respiration 
rate (breaths per minute).
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

weight: increase from baseline of ≥ 10%

heart 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

weight: decrease from baseline of ≥ 10%

heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm.
The following summaries will be produced for each vital sign parameter:

summary statistics for change from baseline to the worst post-baseline value (in both 
directions, i.e., from baseline to the highest post-baseline and from baseline to the 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 group:


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
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 the assessments 
collected later than 30 days after the last treatment/exposure date will be flagged.
10.5.3.5 Other safety data
Data from other tests (e.g. electrocardiogram, pulmonary function tests, LVEF) 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/exposure 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.
10.6
Interim analysis
An efficacy interim analysis will be conducted to allow early termination of the everolimus 
monotherapy arm, in case the efficacy in the everolimus monotherapy arm is by far inferior 
compared to the everolimus + exemestane combination arm. This efficacy interim analysis is 
planned after 75 PFS events have been reached across the following 2 arms: everolimus 
monotherapy and everolimus + exemestane combination treatment.
At the time of interim analysis, the observed hazard ratio along with the 90% confidence 
interval will be provided for decision making. A general guidance is to stop everolimus 
monotherapy arm if the observed hazard ratio is less than 0.20 (i.e., if the everolimus 
monotherapy arm is far inferior when compared to the everolimus + exemestane combination 
arm).
In addition, simulation (Wei L.J. 2007) will also be carried out to predict the hazard ratio and 
90% confidence interval at the final analysis conditional on the data observed at interim.
In summary, only the observed hazard ratio along with its 90% confidence interval will be 
used for decision making. However, the predicted hazard ratio along with its 90% confidence 
interval will be provided as complementary information.
10.7
Sample size calculation
The primary objective of this study is to estimate the hazard ratio of PFS comparing 
everolimus + exemestane versus everolimus alone with approximately 150 PFS events. For 
this number of PFS events, the precision of HR estimation is illustrated by tabulating the 
approximate 90% confidence intervals (Jennison and Turnbull 1999) for the hazard ratio (HR) 
(see Table 10-1) under different point estimates for the HR.


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Table 10-1
Approximate* 90 percent CI bounds for HR
Assuming 146 observed PFS events
Assuming 150 observed PFS events
Estimated HR
Lower bound of 
approximate 90% CI 
for HR
Upper bound of 
approximate 90% CI 
for HR
Lower bound of 
approximate 90% CI 
for HR
Upper bound of 
approximate 90% CI 
for HR
0.55
0.419
0.722
0.420
0.719
0.60
0.457
0.788
0.459
0.785
0.65
0.495
0.853
0.497
0.850
0.70
0.533
0.919
0.535
0.916
0.75
0.571
0.985
0.573
0.981
* Jennison and Turnbull (1999)
A total of 300 patients are planned to be recruited at a uniform rate over an 18-month 
enrollment period and randomized with equal allocation to one of the three treatment arms. 
Assuming the median PFS time to be 7 months in the everolimus + exemestane arm (Baselga 
et al 2012), 4 months in the everolimus monotherapy arm (NCI-Canada), and 6 months in the 
capecitabine monotherapy arm (O’Shaughnessy et al 2012, Stocker et al 2007, Jäger et al 
2010, Kaufmann et al 2010, Robert 2011), the expected time to observe 150 PFS events in 
each of the two pairwise treatment comparisons is about 28 months after the randomization 
date of the first patient in the study, assuming that about 10% of the patients will be lost to 
follow-up or withdraw consent.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.5.
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.


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


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


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13
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Twists and Turns in the Road to Cancer Therapy. Clin Cancer Res 13; 3109-3114.
Awada A, Cardoso F, Fontaine C, et al. (2008) The oral mTOR inhibitor RAD001 
(everolimus) in combination with letrozole in patients with advanced breast cancer: results of 
a phase I study with pharmacokinetics. Eur J Cancer. 44(1):84-91.
Bachelot T, Bourgier C, Cropet C. et al (2012) Randomized Phase II Trial of Everolimus in 
Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human 
Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure 
to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 30(22):2718-24
Baselga J, Semiglazov V, van Dam P, et al. (2009) Phase II randomized study of neoadjuvant 
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14
Appendices
14.1
Appendix 1
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 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
LPLV
Last patient last visit
MRI
Magnetic resonance imaging
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
TTP
Time to progression
UNK
Unknown


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.12 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.28
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.4
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.26
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.


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
Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.1.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.1.26.
14.1.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.


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
For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. 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 the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. 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.


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
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 as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.7
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.4.

Nodal target: See Section 14.1.4.


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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.
14.1.8
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.9
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
14.1.10
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.


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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.
14.1.11
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.1.12
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3. Methodology change See Section 14.1.6.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities:


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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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.


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
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.
14.1.13
Determination of non-target lesion response
Table 14-2
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 baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

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 any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.


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14.1.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.6.
14.1.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.1.8.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.


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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required


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
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)
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.
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

Novartis calculated overall lesion response (based on measurements from Investigator)
The primary analysis of the best overall response will be based on the sequence of 
investigator’s overall lesion responses.


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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.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach).
14.1.18
Time to event variables
14.1.19
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.


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14.1.21
Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
14.1.23
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.


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For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression.
14.1.24
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 14.1.23. It is
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options.

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.


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14.1.25
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization date 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 14.1.26).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.


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
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.26
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.8.
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.


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14.1.27
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
Table 14-5
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) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.=Definitions can be found in Section 14.1.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.


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
(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-5 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation.
14.1.28
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).
14.1.29
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.30
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 14 days of the 
last study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Investigator decision in patient best interest

Protocol deviation

Administrative problems

Subject withdrew consent

Death

Progressive disease
14.1.31
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

Subject withdrew consent

Lost to follow-up

Protocol deviation

Administrative problems

Death

New cancer therapy

Progressive disease

Follow-up phase completed as per protocol
14.1.32
Medical validation of programmed overall lesion response
As RECIST 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 


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whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.35
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.36
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.


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14.1.37
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.39
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 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.


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14.1.40
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
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

SAP_000.pdf: 
Clinical Development
RAD001 (everolimus)
CRAD001Y2201 / NCT01783444
A three-arm, randomized, open label, phase II study of 
everolimus in combination with exemestane versus 
everolimus alone versus capecitabine in the treatment of 
postmenopausal women with estrogen receptor positive, 
locally advanced, recurrent, or metastatic breast cancer after 
recurrence or progression on prior letrozole or anastrozole
RAP Module 3 – Detailed Statistical Methodology –
Addendum1
Author:
 Trial Statistician
Document type:
RAP Documentation
Document status:
Final 
Release date:
27-Oct-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
1
Introduction .........................................................................................................................7
2
Definitions and general methodology .................................................................................7
2.1
Definitions ...............................................................................................................7
2.1.1
Study drug and study treatment...............................................................7
2.1.2
Date of first administration of study drug...............................................7
2.1.3
Date of last administration of study drug................................................7
2.1.4
Date of first administration of study treatment .......................................7
2.1.5
Date of last administration of study treatment ........................................7
2.1.6
Study day.................................................................................................8
2.1.7
Baseline...................................................................................................8
2.1.8
On-treatment assessment/event...............................................................8
2.1.9
Last contact date......................................................................................8
2.2
Data included in the analysis ...................................................................................9
2.3
Definitions of analysis populations .......................................................................10
2.4
Concomitant medications with specific impact on the analysis ............................10
2.4.1
Inducers, inhibitors and substrates of CYP3A ......................................10
2.4.2
Further anti-neoplastic therapy .............................................................11
2.5
Implementation of RECIST 1.1.............................................................................11
2.5.1
Overall lesion response for patients with bone lesions only at 
baseline..................................................................................................11
2.5.2
Disease progression...............................................................................11
2.5.3
Best overall response.............................................................................12
2.5.4
Change in imaging modality.................................................................13
2.5.5
Determination of missing adequate assessments ..................................13
3
Statistical methods used in reporting.................................................................................14
3.1
Enrollment status ...................................................................................................14
3.2
Background and demographic characteristics .......................................................14
3.2.1
Basic demographic and background disease data .................................14
3.2.2
Protocol eligibility criteria ....................................................................14
3.2.3
Diagnosis and extent of cancer .............................................................14
3.2.4
Medical history......................................................................................15
3.2.5
Prior anti-neoplastic therapy .................................................................15
3.2.6
Other......................................................................................................15
3.3
Protocol deviation summaries................................................................................15
3.4
Groupings for analysis...........................................................................................16


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3.5
Patient disposition..................................................................................................16
3.6
Study treatment......................................................................................................16
3.6.1
Duration of study treatment exposure...................................................17
3.6.2
Cumulative dose....................................................................................17
3.6.3
Dose intensity and relative dose intensity.............................................17
3.6.4
Dose reductions or interruptions ...........................................................18
3.7
Concomitant therapy..............................................................................................18
3.8
Efficacy evaluation ................................................................................................19
3.8.1
Primary Efficacy ...................................................................................20
3.8.2
Secondary Efficacy ...............................................................................22
30
3.9
Safety evaluation ...................................................................................................31
3.9.1
Adverse events (AEs)............................................................................32
3.9.2
Laboratory data .....................................................................................34
3.9.3
Vital signs..............................................................................................35
3.9.4
Other safety data ...................................................................................36
36
3.11
Interim analysis......................................................................................................37
3.12
Sample size calculation..........................................................................................38
3.13
Statistical outputs...................................................................................................38
4
Details of the statistical analysis........................................................................................38
4.1
Baseline comparability ..........................................................................................38
4.2
Time-to-event analyses..........................................................................................39
4.2.1
Analysis of time-to-event data with ties................................................39
4.2.2
Kaplan-Meier survival function estimation ..........................................39
4.2.3
Hazard ratio estimation .........................................................................39
4.3
Median follow-up of the study ..............................................................................40
5
References .........................................................................................................................41


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 3
19Jul2017

Section 3.8 updated: due to “Lack of PI oversight and no 
eCRF signatures at Database Lock (DBL) due to PI 
departure and no replacement“, protocol deviation C17 was 
created and details were added on how to analyze efficacy 
patients with this protocol deviation C17

Section 3.2.3: typo corrected ’30.3475’ should be ’30.4375’
Amendment 2
13Jun2017

Section 2.1.6: specification given in study day calculation for 
assessments before start of study treatment

Section 2.2: following protocol amendment, in sentence “The 
final PFS analysis is planned to be conducted when at least
150 PFS events per local tumor assessment have been 
documented...”, ‘at least’ was replaced by ‘approximately’

Section 3.6.4, specifications added on how to count dose 
reductions for Capecitabine

Section 3.8.2 the final OS analysis will be conducted at the 
same time as the final PFS analysis using the same cut-off 
date.

Sections 3.9.1.4 and 4.2: analysis on time to first occurrence 
of stomatitis removed

Section 3.9.1.6 added for the new process related to clinical 
trial safety disclosure.

Section 3.12; In the sentence “The primary objective of this 
study is to estimate the hazard ratio of PFS comparing 
everolimus + exemestane versus everolimus alone with 150 
PFS events”, ‘approximately’ was added. In addition, table 
3-3 is updated to include approximate CI bounds for 146 
observed PFS events.
Amendment 1
16Dec2016

Section 2.2, reworded to include the conduction of interim 
analysis of PFS and the planned timeline for OS analysis to 
be consistent with protocol; 

Section 2.3, definition of Safety set modified as per guidance

Section Error! Reference source not found. on major 
protocol deviations was removed as there is no per protocol 
set

Section 2.4.1, added information of CYP2C9

Deleted Section 2.6.6 for waterfall plot

Section 3.6.1, clarification on capecitabine added

Section 3.6.3, clarification on capecitabine added

Section 3.6.4, clarification on counting interruption when last 
record is 0 mg and also if first dose is lower than the studied 
dose under the protocol

Section 3.8, added non-CR/non-PD in the definition of CBR 

Section 3.8.1, deleted sensitivity analysis of PFS based on 
stratum information obtained from clinical database; deleted 
analyses for missing tumor assessments and subgroup 
analysis for PFS. Also deleted reference to log-rank test.


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Version
Date
Changes

Section 3.8.2, included day 1 for baseline ECOG and QLQ; 
updated categories for questionnaire completion. Also 
definition of CBR is clarified. For QoL questionnaire, 
clarification made that baseline record used for time to 
deterioration should be a record when patient can still 
deteriorate. For overall survival, clarification on the timing of 
each analysis.

Section 3.9.1.2 and 3.9.2, updated to CTCAE v4.03

Section 3.9.1.4, deleted analysis for time to first occurrence 
of G3/4 neutropenia and G3/4 thrombocytopenia, also 
deleted adverse event adusted for patient year exposure.

Section Error! Reference source not found., CNAE 
section replaced by AESI section

Section 3.9.2, specific rules for reporting lab data was added

Section 3.9.3, respiration rate removed as not in CRF


Deleted Section 3.11 for subgroup analyses

Added new Section 3.11 for interim analysis

Section 4.2, Time to first occurrence of stomatitis and time to 
definitive deterioration from baseline in the global health 
status / QoL score of the EORTC QLQ-C30 questionnaire
added

Section 4.2.3, reference to log-rank test removed

Section 4.2.4 removed

Section 5, added more reference

Typo corrections
Addendum 1
27Oct2017
(after DBL)
Duration of exposure for Capecitabine arm will be corrected in order 
to take the rest periods into account. Dose intensity as well as the 
planned dose intensity will be modified accordingly (section 3.6.1 
and 3.6.3)
 
For efficacy endpoints :
-
95% confidence interval for PFS and OS estimates will be 
provided to facilitate the comparison with Bolero 2 data and 
to show the potential increase in variability due to the low 
sample size. 90% CI were pre-planned to be aligned with 
the sample size calculation based on the precision of the 
estimate (width of the 90% CI of the HR) (section 3.8.1 and 
3.8.2)
-
 
 
 
 
 
 
-
To get a more appropriate cox model adjusted on the known 
prognostic factors from the literature as well as to account 


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Version
Date
Changes
for baseline imbalances between arms in some baseline 
characteristics, stratified adjusted cox model for both 
endpoints PFS and OS will be revised to include the 
following covariates : study treatment (eve+exe vs eve 
alone; eve+exe vs. cap.), performance status (0 vs. 1 or 2),
presence of bone lesions only at baseline (yes vs. no), prior 
chemotherapy use (yes vs. no), number of organs involved 
(1 vs. 2 vs. >=3 ), age (<65 years vs. >=65 years old) and 
Race (Caucasian vs. non-caucasian), (section 3.8.1 and 
3.8.2)
-
To further explore the longer PFS in Capecitabine arm
versus the combination of everolimus and exemestane and 
given the observed imbalance in informative censoring 
between the two treatment arms, patient disposition (i.e. 
reasons for end of treatment) for patients censored due to 
“New cancer therapy started” reason in the main primary 
analysis will be presented (section  3.5). 
 
 
Prior medications and further antineoplastic therapies after treatment 
discontinuation
-
To better describe the population at study entry, prior 
metastatic chemotherapy will be summarized using the 
regimen number to account for any possible combination of 
treatments.
-
To better understand the potential impact of the further 
antineoplastic therapy after treatment discontinuation on the 
overall survival (i.e. median OS estimate in the study 
different from the one observed in B2 study),  the first 
therapy given after treatment discontinuation will be 
described taking into account the combination of treatments 
if any.


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1
Introduction
This document describes the detailed statistical methodology of the Report Analysis Plan 
(RAP) of the study CRAD001Y2201: A three-arm, randomized, open-label, multi-center,
international phase II study evaluating the combination treatment of everolimus (10 mg daily) 
with exemestane (25 mg daily) versus everolimus (10 mg daily) versus capecitabine (1250
mg/m2 twice daily for 14 days in 3-week cycles) in patients with estrogen-receptor positive, 
HER2 negative, advanced breast cancer after recurrence or progression on letrozole or 
anastrozole. The data will be analyzed by Novartis. It is planned that data from all centers that 
participate in this study will be used.
2
Definitions and general methodology
2.1
Definitions
2.1.1
Study drug and study treatment
Study drug is defined as everolimus, exemestane or capecitabine. All study drugs are open-
label.
Study treatment is defined as everolimus + exemestane, everolimus monotherapy or 
capecitabine monotherapy.
2.1.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug is administered and recorded on the dose administration record (DAR) eCRF. 
For the sake of simplicity, the date of first administration of study drug will also be referred to 
as the start of study drug.
2.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non -zero dose 
of study drug is administered and recorded on the DAR eCRF.
2.1.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non -zero 
dose of any component of study treatment is administered and recorded on the DAR eCRF. 
For the sake of simplicity, the date of first administration of study treatment will also be 
referred to as the start of study treatment.
2.1.5
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on the DAR eCRF.


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2.1.6
Study day
The study day for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption, etc.) will be calculated as the 
difference between the date of the assessment and the start of study treatment plus 1. (Note: 
except in the case when the assessment is before start of study treatment in which case study 
day is calculated as the difference between the date of the assessment and the start of study 
treatment. In this particular case, the study day displayed on the listing will be negative.)
The study day for all other, i.e., non-safety assessments (tumor assessment, death, disease 
progression, tumor response, ECOG performance status, QoL assessment) will be calculated 
as the difference between the date of the event and the randomization date plus 1. In other 
words, all efficacy time-to-event variables (e.g., progression-free survival, overall survival, 
time to response) will be calculated from date of randomization. (Example: if randomization 
date is 02JAN2007, start of study drug is on 05JAN2007, and the date of death is 09JAN2007,
then the study day when death occurred is 8.). 
The study day will be displayed in data listings.
2.1.7
Baseline
Baseline value(s) is (are) the result of an investigation describing the “true” uninfluenced state 
of the subject. 
For efficacy evaluations, the last available assessment before or at the date of randomization 
is taken as ‘baseline’ value or ‘baseline’ assessment. In the context of the definition of 
baseline, efficacy evaluations also include the ECOG performance status, patient-reported 
outcome measures and clinical measurements included in the stratification.
For safety evaluations (i.e., laboratory and vital signs), the last available assessment before or 
at the date of the start of study treatment is taken as ‘baseline’ assessment.
If patients have no value as defined above, the baseline measurement will be missing.
2.1.8
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. On-treatment assessment/event is defined as any assessment/event 
obtained in the 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: The calculation of study treatment
duration, however, may use different rules as specified in Section 3.6.1.)
2.1.9
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the sources presented in Table 2-1 below:


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Table 2-1 
Last contact date data sources
Source data
Condition
Last contact date/last date patient was known to 
be alive from survival follow-up page 
Patient status is reported to be alive.
Do not use if patient status is reported 
unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
Tumor (RECIST) assessment date
Evaluation is marked as ‘done’.
Laboratory/PK collection dates
Sample collection marked as done. 
Vital signs date
At least one non-missing parameter value.
Performance status date
Non-missing performance status.
Start/End dates of AE 
Non-missing verbatim term.
The last contact date on or before the data cut-off date should be used; the cut-off date should 
not be used as the censoring date (even in presence of post cut-off data) unless the patient was 
seen or contacted on the cut-off date.   
Imputed dates (e.g., analysis cut-off date programmatically imputed to replace the missing 
end date of a dose administration record) will not be used to derive the last contact date.
Partially imputed dates (i.e., only day or day and month imputed) are allowed to be used for 
last contact date only if coming from Survival Follow-up page.
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Data included in the analysis
An efficacy interim analysis of PFS was conducted to allow early termination of the 
everolimus monotherapy arm, in case the efficacy in the everolimus monotherapy arm was by 
far inferior compared to the everolimus + exemestane combination arm. This efficacy interim 
analysis was planned after 75 PFS events have been reached across the following 2 arms:
everolimus monotherapy and everolimus + exemestane combination treatment.
The final PFS analysis is planned to be conducted when approximately 150 PFS events per 
local tumor assessment have been documented in each of the two following groups:

the everolimus + exemestane combination arm combined with the everolimus 
monotherapy arm, and


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
the everolimus + exemestane combination arm combined with the capecitabine 
monotherapy arm.
The final OS analysis was planned to be conducted 2 years after the randomization of the last 
patient. Following protocol amendment, the final OS analysis will be conducted at the time of 
the planned final PFS analysis.
The final statistical analysis 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.
2.3
Definitions of analysis populations
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. All efficacy analyses will be conducted using data from this 
population according to the intent-to-treat (ITT) principle, i.e., patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
The Safety Set includes all patients who received any study treatment. In analyses of the 
safety set, patients will be analyzed according to the study treatment they actually received.
The actual treatment received corresponds to:
-
the randomized treatment if patients took at least one dose of that treatment.
-
the first treatment received if the randomized treatment was never received
2.4
Concomitant medications with specific impact on the analysis
2.4.1
Inducers, inhibitors and substrates of CYP3A
Everolimus is metabolized by CYP3A4 in the liver and, to some extent, in the intestinal wall.
Capecitabine and its metabolites do not inhibit the metabolism of CYP3A4 substrates but may 
inhibit the metabolism of CYP2C9 substrates. Therefore:

Co-administration of CYP2C9 substrates (e.g. Irbesartan, Losartan, Phenytoin, 
Cyclophosphamide) should be exercised with caution and monitored closely per 
capecitabine local label.

co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
ritonavir) or P-glycoprotein (PgP) inhibitor is to be avoided;

co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors is to be used with caution;

concomitant use of seville orange, star fruit, grapefruit and their juices that affect CYP3A4 
and PgP activity is to be avoided;

concomitant use of strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, 
rifabutin, phenobarbital, St. John’s wort is to be avoided.
The following will be tabulated and summarized:


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1. clinically relevant drug interactions: substrates, inducers, and inhibitors of isoenzyme 
CYP3A;
2. list of clinically relevant drug interactions mediated by PgP substrates;
3. list of clinically relevant drug interactions mediated by PgP inhibitors;
4. list of clinically relevant drug interactions mediated by PgP inducers.
Despite the fact that some of these drugs should be avoided completely and some used with 
caution, there may be patients who took these drugs during the study. In that case, the 
concomitant medications need to be identified and classified (review to be performed by a 
Clinical Pharmacologist) and then tabulated and/or listed in the Clinical Study Report as 
appropriate. 
2.4.2
Further anti-neoplastic therapy 
Administration of anti-neoplastic drugs (apart from study treatment) and other investigational 
drugs is not allowed during study treatment. Patients who take such anti-neoplastic drugs after 
randomization but before the end of treatment will be identified as protocol deviations. In 
addition, their efficacy data (other than overall survival) will be censored so that tumor 
assessments made after the start of anti-neoplastic drugs will not be included in the primary 
efficacy analyses for PFS. The same rule will apply to efficacy analyses for best overall 
response (BOR), ECOG performance status and QoL assessments. For details on the 
censoring rules, see [Appendix 1 of the study protocol].
Clinical review of study data will be performed to identify anti-neoplastic medications that are 
not allowed during study treatment.
2.5
Implementation of RECIST 1.1
Response and progression evaluation will be performed according to the RECIST 1.1 
guideline (as described in detail in [Appendix 1 of the study protocol]). The text below 
provides more detailed instructions and rules needed for programming purposes.
2.5.1
Overall lesion response for patients with bone lesions only at baseline
For patients with lytic or mixed lytic-blastic bone lesions only at baseline, RECIST 1.1 will be 
extended to allow the evaluation of overall lesion response in such patients, which will be 
based solely on non-target lesion responses and/or an occurrence of a new lesion. Bone 
lesions will be entered as non-target lesions. Specifically, in the absence of new lesions, the 
overall lesion response at each assessment will be one of the following: complete response, -
non-CR/non-PD, unknown response, or progressive disease based on non-target lesion 
responses. -Non-CR/non-PD response -will include all assessments not qualifying for 
complete response, progressive disease or unknown response. In the presence of a new lesion, 
the overall lesion response will be progressive disease.
2.5.2
Disease progression
For patients with measurable disease at baseline, disease progression will only be assigned if 
it is documented as per RECIST 1.1 by an unbiased assessment method (e.g., CT scan, MRI, 


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X-ray, photography for skin lesions, etc.). A new lesion will be entered on the ‘New lesion’ 
RECIST eCRF with the corresponding measurement method (or method=‘Other’).
Discontinuation due to disease progression without supporting objective evidence (as defined 
above) will not be attributed to progressive disease.
Patients with bone only lesions, lytic or mixed lytic-blastic, will be allowed to enter the study
but such lesions will not be considered as measurable lesions in this study. The following 
criteria will be used to declare disease progression among these patients:

the appearance of one or more new lytic lesions in bone,

the appearance of one or more new lesions outside of bone,

unequivocal progression of existing bone lesions.
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression unless one of the above-mentioned 
criteria is fulfilled.
2.5.3
Best overall response
The best overall tumor response will be assessed per RECIST 1.1. The definitions and details 
of the derivation are given in [Appendix 1 of the study protocol].
Only tumor assessments performed before the start of any further anti-neoplastic therapies 
(i.e., any additional anti-neoplastic medications or surgery) will be considered in the 
assessment of best overall response. These anti-neoplastic therapies will be identified from the 
data collected on ‘Anti-neoplastic therapies since discontinuation of study drug’ eCRF.
Since, in this study, tumor assessments are performed every 6 weeks, allowing for a ± 1-week 
deviation window, the standard definition of a best overall response evaluation of “stable 
disease”, “progressive disease” or “unknown” given in [Appendix 1 of the study protocol] 
requires an adjustment.
The following definitions will be used:

The determination of CR and PR remains the same as stated in [Appendix 1 of the 
study protocol].

SD = at least one SD assessment (or better) after randomization (and not qualifying for 
CR or PR). Because the first assessment after randomization is scheduled at 6 weeks, 
allowing for a 1-week deviation window, SD is defined as at least one SD assessment 
(or better) > 5 weeks after randomization (and not qualifying for CR or PR).

If progression is detected as the first evaluable assessment in ≤ 9 weeks after 
randomization, the best overall response evaluation will be “progressive disease.”

UNK = all other cases (i.e., not qualifying for confirmed CR or PR and without SD for 
more than 5 weeks or early progression within the first 9 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-randomization assessment,

all post-randomization assessments have overall response UNK,


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
new anti-neoplastic therapy started before first post-randomization assessment,

SD in less than 5 weeks post-randomization (‘SD too early’),

PD after more than 9 weeks post-randomization (‘PD too late’).
Special (and rare) cases where best overall response is “unknown” due to both SD in less than 
5 weeks and PD after more than 9 weeks post-randomization will be classified as ‘SD too 
early.’
2.5.4
Change in imaging modality
Per RECIST 1.1, the imaging method used at baseline should be matched at all subsequent 
assessments. A change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use or vice-
versa, regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator if a definitive response assessment can be justified, based on the available 
information.
2.5.5
Determination of missing adequate assessments
The term ‘missing adequate assessment’ is defined as a tumor assessment that is not done or 
for which the overall lesion response is ‘unknown’. For the sake of simplicity, a ‘missing 
adequate assessment’ is also referred to as a ‘missing assessment’.
As detailed in Appendix 1 to the study protocol, the PFS censoring and event date options 
depend on the presence and the number of missing tumor assessments. For example: 
1. in the primary analysis of PFS, an event occurring after two or more consecutive 
missing assessments is censored at the last adequate assessment, i.e., the last 
assessment preceding the missing assessment(s);
2. in one of the sensitivity analyses of PFS, an event occurring after one or more missing 
assessments is back-dated to the date of the next scheduled assessment.
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule is based on the time interval (distance) between the last adequate tumor 
assessment date and the event date. 
If the distance is greater than threshold D1 = 6+2 = 8 weeks, the analysis will assume one 
missing assessment. If the distance is greater than D2 = (2*6)+2 = 14 weeks, the analysis will 
assume two missing assessments. The threshold D1 is formed based on the protocol-specified 
interval between consecutive tumor assessments plus the protocol-allowed window around the
assessments. Similarly, the threshold D2 is formed based on the two-fold of the protocol-
specified interval between consecutive tumor assessments plus the protocol-allowed window 
around the assessments.
Therefore, using the D2 definition above, the censoring of an event occurring after ≥2 missing
TAs (in 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, the patient will be censored and 
the censoring reason will be 'Event documented after two or more missing tumor assessments'.


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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 first of the following dates:
1. analysis cut-off date
2. start date of further anti-neoplastic therapy 
3. date of study treatment discontinuation due to consent withdrawal
4. date of study treatment discontinuation due to loss to follow-up 
is smaller or equal to D2, the censoring reason will be 1.‘Ongoing’, 2. ‘New cancer therapy
added’, 3. ‘Withdrew consent’ or 4. ‘Loss to follow-up’, respectively, depending on the case. 
However, if this distance is larger than D2, the censoring reason will always default to 
‘Adequate assessment no longer available’.
3
Statistical methods used in reporting
3.1
Enrollment status
Number of patients screened will be summarized by country, center and randomization 
stratum.
Number of patients randomized
will be summarized by country, center, 
randomization stratum and treatment group.
3.2
Background and demographic characteristics
The Full Analysis Set (FAS) will be used for all baseline disease characteristics, demographic 
summaries and data listings.
3.2.1
Basic demographic and background disease data
All demographic and background disease characteristics will be listed in detail. Qualitative 
data such as sex, race, disease stage, ECOG performance status, etc. will be presented by 
treatment arm using frequency tables (counts and proportions by category). Relevant 
descriptive statistics (mean, median, minimum, maximum and standard deviation in most 
cases) by treatment arm will be used to present quantitative data such as age, body weight, etc.
Number of patients in each randomization stratum (stratification information obtained from 
IRT) will be presented. Potential discrepancies between randomization stratification 
information (obtained from IRT) and strata formed based on baseline factors collected on 
eCRFs will be tabulated and listed.
3.2.2
Protocol eligibility criteria
Protocol eligibility criteria as per eCRFs will be summarized and listed.
3.2.3
Diagnosis and extent of cancer
Summary statistics will be tabulated for diagnosis and extent of cancer. According to data 
collected on the eCRF, this analysis will include the following variables: primary site of 
cancer, details of tumor histology/cytology, histological grade, time since initial diagnosis, 


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date of first metastatic recurrence, date of most recent recurrence/metastasis, presence/absence 
of target and non-target lesions, number and type of organs involved.
The numbers and percentages of patients in categories defined by the following variables 
‘presence/absence of target and non-target lesions’, ‘number of organs involved’ and ‘organ 
types involved’ will be based on data collected on the radiology RECIST, and eCRFs for
diagnosis and extent of cancer, in particular, on the individual target and non-target lesion 
codes. 
Time since initial diagnosis, time since first recurrence/metastasis, as well as time between 
first diagnosis and first recurrence/metastasis will be summarized in months. A month is 
defined as 365.25 / 12 = 30.4375 days.
3.2.4
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms, 
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 Medical 
dictionary for regulatory activities [MedDRA] terminology.)
3.2.5
Prior anti-neoplastic therapy
Prior anti-neoplastic therapy will be listed in three separate listings: 1. medications, 2. 
radiotherapy, 3. surgery.
The numbers and percentages of patients recording any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy and prior anti-neoplastic surgery will be summarized by 
treatment.
Prior anti-neoplastic medications will be summarized by therapy type (radiotherapy, surgery,
NSAI (defined as “Letrozole”, “Anastrozole”), hormonal therapy other than NSAI, 
chemotherapy, immunotherapy, targeted therapy and others). Any indication-specific 
significant prior anti-neoplastic medications will be identified from the summaries mentioned 
above.
In addition, the type of prior chemotherapies received will be summarized by treatment arms
(i.e. for monotherapy regimens, the drug received will be reported; for regimen comprised of 
a combination of several drugs the combination will be reported).
3.2.6
Other
All data collected at baseline, including source of subject referral and child bearing potential, 
will be listed.
3.3
Protocol deviation summaries
The number and percentage of patients in the Full Analysis Set with any protocol deviation 
will be tabulated by the deviation category (as specified in the VAP documents) and by 
treatment group. The protocol deviations will also be summarized by center.


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Protocol deviations leading to the exclusion from the analysis populations will be tabulated 
separately by treatment group. 
All protocol deviations will be listed.
3.4
Groupings for analysis
The number and percentage of patients in each analysis population (definitions are provided 
in Section 2.3) will be summarized by treatment group and randomization stratum. The 
distribution of patients in screening and in selected analysis populations will also be 
summarized by country, center, treatment group and randomization stratum.
3.5
Patient disposition
The Full Analysis Set will be used for patient disposition summaries. Based on the two eCRF
pages ‘End of Treatment’ and ‘Study Evaluation Completion’ there will be one combined 
summary, stratified by treatment, showing:

Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of Treatment’ page);

Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment’ page);

Reasons for study treatment discontinuation (based on the ‘End of Treatment’ page).

Number (%) of patients who entered the post-treatment evaluation phase (based on the 
‘End of Treatment’ page);

Number (%) of patients who discontinued from the post-treatment evaluations (based 
on the ‘Study Evaluation Completion’ page); 

Reasons for discontinuation from the post-treatment evaluations phase (based on the 
‘Study Evaluation Completion’ page).
The summary of reasons for End of treatment discontinuation will also be presented 
separately for patients who have been censored in the primary PFS analysis due to the reason 
of “Antineoplastic therapy started” reason. 
3.6
Study treatment
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. In addition, the duration of exposure to 
study treatment will be categorized into time intervals; frequency counts and percentages will 
be presented for the number of patients in each interval. The number of patients, who have 
dose reductions or interruptions, and the reasons, will be summarized by treatment.
Listings of all doses of the study treatment along with dose change reasons will be produced. 
The Safety Set will be used for all summaries and listings of study treatment.


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3.6.1
Duration of study treatment exposure
The following algorithm will be used for everolimus and exmestane to calculate the duration 
of study treatment exposure for patients who took at least one dose of any of the components 
of the study treatment:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first
administration of study treatment) + 1.
For capecitabine, the duration of exposure will include the rest periods and will be then 
defined as:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first
administration of study treatment) + 7 days (corresponding to the theoretical rest period) + 1.
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason).
Duration of exposure to each component of the study treatment will also be calculated.
3.6.2
Cumulative dose
Cumulative dose is defined as the total dose given during the study treatment exposure period 
and will be summarized for each of the study treatment components separately. For patients 
who do not receive any drug, the cumulative dose will be set to zero.
3.6.3
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:
DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of
time).
For patients who do not receive any drug, the DI will be set to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol in the same dose unit and unit of time as that of the Dose Intensity.
For Capecitabine, the planned dose recommended as per protocol is 1250 mg/m2 twice daily 
for 14-days every 3 weeks (i.e. 3-week cycle). The planned dose intensity including the rest 
period of 7 days is calculated as:
PDI (Cap.) = 1250 mg/m2*2*14 days / 21 days = 1666.67 mg/m2/day. 
Relative dose intensity (RDI) is defined as follows:
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, but 
using the duration of the study treatment exposure, not the duration of exposure to each of the 
components. 
For the calculation of the assigned body-surface-area-adjusted capecitabine dose at every 
cycle, the following formula will be used: 


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BSA [m2] = 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000. 
according to the height at baseline and the last available weight at or before the cycle start 
date. 
3.6.4
Dose reductions or interruptions
The number of patients, who have dose reductions or interruptions, and the reasons for such 
reductions/interruptions, will be summarized separately for each of the study treatment 
components.
An interruption is defined as a 0mg dose given on one or more days. However, for last records, 
it will be counted as an interruption only if there are 2 or more last records with 0 mg dose.
If a patient moves from a dose level that is higher than the studied dose under the protocol to 
the dose level that is being studied in the protocol, such changes will not be counted as 
reductions. However, if any patient moves directly from a higher than studied dose down to a 
lower than protocol-studied dose, or to the dose level being studied under the protocol but on 
a less frequent regimen, such changes will be counted as reductions. If first dose is lower than 
the studied dose under the protocol, it will be counted as a dose reduction.
For everolimus and exemestane, reductions count should be based on the actual total daily 
dose (mg). 
For capecitabine, reductions count should be based on the actual total daily dose adjusted to 
BSA (mg/m2) with an acceptance windows of 10%: if the difference compared to the previous 
non-zero dose (mg/m2) is greater than 10% then it is a reduction. If first dose is lower than the 
studied dose under the protocol (mg/m2) by more than 10%, it will be counted as a dose 
reduction.
If one drug is permanently discontinued (before a protocol-planned discontinuation date) 
while the other is ongoing, such discontinuations will be classified as interruptions.
Dose reductions and interruptions will be tabulated both separately and in a combined fashion. 
In the combined summary, dose interruptions will be considered as dose reductions to 0 mg,
and therefore all reductions/interruptions will be labeled as reductions and tabulated in one 
table. Dose escalations will be summarized by treatment and level of reduced dose (-1 versus -
2) for all patients with dose reductions in a separate table.
3.7
Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, preceding or coinciding with 
the study assessment period.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. In addition to categorizing 
medication data by preferred term, drugs will be classified according to their ATC 
classification in order to present and compare how they are being utilized. 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug(s) will be listed and summarized by ATC class, preferred term and treatment arm by 


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means of frequency counts and percentages. 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 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.,
efficacy analyses) will be identified prior to database lock. Separate summaries of these 
concomitant medications will be produced and the corresponding analysis populations will be 
used. Strong and moderate inhibitors, inducers, or substrates of the isoenzyme CYP3A will be 
identified as described in Section 2.4.1. The strong ones will be tabulated by ATC code. Both 
strong and moderate ones will be listed. New anti-neoplastic therapies will be listed based on 
their identification (by the method given in Section 2.4.2) by the protocol deviation process.
Anti-neoplastic therapies since discontinuation of study drug will be listed and summarized by 
ATC class, preferred term and treatment arm by means of frequency counts and percentages 
in separate summaries using the Full Analysis Set. In addition, the first regimen with 
combination of several drugs if any after the study treatment discontinuation will be 
summarized by treatment arms, using the full analysis set population. 
3.8
Efficacy evaluation
The efficacy endpoints based on tumor assessments will be derived according to RECIST 1.1
(see Appendix 1 of the study protocol for details). The tumor endpoint derivation is based on 
the sequence of overall lesion responses at each assessment/time point. The overall lesion 
response at a given assessment/time point will be provided by the local (treating center’s) 
radiologist/investigator.
In 
particular, 
the 
final 
local 
(treating 
center’s) 
radiologist’s/investigator’s visit response for each assessment/time point collected on the 
RECIST 1.1 overall lesion response CRF page will be used to derive the primary efficacy 
endpoint. The tumor assessment dates will be derived by Novartis using the dates of the 
individual lesion measurements. 
Data included in efficacy analyses
Efficacy analyses will include all data observed in patients from the FAS regardless of 
whether the data were observed on-treatment or after the study treatment discontinuation until 
the analysis cut-off date. In particular, the “30 days” rule applied to all safety analyses will 
NOT be used for efficacy analyses.
For patients who took other anti-neoplastic drugs, their efficacy data (other than overall 
survival) will be censored so that the tumor assessments made after the administration of the 
other anti-neoplastic drugs are not included in the primary efficacy analyses.
For patients with protocol deviation code C17 (“Lack of PI oversight and no eCRF signatures 
at Database Lock (DBL) due to PI departure and no replacement”), efficacy data will be 
analyzed as follows:


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
Progression-Free Survival will be censored at randomization date with censoring 
reason “Adequate assessment no longer available”

Overall Survival will be censored at randomization date with censoring reason “Lost 
to follow-up”

Best Overall Response will be set to UNK with reason “No valid post-baseline 
assessment”

Overall Response status as non-responder

Clinical Benefit status as non-responder
3.8.1
Primary Efficacy
Progression-free survival (PFS) derived from an investigator’s assessment of radiology data 
will be used as the primary efficacy variable. The 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, whichever occurs first. If a patient has not progressed or died at the analysis cut-off 
date, or if she receives any further anti-neoplastic therapy, PFS will be censored at the time of 
the last tumor assessment before the cut-off date or the anti-neoplastic therapy date whichever 
occurs first. Further anti-neoplastic therapies will be identified via protocol deviations and 
from data collected on ‘Antineoplastic therapies since discontinuation of study drug’ eCRF. 
Definitions and further details on PFS can be found in Appendix 1 of the protocol.
Discontinuation due to disease progression (collected on the “End of treatment” and “Study 
Evaluation Completion” page) without supporting objective evidence satisfying progression 
criteria per RECIST 1.1 will not be considered a progressive disease. 
Primary analysis
The primary objective of this study is to estimate the hazard ratio of a progression-free 
survival event comparing the everolimus + exemestane combination therapy with the 
everolimus monotherapy in postmenopausal women with ER-positive, HER2-negative, 
advanced breast cancer (ABC) after recurrence or progression on letrozole or anastrozole.
The primary analysis of PFS will be based on data from investigator/local radiology review. 
The analysis will be performed on the FAS following the intention-to-treat (ITT) principle, 
i.e., patients will be analyzed according to the treatment group they were randomized and the 
stratum they were assigned to at baseline. The analysis will use the default censoring and
event date definitions from Table 3-1 of Appendix 1 of the study protocol, i.e. A(1), B(1), 
C1(1), C2(1), D(1), E(1), and F(1). In particular, PFS will be censored at the last adequate 
tumor assessment if one of the following occurs: absence of a PFS event; a PFS event occurs
after a new anticancer therapy is given; a PFS event occurs after two or more missing tumor 
assessments (see Section 2.5.5). Discontinuation of study treatment (for any reason) will not 
be considered as a reason for censoring. 


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Kaplan-Meier estimates
The Kaplan-Meier (KM) estimate of the progression-free survival function will be computed 
for each treatment group using PROC LIFETEST with method=KM option in SAS. The 
results will also be plotted graphically (Kaplan-Meier curves) by treatment and by 
randomization strata as assigned through IRT. The plots will display the number of patients at 
risk at equidistant time points. 
The estimated median PFS for each treatment group will be provided along with the 
approximate 90% confidence intervals (Brookmeyer and Crowley, 1982). Additionally, the
25th and 75th percentiles will also be computed. The progression-free survival probabilities at 
2, 4, 6 and 9 months (timepoints to be adapted depending on the length of the follow-up), 
along with 90% confidence intervals, will be presented by treatment group. The log-log 
transformation available within PROC LIFETEST will be used to compute the confidence 
intervals.
Hazard ratio estimate
The hazard ratio estimate of a PFS event comparing the everolimus + exemestane 
combination therapy with everolimus monotherapy, along with the two-sided 90% confidence 
interval, will be obtained from the stratified Cox proportional hazards model, fitted using SAS 
PHREG procedure with ties=EXACT option and the stratification information obtained 
through IRT. In the PHREG procedure, the MODEL statement will include the indicator of 
assignment to the everolimus + exemestane arm as the only covariate. The baseline hazard 
function will be allowed to vary across strata, i.e., the STRATA statement will include the 
stratification variable obtained through IRT.
Sensitivity and other supportive analyses of the primary endpoint PFS
To assess the impact of stratification, a sensitivity analysis will be performed to estimate the 
PFS treatment effect (everolimus + exemestane versus everolimus alone) using the 
unstratified Cox regression model yielding the hazard ratio estimate of a PFS event along with 
the 90% confidence interval. 
The following sensitivity PFS analyses will be performed to assess the impact of 
missing/unknown tumor assessments (analyses 1 and 2 below) and to assess the impact of 
PFS censoring due to another anti-neoplastic therapy (analysis 3 below):

PFS using local radiology assessments on the FAS and using the following options in
Table 14-5 on page 121 of Appendix 1 in the study protocol: A(1), B(1), C1(1), C2(3), 
D(1), E(1), and F(1), i.e., taking the event whenever it occurs even after two or more 
missing tumor assessments (see Section 2.5.5). In the summary table, this approach will 
be referred to as the ‘actual event PFS analysis’.

PFS using local radiology assessments on the FAS and using the following options in 
Table 14-5 on page 121 of Appendix 1 in the study protocol: A(1), B(1), C1(2), C2(2), 
D(1), E(1), and F(1), i.e., backdating of events occurring after missing tumor assessments.
In the summary tables, this approach will be referred to as the ‘backdating PFS analysis’. 

PFS using local radiology assessments on the FAS and using the following options in 
Table 14-5 on page 121 of Appendix 1 in the study protocol: A(1), B(1), C1(1), C2(1), 


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D(1), E(1), and F(4), i.e., and not censoring patients at the start of new anti-neoplastic 
therapies (if tumor assessment data are available following the start of new anti-neoplastic 
therapies).
A multivariate stratified Cox regression model will be used to evaluate the effect of baseline
demographic and disease characteristics of potential prognostic value on PFS. Robustness of 
the PFS hazard ratio estimate to the adjustment for various prognostic factors in the stratified 
Cox model including prior chemotherapy use (yes vs. no), performance status (0 vs. 1 or 2),
presence of bone lesions only at baseline (yes vs. no), time since first diagnosis of 
metastasis/recurrence to randomization (< 6 months vs. >= 6 months), non-steroidal 
aromatase inhibitor (NSAI) (letrozole or anastrozole) use (adjuvant vs. metastatic setting), 
number of organs involved (1 vs. 2 vs. >=3 – to be adapted depending on the number of 
patients in each category), and PgR status (positive vs. negative) will be assessed. The strata 
will be based on stratification information obtained through IRT. A revised multivariate 
stratified cox model including the key prognostic factors as well as the baseline covariates 
where imbalances between arms have been observed will be provided: performance status (0 
vs. 1 or 2), presence of bone lesions only at baseline (yes vs. no), number of organs involved 
(1 vs. 2 vs. >=3), prior chemotherapy use (yes vs. no), age (<65 years vs. >=65 years old) and 
Race (Caucasian vs. non-caucasian). 
Further supportive analyses will include:

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. The following categories will be used as appropriate 
(based on the end of treatment page, the study evaluation completion page and the 
survival page and based on the distance D2 defined in Section 2.5.5):

Ongoing without event

Adequate assessment no longer available (when follow-up for progression is 
stopped at a certain time or interrupted for a certain time period before cut-off for 
any reason, e.g., due to loss to follow-up or consent withdrawal)

New cancer therapy added

Event documented after two or more missing tumor assessments (for primary 
analysis only)

Timing of all tumor assessments will be depicted graphically as per local radiology
review by treatment arm

95% confidence intervals will be provided for all estimates of the main primary 
analysis (i.e. median, survival probabilities and hazard ratio)
3.8.2
Secondary Efficacy
Key Secondary Objective
The key secondary objective of this study is to estimate the hazard ratio of a PFS event using 
local investigator’s/radiologist’s tumor assessments comparing the everolimus + exemestane 


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combination therapy with the capecitabine therapy in postmenopausal women with ER-
positive, HER2-negative, advanced breast cancer after recurrence or progression on letrozole 
or anastrozole.
The stratified Cox regression model will be used to estimate the hazard ratio of a PFS event, 
along with the associated 90% confidence interval, comparing the everolimus + exemestane 
combination therapy with the capecitabine therapy where the stratification information will be 
obtained through IRT. The confidence interval for the hazard ratio will not be adjusted for 
multiple comparisons.
Distribution of PFS will be assessed using the Kaplan-Meier estimation method. The 
estimated median PFS for each treatment group will be provided along with the approximate 
90% confidence intervals. Additionally, the 25th and 75th percentiles will also be computed.
The progression-free survival probabilities at 2, 4, 6 and 9 months (timepoints to be adapted 
depending on the length of the follow-up), along with 90% confidence intervals, will be 
presented by treatment group.
The same statistical principles will be applied and supportive analyses conducted as described
in Section 3.8.1 “Sensitivity and other supportive analyses of the primary endpoint PFS” for 
the key secondary treatment comparison of everolimus + exemestane combination therapy 
versus capecitabine therapy.
Other Secondary Objectives
Other secondary objectives of this study are to evaluate each of everolimus + exemestane 
versus everolimus monotherapy and everolimus + exemestane versus capecitabine 
monotherapy with respect to overall survival (OS), overall response rate (ORR), clinical 
benefit rate (CBR), deterioration in the ECOG performance status, changes in quality of life 
scores over time, and safety.
The analysis of all secondary efficacy endpoints (mentioned above) will be performed on the 
FAS.
Overall survival (OS)
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death due to any cause. The cut-off date for the planned final OS analysis was specified 2 
years after the randomization of the last patient. However, at that time, the number of PFS 
events needed for final PFS analysis was not reached. Therefore the final OS analysis will be 
conducted at the time of the planned final PFS analysis using the same cut-off date. If death 
has not been observed by the analysis cut-off date, then OS will be censored at the date of last 
contact.
The OS analysis will be based on data from the FAS on the ITT basis, i.e., according to the 
treatment group patients are randomized to at baseline. Distribution of OS in each of the three 
treatment arms will be assessed using the Kaplan-Meier (KM) estimation method, and the
treatment-specific KM curves will be graphically displayed. The estimated median OS and 
probability of surviving at the estimated median OS, along with 90% confidence intervals, 
will be presented for the three treatment arms. Stratified Cox regression models will be used 
to estimate the hazard ratio (HR) of death from any cause, along with the associated 90% 


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confidence interval, comparing (i) the everolimus + exemestane combination therapy with 
everolimus monotherapy, and (ii) the everolimus + exemestane combination therapy with 
capecitabine therapy where the stratification information will be obtained through IRT and the 
baseline hazard functions will be allowed to vary across strata.
As a sensitivity analysis, a stratified multivariate Cox regression model will be fitted after 
additional adjustment for key potential prognostic factors including prior chemotherapy (yes 
vs. no), performance status (0 vs. 1, 2), presence of bone lesions only at baseline (yes vs. no), 
time since first diagnosis of metastasis/recurrence to randomization (<6 Months, >= 6 
Months), non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) usage (adjuvant 
vs. metastatic), number of organs involved (1 vs. 2 vs. ≥ 3 – to be adapted depending on the 
number of patients in each category) and PgR status (positive vs. negative). A revised 
multivariate stratified cox model including the key prognostic factors as well as the baseline 
covariates where imbalances between arms have been observed will be added: performance 
status (0 vs. 1 or 2), presence of bone lesions only at baseline (yes vs. no), number of organs 
involved (1 vs. 2 vs. >=3), prior chemotherapy use (yes vs. no), age (<65 years vs. >=65 years 
old) and Race (Caucasian vs. non-caucasian). The strata will be based on stratification 
information obtained through IRT. 
Survival status, reason for censoring and death cause will be listed. Patients not known to 
have died will be censored for ‘Lost to follow-up’ if the time between their last contact date 
and the analysis cut-off date is longer than 3 months and 2 weeks (104 days).
95% confidence intervals for the median, hazard ratio and survival probabilities of the overall 
survival will be also provided as supportive analysis.
Overall response rate (ORR)
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.1 (Appendix 1). 
ORR will be calculated based on the FAS according to the ITT principle, using local 
radiologist’s/investigator’s tumor assessment. Patients with bone lesions only at baseline will 
be included in the numerator if they achieve a complete response. ORR estimates will be 
presented by treatment group along with exact 90% confidence intervals (Clopper and 
Pearson 1934). The estimation procedure will be repeated based on data for a subset of 
patients in the FAS with measurable disease only at baseline.
Clinical benefit rate (CBR)
Clinical benefit rate (CBR) is defined as the proportion of patients with best overall response 
of CR, PR, or overall lesion response of stable disease (SD for measurable disease and non-
CR/non-PD (NCRNPD) for non-measurable disease) with duration of 24 weeks or longer. A 
patient will be considered to have a SD/NCRNPD for 24 weeks or longer if SD/NCRNPD is 
recorded at 24 weeks or later after randomization. Taking into account the allowed time 
window for tumor assessment visits, the SD/NCRNPD response has to be recorded at 23 
weeks or later after randomization to be included in the CBR calculation. Best overall 


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response of CR, PR and overall lesion response of SD/NCRNPD are defined according to 
RECIST 1.1 (see Appendix 1). CBR will be calculated based on the FAS according to the ITT 
principle, using local radiologist’s/investigator’s tumor assessment. Patients with non-
measurable disease only at baseline will be included in the numerator if they achieve a 
complete response. CBR estimates will be presented by treatment group along with exact 90% 
confidence intervals.
ECOG performance status
ECOG performance status (PS) scale will be used to assess physical health of patients, 
ranging from 0 (most active) to 5 (least active):
Table 3-1
ECOG Performance Status 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
ECOG performance status will be assessed and recorded at baseline, on Treatment Day 1, at 
week 6 and every 6 weeks thereafter as well as at discontinuation from the study treatment 
(within one week after discontinuation). If patients discontinue study treatment for any reason 
other than progression, lost to follow-up or consent withdrawal, the ECOG performance status 
will continue to be performed every 6 weeks until progression, lost to follow-up, consent 
withdrawal or investigator decision in patient best interest.
Time windows will be defined for summaries of ECOG data. If more than one assessment is 
available in the same time window, the assessment closest to the planned date will be 
considered. If two assessments are obtained with the same time difference compared to the 
scheduled visit day, the assessment with the worst value will be considered. Data obtained at 
the end of treatment will be classified as other assessment in the corresponding time window. 
Note that only data collected under treatment (i.e. while the patient is treated and up to 7 days 
after last dose intake) will be included in the time to deterioration analysis. Post-treatment 
data will be summarized separately. The end of treatment assessment will be included if 
collected within 7 days of the last dose intake.   
Time Window
Planned visit timing
Time Window Definition
Baseline
On or before Study Day 1
<= Study Day 1
Week 6
Study Day 43
Study Days 22-63


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Week 12
Study Day 85
Study Days 64-105
Week 18
Study Day 127
Study Days 106-147
Every 6 weeks thereafter,
Week y=18+6*k
(with k=1,2 …)
Study Day (18+6*k)*7+1
Study Days (18+6*k)*7-20 to 
(18+6*k)*7+21
Note: EOT data visit are 
included if obtained within 7
days of last non-0 dose intake.
Study Day 1 = randomization date 
Frequencies of patients with ECOG PS values of 0, 1 or >=2 will be used to summarize the
ECOG PS data at each time window. .
An analysis of the time to definitive deterioration of the ECOG PS by at least one category of 
the score from baseline will be performed. A deterioration will be considered definitive if no 
improvements in the ECOG PS are observed at subsequent measurement times during the 
treatment period following the time point at which the deterioration is observed. (Example 1: 
if the score is 1 at baseline and then 1, 2, 1, 2, 3 at study days 28, 57, 83, 115, 150, 
respectively, then the time to definitive worsening is 115 days. Example 2: if the score is 1 at 
baseline and then 1, 1, 2 at study days 28, 57, 83, respectivel y, with no assessment of the 
ECOG performance status after day 83, then the time to definitive worsening is 83 days.)
Death will be considered as worsening of the ECOG PS if it occurs close to the last available 
assessment where “close” is defined as being within twice the planned period between two 
assessments. Patients who die after more than twice the planned period between two 
assessments will be censored at the date of their last assessment before the cut-off. This 
avoids overestimating the time to definitive worsening in patients dying after an irregular 
assessment scheme. For example, if the last assessment is at week 6 and the patient dies at
week 16, the definitive deterioration date will be week 16. On the other hand, if the last 
assessment is at week 6 and the patient dies at week 22, which is after more than twice the 
planned period between two assessments (6 weeks) since the last assessment (at week 6), then 
the patient is censored for definitive deterioration and the censoring date will be week 
6.Patients receiving any further anti-neoplastic therapy prior to definitive worsening will be 
censored at their date of last assessment prior to the start of therapy. Patients that have not 
worsened at the data cut-off point will be censored at the date of last assessment prior to the 
cutoff.
The Kaplan-Meier estimation method will be used to assess the distribution of time to 
definitive worsening in the ECOG PS score, stratified by treatment. The estimated treatment-
specific median times to definitive worsening will be presented along with 90% confidence 
intervals. The stratified Cox regression model will be used to estimate the hazard ratio of a 
definitive worsening in the ECOG PS score, along with the associated 90% confidence 
interval, comparing the everolimus + exemestane combination therapy with everolimus alone 
and comparing the everolimus + exemestane combination therapy with the capecitabine 
therapy.


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Patient reported outcomes (PRO)
The FAS will be used for all PRO summaries and listings.
Quality of life questionnaire (QLQ)
The EORTC QLQ-C30 questionnaire along with the breast module (BR23) will be used to 
collect patients’ quality of life (QoL) data. Raw QoL data will be scored according to the 
EORTC scoring manual. If at least half of the items comprising the scale have been answered, 
the score for this scale will be calculated.  For single item scales with missing responses and 
scales where less than half of the items have been answered, the score for these scales will be 
set to missing. The global health status/QoL scale score is identified as the primary QoL 
variable of interest. Physical functioning, emotional functioning and social functioning scale 
scores in QLQ-C30, and functional and symptom scale scores in BR23 are identified as 
secondary QoL variables of interest.
QLQ-C30 and BR23 will be assessed and recorded at baseline, on Treatment Day 1, at week 6 
and every 6 weeks thereafter as well as at discontinuation from the study treatment (within 
one week after discontinuation). If patients discontinue study treatment for any reason other 
than progression, lost to follow-up or consent withdrawal, the QLQ-C30 and BR23
performance status and will continue to be performed every 6 weeks until progression, lost to 
follow-up, consent withdrawal or investigator decision in patient best interest.
Time windows will be defined for descriptive summaries of PRO data. If more than one 
assessment is available in the same time window, the assessment closest to the planned date 
will be considered. If two assessments are obtained with the same time difference compared 
to the scheduled visit day, the assessment obtained prior to scheduled visit day will be 
considered. Data obtained at the end of treatment will be classified as other assessment in the 
corresponding time window. Note that only data collected under treatment (i.e. while the 
patient is treated and up to 7 days after last dose intake) will be included in the time to 
deterioration analysis. Post-treatment data will be summarized separately. The end of 
treatment assessment will be included if collected within 7 days of the last dose intake.  
Time Window
Planned visit timing
Time Window Definition
Baseline
On or before Study Day 1
<= Study Day 1
Week 6
Study Day 43
Study Days 22-63
Week 12
Study Day 85
Study Days 64-105
Week 18
Study Day 127
Study Days 106-147
Every 6 weeks thereafter,
Week y=18+6*k
(with k=1,2 …)
Study Day (18+6*k)*7+1
Study Days (18+6*k)*7-20 to 
(18+6*k)*7+21
Note: EOT data visit are 
included if obtained within 7
days of last non-0 dose intake.
Study Day 1 = randomization date 


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The number of patients filling QoL data and the number of patients missing/expected to have 
QoL assessments will be summarized by each treatment group for scheduled assessment time 
points. Furthermore, the amount and the pattern of missing data will be explored by treatment 
group and over time. The following categories will be used to describe whether the 
questionnaire was completed at a specific time point:
- yes, fully completed
- yes, partially completed
- no, patient (or subject) missed scheduled assessment visit
- no, patient refused due to poor health
- no, patient (or subject) refused (unrelated to health)- no, study staff felt patient was too ill
- no, questionnaire not available
- no, institutional error
- no, other
Other exploratory analyses may be performed to better understand the missingness pattern for 
QoL data.
Descriptive statistics (count, mean, median, standard deviation, first and third quartile) will be 
used to summarize domains at each scheduled assessment time. Patients will be included if 
they completed at least one questionnaire item. Additionally, change from baseline in the 
scale scores at the time of each assessment will be summarized. Patients with an evaluable 
baseline score and at least one evaluable post-baseline score during the treatment period will 
be included in the change from baseline analysis.
Time to definitive 10% deterioration in the global health status / QoL score, and in each of the 
three secondary scales, will be examined for the three treatment arms. In addition, time to 
definitive 5-point and 10-point deterioration in the global health status / QoL score will be 
explored for each treatment arm. The assessed distributions will be presented descriptively 
using Kaplan-Meier curves. Summary statistics based on Kaplan-Meier distributions will be 
presented, including the estimated median time to definitive 10% (5-, 10-point) deterioration 
and the probability of not experiencing definitive 10% (5-, 10-point) deterioration by 12 and 
24 weeks. Both point estimates and 90% confidence intervals will be presented.
Definitive 10% (5- or 10-point) deterioration is defined as a decrease in score by at least 10% 
(5 or 10 points) compared to baseline, with no later increase above this threshold observed 
during the course of the study. Baseline is defined as the latest available assessment made on 
or before the date of randomization when patient can still deteriorate. Time to definitive 
deterioration is the number of days between the date of randomization and the date of the 
assessment at which definitive deterioration is seen.
Death will be considered as deterioration of symptoms/QoL if it occurs close to the last 
available assessment where “close” is defined as twice the planned period between two 
assessments. This avoids overestimating the time to definitive worsening in patients dying 
after an irregular assessment scheme. Patients who die after more than twice the planned 


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period between two assessments since the last assessment will be censored at the date of their 
last available questionnaire.
Patients receiving any further anti-neoplastic therapy before definitive worsening will be 
censored at the date of their last assessment before starting this therapy. Patients that have not 
worsened as of the cut-off date for the analysis will be censored at the date of their last 
assessment (questionnaire) before the cut-off.
Treatment satisfaction questionnaire for medication (TSQM)
Patients’ self-reported satisfaction or dissatisfaction with the study treatment will be measured 
using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. TSQM is 
planned to be administered at week 3, 6, 12, and the end-of-treatment (EOT) visit. The 
questionnaire will be administered in the patients’ local language.
TSQM items will be divided into four scales: side effects, effectiveness, convenience, and 
global satisfaction. Raw TSQM data will be scored according to the scoring manual. Only 
scale scores with not more than one missing item will be computed.
The following time-based intervals will be used to group TSQM data over time. Day x is 
defined as date of TSQM administration – randomization date + 1. If more than one 
assessment is available in the same time window, the assessment closest to the planned date 
will be considered. If two assessments are obtained with the same time difference compared 
to the scheduled visit day, the assessment obtained prior to scheduled visit day will be 
considered.
Time 
window
Planned visit timing
Time  Window Definition
Week 3
Study Day 22
Days 11 to 31
Week 6
Study Day 43
Days 32 to 63
Week 12
Study Day 85
Days 64 to 105
EOT
EOT Day
Days (EOT-20) to (EOT+7)
If EOT occurs at the same time of week 3, week 6 or week 12 time window, priority is given 
for reporting at EOT time window.
All summaries of TSQM data will be based on the FAS according to the ITT principle. The 
number of patients filling TSQM data and the number of patients missing/expected to have 
TSQM assessments will be summarized by each treatment group for scheduled assessment 
time points. Furthermore, the amount and the pattern of missing data will be explored by 
treatment group and over time. The following categories will be used to describe whether the 
questionnaire was completed at a specific time point:
- yes, fully completed
- yes, partially completed


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- no
- no, patient (or subject) missed scheduled assessment visit
- no, patient refused due to poor health
- no, patient (or subject) refused (unrelated to health)
- no, study staff felt patient was too ill
- no, questionnaire not available in the appropriate language
- no, institutional error
- no, other
Other exploratory analyses may be performed to better understand the missingness pattern for 
TSQM data.
Descriptive statistics (count, mean, median, standard deviation, first and third quartile) will be 
used to summarize individual item and multi-item scale scores by treatment group and 
assessment time point (week 3, week 6, week 12, and EOT). Differences in mean scale scores 
at weeks 3 and 12, and differences in mean change in scale scores between weeks 3 and 12 
along with 90% confidence intervals comparing treatment satisfaction with everolimus + 
exemestane versus everolimus alone, and everolimus + exemestane versus capecitabine will 
be reported (no significance testing will be performed). The normal approximation will be 
used in the computation of confidence intervals.


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3.9
Safety evaluation
For all safety analyses, the safety set will be used. The assessment of safety will be based 
mainly on the frequency of adverse events and on the number of laboratory values that fall 
outside of pre-determined ranges. 
The overall observation period will be divided into three mutually exclusive segments:

pre-treatment period: from day of patient’s informed consent to the day before first 
dose of study treatment

on-treatment period: from day of first dose of study medication to 30 days after last 
dose of study treatment

post-treatment period: starting on day 31 after last dose of study treatment.
Safety summary tables will only include on-treatment events/assessments, i.e., those collected 
no later than 30 days after the date of the last study treatment administration. All safety 
events/assessments will be listed and those collected in the pre- and post-treatment period will 
be flagged.


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3.9.1
Adverse events (AEs)
3.9.1.1
Coding of AEs
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
3.9.1.2
Grading of AEs
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 AE is not necessarily twice as severe as a grade 1
AE).
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 not be used in this study; rather, this information will be collected on the “End of 
Treatment”, “Study Evaluation Completion” or “Survival Information” eCRF pages.
3.9.1.3
General rules for AE Reporting
AE summaries will include all AEs starting on or after study day 1 (i.e., on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last 
treatment/exposure date. All AEs will be listed. AEs starting prior to study day 1 and AEs 
starting later than 30 days after the last treatment/exposure date will be flagged in the listings.
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary system organ class 
(SOC_TXT), and for each preferred term (PT_TXT) using MedDRA coding. A subject with 
multiple occurrences of an AE will be counted only once in the AE category.
Separate AE summaries will be presented by primary system organ class, preferred term, an d 
maximum CTC grade (AEVGRD1C). A patient with multiple CTC grades for an AE will be 
summarized under the maximum CTC grade recorded for the event. In the summaries 
presented by grade, all AEs will be pooled regardless of whether they are CTC gradable or not, 
i.e., regardless of whether the question “CTC AE” (variable CTIAEV1C) on the Adverse 
Events eCRF is answered ‘Yes’ or ‘No’.
The frequency of CTC grade 3 and 4 AEs will be summarized separately.
Any information collected (e.g., CTC grades, relatedness to study drug, action taken, etc.) will 
be listed as appropriate.
3.9.1.4
AE summaries
The following adverse event summaries will be produced:


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
Adverse events, regardless of study drug relationship by primary system organ class and 
preferred term

Adverse events with suspected relationship to study drug by primary system organ class, 
preferred term

Adverse events with an overall incidence rate of 5% or more in either treatment arm, 
regardless of study drug relationship by primary system organ class and preferred term 

Adverse events, regardless of study drug relationship by primary system organ class, 
preferred term and maximum CTC

Adverse events with suspected study drug relationship by primary system organ class, 
preferred term and maximum CTC

CTC grade 3 or 4 adverse events, regardless of study drug relationship by primary system 
organ class and preferred term

CTC grade 3 or 4 adverse events with suspected study drug relationship by primary 
system organ class and preferred term

Deaths, by primary system organ class and preferred term

On-treatment deaths, by primary system organ class and preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Serious adverse events with suspected study drug relationship, by primary system organ 
class and preferred term

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term

Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term

Adverse events requiring additional therapy, regardless of study drug relationship, by 
primary system organ class and preferred term

All grade 3/4 non-hematological adverse events
3.9.1.5
AEs of special interest (AESIs)
Specific groupings of adverse events (AESIs) will be considered and the number of patients 
with at least one event in each grouping will be reported for the entire population. Such 
groups consist of adverse events for which there is a specific clinical interest in connection 
with RAD001 treatment (i.e. where RAD001 may influence a common mechanism of action 
responsible for triggering them) or adverse events which are similar in nature (although not 
identical). The latest version of Case Retrieval Strategy (CRS) sheet should be used.
3.9.1.6
Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set 
population.


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If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
3.9.2
Laboratory data
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTCAE).
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
group. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by parameter and treatment group.
Laboratory data summaries will include all laboratory assessments collected no later than 30
days after the last treatment/exposure date. All laboratory assessments will be listed and those 
collected later than 30 days after the last treatment/exposure date will be flagged in the 
listings.
Laboratory data will be classified (by Novartis biostatistics/SAS programming) into CTC 
grades according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03. A severity grade of 0 will be assigned when the value is within normal limits. In the 
case when a local laboratory normal range overlaps into the higher (i.e., non-zero) CTC grade, 
the laboratory value will still be taken as within normal limits and assigned a CTC grade of 
zero.
The following rules will be applied: 

Conflict between normal range and grade definition: because many institutions have 
differences for normal ranges of metabolic laboratory and hematology values, the CTCAE 
often uses the terms 'Upper Limit of Normal (ULN)' and 'Lower Limit of Normal (LLN)' 
in lieu of actual numerical values. In some cases, an institution's LLN might be beyond the 
range specified for a grade. In this case, the institutional limits of normal should take 
precedence over the CTCAE values: the laboratory value will still be taken as within 
normal limits and assigned a CTC grade of zero.

For the few parameters having comparison to baseline in CTCAE grading definition 
(Fibrinogen, INR, Hemoglobin, Creatinine), the highest grade will be retained. In other 
words, in the particular case when a value is grade x as per CTC grade definition based on 
threshold/ranges and also grade x+1 when comparing to baseline, grade x+1 is retained. 


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
Grade 5 will not be used. Grade values will be integers from -4 to 4.

For calcium, CTCAE grading is based on Corrected Calcium and not on Calcium. 
Corrected Calcium (CALC) will be calculated from Albumin and Calcium: Corrected 
Calcium (mg/dL) = Calcium (mg/dL) –0.8 [Albumin (g/dL)-4].

GFR will be calculated based on creatinine (CREA parameter) collected regularly during 
treatment and the CTC grade will be determined for GFR.

For creatinine clearance (CRCLCG parameter), no calculation of CTC grade will be done.
The following summaries will be produced for the laboratory data (by laboratory parameter
and treatment):

Number and percentage of patients with worst post-baseline CTC grade (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.
The following listings will be produced for the laboratory data:

Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges. 

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
3.9.3
Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters expected to be collected include: height (cm), weight (kg), body temperature (°C), 
pulse rate (beats per minute), systolic and diastolic blood pressure (mmHg).
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

weight: increase from baseline of ≥ 10%

pulse rate: ≥ 120 bpm with increase from baseline ≥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


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
body temperature: ≤35°C

weight: decrease from baseline of ≥ 10%

pulse rate: ≤ 50 bpm with decrease from baseline ≥15 bpm.
The following summaries will be produced for each vital sign parameter:

summary statistics for change from baseline to the worst post-baseline value (in both 
directions, i.e., from baseline to the highest post-baseline and from baseline to the 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 group:

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 the assessments 
collected later than 30 days after the last treatment/exposure date will be flagged.
3.9.4
Other safety data
Data from other tests (e.g., electrocardiogram, pulmonary function tests, LVEF) 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/exposure 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.


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3.11
Interim analysis
One efficacy interim analysis of PFS was conducted to allow early termination of the
everolimus monotherapy arm, in case of far inferior efficacy as compared to the everolimus +
exemestane combination treatment arm. The efficacy interim analysis was planned after 75 
PFS events have been observed as per local tumor assessment, across the following 2 arms: 
everolimus monotherapy and everolimus + exemestane combination arm.
Based on simulations, the probability of stopping the everolimus monotherapy arm was 
calculated. 
Table 3-2
Probability (from 2000 simulated trials) of stopping a single agent arm 
under different truth
True hazard ratio
Probability of stopping everolimus 
monotherapy arm at 75 PFS events
0.1
99.30%
0.2
48.75%
0.3
6.45%
0.4
0.5%
0.5                                   0%
A general guidance was to stop the single agent arm if the observed hazard ratio was less than 
0.20, (i.e., if the everolimus monotherapy arm was far inferior when compared to the 
everolimus + exemestane combination arm). The proposed decision guidance yielded high 
probability to stop the control arm if the combination arm is highly superior (HR≤0.1), while 
keeping the probability low if the superiority was not so extreme (HR≥0.3). 
At the time of interim analysis, the observed hazard ratio along with the 90% co nfidence 
interval was provided for decision making. Simulation (L.J. Wei, 2007) was also carried out to 
predict the hazard ratio and 90% confidence interval at the final analysis, based on the data 
observed at interim. 
The predicted hazard ratios and 90% confidence intervals were provided by the independent 
statistician to independent programmer as per following process:

Trial statistician created R program that was used to calculate predicted hazard ratios 
and 90% confidence intervals and put this program into GPS under source control in 
the unrestricted area.

Independent statistician imported this R program in the restricted area, put it under 
source control and used it to produce a csv file in the restricted area containing the 
predicted hazard ratios and 90% confidence intervals.

Independent programmer used the csv file created by independent statistician to 
produce outputs displaying the predicted hazard ratios and 90% confidence intervals.
Based on the interim analysis results and DMC recommendation, the study continues without
change.


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3.12
Sample size calculation
The primary objective of this study is to estimate the hazard ratio of PFS comparing 
everolimus + exemestane versus everolimus alone with approximately 150 PFS events. For 
this number of PFS events, the precision of HR estimation is illustrated by tabulating the 
approximate 90% confidence intervals (Jennison and Turnbull 1999) for the hazard ratio (HR) 
(see Table 3-3) under different point estimates for the HR.
Table 3-3
Approximate* 90 percent CI bounds for HR 
Assuming 146 observed PFS events
Assuming 150 observed PFS events
Estimated HR
Lower bound of 
approximate 90% 
CI for HR
Upper bound of 
approximate 90% 
CI for HR
Lower bound of 
approximate 90% 
CI for HR
Upper bound of 
approximate 90% 
CI for HR
0.55
0.419
0.722
0.420
0.719
0.60
0.457
0.788
0.459
0.785
0.65
0.495
0.853
0.497
0.850
0.70
0.533
0.919
0.535
0.916
0.75
0.571
0.985
0.573
0.981
* Jennison and Turnbull (1999)
A total of 300 patients are planned to be recruited at a uniform rate over an 18 -month 
enrollment period and randomized with equal allocation to one of the three treatment arms. 
Assuming the median PFS time to be 7 months in the everolimus + exemestane arm (Baselga 
et al 2012), 4 months in the everolimus monotherapy arm (NCI-Canada), and 6 months in the 
capecitabine arm (O’Shaughnessy et al 2012, Stocker et al 2007, Jäger et al 2010, Kaufmann 
et al 2010, Robert 2011), the expected time to observe 150 PFS events in each of the two 
pairwise treatment comparisons is about 28 months after the randomization date of the first 
patient in the study, assuming that about 10% of the patients will be lost to follow-up or 
withdraw consent.
3.13
Statistical outputs
Tables, figures and listings will be generated as described in [CRAD001Y2201 RAP module 
7 – CSR deliverables].
4
Details of the statistical analysis
4.1
Baseline comparability
Appropriate descriptive statistics of baseline variables 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 presented by 
treatment group, but no p-values will be provided.


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4.2
Time-to-event analyses
The following sections present a general methodology to be used to analyze the following 
time-to-event variables:

Progression-free survival

Overall survival

Time to definitive deterioration in the ECOG score by one category of the score from
baseline

Time to definitive 10%  deterioration from baseline in the global health status / QoL 
score of the EORTC QLQ-C30 questionnaire

Time to definitive 5-point deterioration from baseline in the global health status / QoL 
score of the EORTC QLQ-C30 questionnaire

Time to definitive 10-point deterioration from baseline in the global health status / 
QoL score of the EORTC QLQ-C30 questionnaire

Time to definitive 10% deterioration from baseline in each of the three secondary 
scales (physical functioning, emotional functioning, and social functioning) of the 
EORTC QLQ-C30 questionnaire
4.2.1
Analysis of time-to-event data with ties
The STRATA statement in the SAS LIFETEST procedure will be used to analyze time-to-
event data with ties. The SAS PHREG procedure with option TIES=EXACT will be used to 
fit the Cox proportional hazards model.
4.2.2
Kaplan-Meier survival function estimation
The survival function in each treatment group will be estimated using the Kaplan-Meier
(product-limit) method as implemented in PROC LIFETEST (see Figure 4-2 below). In each 
treatment group, the estimated median PFS time, along with the approximate 90% confidence 
interval, will be obtained from the PROC LIFETEST output. The log-log transformation 
option available within PROC LIFETEST will be used to compute the confidence intervals. 
The Kaplan-Meier graphs will be obtained from the SAS software. The hazard ratio point and 
interval estimates will be displayed in the figures.
4.2.3
Hazard ratio estimation
The hazard ratio as a measure of treatment effect will be derived from the Cox proportional
hazards model using SAS procedure PHREG with TIES=EXACT option in the MODEL
statement. The stratified unadjusted Cox model will be used (where the baseline hazard
function is allowed to vary across strata) for the primary and key secondary analyses, i.e., the 
MODEL statement will include the indicator of assignment to the everolimus + exemestane 
arm as the only covariate, and the STRATA statement will include the stratification variable 
obtained through IRT.
General SAS code for the stratified Cox model
PROC PHREG data=dataset;
MODEL survtime*censor(1)=trt / TIES=EXACT;
STRATA stratum 1 .. <stratum k>;


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RUN;
/* survtime represents variable containing event/censoring times;
censor represents censoring variable (1=censored, 0=event);
trt represents treatment group variable;
stratum1 to stratumk represent stratification variables */
The two-sided 90% asymptotic confidence interval for the hazard ratio will be based on the 
Wald test.
4.3
Median follow-up of the study
Median study follow-up (in months) in this study will be calculated as 
([analysis cut-off date] - [median randomization date] + 1)/30.4375, where 30.4375 is the 
average duration of a month in days: 365.25/12 ≈ 30.4375.
The median randomization date is obtained by first sorting all patients in the FAS by the 
randomization dates, respectively, and then taking the date of the median patient (i.e., the 
patient in the middle of the sorted list in case of an odd number of patients or the average 
between the two patients in the middle of the sorted list in case of an even number of patients).
The time from last contact date to data cut-off date will be summarized by time intervals in 
increments of 6 weeks.
The number of patients at risk of death and the number of deaths in intervals of time with 
increments of 6 weeks will be summarized during the course of the trial using the life table 
method. The Kaplan-Meier estimates of survival probabilities and associated standard errors 
will be provided.


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5
References
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O'Shaughnessy JA, Kaufmann M, Siedentopf F, et al. (2012) Capecitabine monotherapy: 
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treatment of human epidermal growth factor receptor 2-negative, locally recurrent or 
metastatic breast cancer. J Clin Oncol. 29(10):1252-60.
Jäger E, Al-Batran S, Saupe S, et al. (2010) A randomized phase III study evaluating 
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Stockler M, Sourjina T, Grimison P, et al (2007) A randomized trial of capecitabine (C) given 
intermittently (IC) rather than continuously (CC) compared to classical CMF as first-line 
chemotherapy for advanced breast cancer (ABC). J Clin Oncol, 25:18s (2007 ASCO Annual 
Meeting Proceedings Part I., 2007: 1031)
Jenninson, C, Turnbull, BW: Group sequential methods with applications to clinical trials.
Chapman and Hall/CRC. 2000
Brookmeyer, R. and Crowley, J. (1982): A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.