A Phase IIIb, Multi-center, Open-label Study of RAD001 in Combination With EXemestane in Post-menopausal Women With EStrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Locally Advanced or Metastatic Breast Cancer
Phase: PHASE3
Conditions: Post Menopausal Breast Cancer
Sponsor: Novartis Pharmaceuticals

Clinical Development 
Everolimus (RAD001) 
Protocol Number CRAD001JIC06 / NCT03176238
A phase IIIb, multi-center, open-label study of EVERolimus 
(RAD001) in combination with EXemestane in post-
menopausal women with EStrogen receptor positive, 
human epidermal growth factor receptor 2 negative locally 
advanced or metastatic breast cancer EVEREXES 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Development phase 
IIIb 
Version number 
02 (Clean) 
Document status 
Final 
Release date 
07-Jul-2014
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 tables ................................................................................................................... 6 
List of figures .................................................................................................................. 7 
List of abbreviations ........................................................................................................ 8 
Glossary of terms .......................................................................................................... 11 
Amendment 2................................................................................................................ 12 
Amendment 1................................................................................................................ 14 
Protocol summary ......................................................................................................... 17 
1 
Background ................................................................................................................... 22 
1.1 
Epidemiology, pathogenesis, and current treatments of advanced breast 
cancer ................................................................................................................ 22 
1.2 
Overview of investigational treatments .............................................................. 25 
1.2.1 
Overview of Everolimus .................................................................... 25 
1.2.2 
Potential role of mTOR inhibition in the treatment of bone 
metastases .......................................................................................... 32 
1.2.3 
Overview of Exemestane ................................................................... 32 
2 
Rationale ....................................................................................................................... 33 
2.1 
Study rationale and purpose ............................................................................... 33 
2.2 
Rationale for the study design ............................................................................ 33 
2.3 
Rationale for dose and regimen selection ........................................................... 34 
3 
Objectives and endpoints ............................................................................................... 34 
3.1 
Primary objectives ............................................................................................. 34 
3.1.1 
Primary endpoints .............................................................................. 34 
3.2 
Secondary objectives ......................................................................................... 34 
3.2.1 
Secondary endpoints .......................................................................... 35 
 
 35 
 
 35 
4 
Study design ................................................................................................................. 37 
4.1 
Description of study design ................................................................................ 37 
4.2 
Definition of end of the study............................................................................. 39 
4.3 
Early study termination ...................................................................................... 40 
5 
Population ..................................................................................................................... 40 
5.1 
Inclusion criteria ................................................................................................ 40 
5.2 
Exclusion criteria ............................................................................................... 42 

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6 
Treatments .................................................................................................................... 43 
6.1 
Study treatments ................................................................................................ 43 
6.1.1 
Everolimus......................................................................................... 44 
6.1.2 
Exemestane ........................................................................................ 44 
6.1.3 
Dosing regimen.................................................................................. 44 
6.1.4 
Treatment duration ............................................................................. 45 
6.2 
Dose modifications ............................................................................................ 45 
6.2.1 
Dose adjustment and interruption ....................................................... 45 
6.2.2 
Follow-up for toxicities ...................................................................... 48 
6.3 
Known undesirable effects of the study drugs .................................................... 48 
6.3.1 
Non-infectious pneumonitis ............................................................... 49 
6.3.2 
Infections ........................................................................................... 49 
6.3.3 
Management of Hepatitis reactivation/flare ........................................ 50 
6.4 
Concomitant medication .................................................................................... 52 
6.4.1 
Prohibited concomitant therapy .......................................................... 53 
6.5 
Discontinuation of the study drugs ..................................................................... 55 
6.6 
Patient numbering .............................................................................................. 56 
6.7 
Study drug preparation and dispensation ............................................................ 56 
6.7.1 
Packaging and labeling ...................................................................... 56 
6.7.2 
Drug supply and storage..................................................................... 56 
6.7.3 
Study drug compliance....................................................................... 57 
6.7.4 
Study drug accountability................................................................... 57 
6.7.5 
Disposal and destruction .................................................................... 58 
7 
Visit schedule and assessments...................................................................................... 58 
7.1 
Study flow and visits schedule ........................................................................... 58 
7.1.1 
Screening period ................................................................................ 62 
7.1.2 
Treatment period ................................................................................ 63 
7.1.3 
Treatment exposure and compliance .................................................. 63 
7.1.4 
Discontinuation of the study drugs ..................................................... 63 
7.1.5 
End of the study ................................................................................. 64 
7.2 
Safety and tolerability assessments .................................................................... 65 
7.2.1 
Physical examination, height and weight ............................................ 65 
7.2.2 
Vital signs .......................................................................................... 65 
7.2.3 
Laboratory evaluations ....................................................................... 65 
7.2.4 
Pulmonary function tests (PFTs) ........................................................ 67 
7.3 
Efficacy assessments .......................................................................................... 68 

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7.4 
ECOG Performance Status ................................................................................. 69 
 
 70 
8 
Safety monitoring and reporting .................................................................................... 70 
8.1 
Adverse events................................................................................................... 70 
8.1.1 
Definitions and reporting ................................................................... 70 
8.1.2 
Laboratory test abnormalities ............................................................. 71 
8.1.3 
Adverse events of special interest....................................................... 72 
8.2 
Serious adverse events ....................................................................................... 72 
8.2.1 
Definitions ......................................................................................... 72 
8.2.2 
Reporting ........................................................................................... 73 
8.3 
Emergency unblinding of treatment assignment ................................................. 74 
8.4 
Pregnancies........................................................................................................ 74 
8.5 
Warnings and precautions .................................................................................. 74 
9 
Data collection and management ................................................................................... 74 
9.1 
Data confidentiality............................................................................................ 74 
9.2 
Site monitoring .................................................................................................. 75 
9.3 
Data collection ................................................................................................... 75 
9.4 
Database management and quality control ......................................................... 76 
10 Statistical methods and data analysis ............................................................................. 76 
10.1 
Analysis sets ...................................................................................................... 76 
10.2 
General statistical methods................................................................................. 77 
10.3 
Patient demographics and baseline characteristics .............................................. 77 
10.4 
Treatments (study drugs, concomitant therapies) ................................................ 77 
10.5 
Primary objective ............................................................................................... 78 
10.6 
Secondary objectives ......................................................................................... 78 
10.6.1 
Efficacy endpoints ............................................................................. 78 
10.6.2 
Other endpoints.................................................................................. 80 
10.7 
Sample size calculation ...................................................................................... 80 
11 Ethical considerations and administrative procedures .................................................... 80 
11.1 
Regulatory and ethical compliance ..................................................................... 80 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 80 
11.3 
Informed consent procedures ............................................................................. 81 
11.4 
Discontinuation of the study .............................................................................. 81 
11.5 
Publication of study protocol and results ............................................................ 81 
11.6 
Study documentation, record keeping and retention of documents...................... 81 
11.7 
Confidentiality of study documents and patient records ...................................... 82 

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11.8 
Audits and inspections ....................................................................................... 82 
12 Protocol adherence ........................................................................................................ 83 
12.1 
Amendments to the protocol .............................................................................. 83 
13 References (available upon request) .............................................................................. 84 
14 Appendices ................................................................................................................... 87 
14.1 
Appendix 1: Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1) ............... 87 
14.1.1 
Introduction ....................................................................................... 89 
14.1.2 
Efficacy assessments .......................................................................... 89 
14.1.3 
Definitions ......................................................................................... 89 
14.1.4 
Eligibility based on measurable disease.............................................. 90 
14.1.5 
Methods of tumor measurement - general guidelines .......................... 90 
14.1.6 
Baseline documentation of target and non-target lesions .................... 92 
14.1.7 
Follow-up evaluation of target and non-target lesions ........................ 93 
14.1.8 
Follow-up and recording of lesions .................................................... 93 
14.1.9 
Non-nodal lesions .............................................................................. 93 
14.1.10 
Nodal lesions ..................................................................................... 94 
14.1.11 
Determination of target lesion response.............................................. 94 
14.1.12 
Determination of non-target lesion response....................................... 96 
14.1.13 
New lesions ....................................................................................... 97 
14.1.14 
Evaluation of overall lesion response ................................................. 97 
14.1.15 
Efficacy definitions ............................................................................ 98 
14.1.16 
Best overall response ......................................................................... 98 
14.1.17 
Time to event variables .................................................................... 101 
14.1.18 
Progression-free survival ................................................................. 101 
14.1.19 
Overall survival ............................................................................... 101 
14.1.20 
Time to progression ......................................................................... 101 
14.1.21 
Time to treatment failure .................................................................. 101 
14.1.22 
Duration of response ........................................................................ 102 
14.1.23 
Time to response .............................................................................. 102 
14.1.24 
Definition of start and end dates for time to event variables ............. 103 
14.1.25 
Handling of patients with non-measurable disease only at baseline .. 104 
14.1.26 
Sensitivity analyses .......................................................................... 105 
14.1.27 
Data handling and programming rules .............................................. 107 
14.1.28 
Study/project specific decisions ....................................................... 107 
14.1.29 
End of treatment phase completion .................................................. 107 
14.1.30 
End of post-treatment follow-up (study phase completion) ............... 108 

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14.1.31 
Medical validation of programmed overall lesion response .............. 109 
14.1.32 
Programming rules ........................................................................... 109 
14.1.33 
Calculation of ‘time to event’ variables ............................................ 109 
14.1.34 
Incomplete assessment dates ............................................................ 109 
14.1.35 
Incomplete dates for last known date patient alive or death .............. 110 
14.1.36 
Non-target lesion response ............................................................... 110 
14.1.37 
Study/project specific programming ................................................. 110 
14.1.38 
Censoring reason ............................................................................. 110 
14.1.39 
References (available upon request) ................................................. 111 
 
 
List of Appendices 
Appendix 1: Guidelines for response, duration of overall response, TTF, TTP, progression-
free survival and overall survival (based on RECIST 1.1) 
 
 
List of tables 
Table 1-1 
Study Y2301 (BOLERO-2): Most common Adverse Events (equal 
or greater than 10% of patients) ......................................................... 31 
Table 3-1 
Objectives and related endpoints ........................................................ 36 
Table 6-1 
Starting dose and treatment schedule .................................................. 44 
Table 6-2 
Everolimus dose reduction steps ........................................................ 45 
Table 6-3 
Everolimus: dose modification guidelines for hematologic 
toxicities ............................................................................................ 46 
Table 6-4 
Everolimus: dose modification guidelines for non-hematologic 
toxicities ............................................................................................ 47 
Table 6-5 
Actions recommended base on hepatitis B screening results ............... 50 
Table 6-6 
Guidelines for management of hepatitis B .......................................... 51 
Table 6-7 
Guidelines for management of hepatitis C .......................................... 52 
Table 6-8 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A ............................................................................. 54 
Table 6-9 
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors .............................. 55 
Table 7-1 
Schedule of assessments .................................................................... 59 
Table 7-2 
Imaging collection plan ...................................................................... 69 
Table 7-3 
ECOG Performance Status ................................................................. 69 

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Table 14-1 
Response criteria for target lesions ..................................................... 94 
Table 14-2 
Response criteria for non-target lesions .............................................. 96 
Table 14-3 
Overall lesion response at each assessment ........................................ 98 
Table 14-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................ 104 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response ....... 106 
 
 
List of figures 
Figure 1-1 
Tumor Growth Changes in the HBCx-3 Breast Xenograft Model ....... 27 
Figure 4-1 
Study design ...................................................................................... 39 
 
 

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List of abbreviations 
Ab 
Antibody 
ABC 
Advanced Breast Cancer: locally advanced, recurrent or metastatic breast cancer 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
Ag 
Antigen 
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 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AS(A)T 
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/SGOT 
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 
 
 
BC 
Breast Cancer 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CFR 
Code of Federal Regulation 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
Cmax 
Maximum Blood Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
CYP 
Cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 isoenzyme 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
E2 
17β-estradiol 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/record Form 
EDC 
Electronic Data Capture 
EGM 
Emergent Growth Market 
EMA 
European Medicines Agency 

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EOT 
End Of Treatment 
EPAR 
European public assessment report 
ER 
Estrogen Receptor 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (USA) 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
Hb 
Hemoglobin 
HBcAb 
Hepatitis B core antibodies 
HBs Ab 
Hepatitis B surface antibodies 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hep B 
Hepatitis B 
Hep C 
Hepatitis C 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
3-Hydroxy-3Methyl-Glutaryl Coenzyme A 
HR 
Hazard ratio 
HR 
Hormone Receptor 
HRT 
Hormone Replacement Therapy 
HUVECs 
Human Umbilical Vein Endothelial Cells 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
ImmunoHistoChemistry 
IMS 
Integrated Medical Safety  
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LMWH 
Low Molecular Weight Heparin 
MBC 
Metastatic Breast Cancer 
MRI 
Magnetic Resonance Imaging 
MRP 
Mutual Recognition Procedure (EU) 
mTOR 
mammalian Target of Rapamycin 
mTORC1 
mTOR-raptor (regulatory-associated protein of mTOR, Raptor) signal transduction complex 1  
NCI 
National Cancer Institute 
NDA 
New Drug Application 

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NSAI 
Non-Steroidal Aromatase Inhibitors 
o.d.  
omnia die/once a day 
O2 
Oxygen 
ORR 
Objective Response Rate 
OS 
Overall Survival 
p.o. 
per os / by mouth / orally / by oral route of administration 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PFT 
Pulmonary Function Test 
P-gp 
P-glycoprotein 
PgR 
Progesterone Receptor 
PHI 
Protected Health Information 
PI3K 
Phosphatidylinositol 3-Kinase (upstream effector of the mTOR signaling pathway) 
 
 
PJP 
Pneumocystis jirovecii pneumonia 
pNET 
Primitive Neuroectodermal Tumor(s) 
PR 
Partial Response 
PS 
Performance Status 
Pt 
Patient 
Raptor 
Regulatory-Associated Protein of mTOR 
RBC 
Red Blood Cell Count 
REB 
Research Ethics Board  
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
S6K1 
serine / threonine kinase p70S6 kinaseS6 Kinase 1 
SAE 
Serious Adverse Events 
SD 
Stable Disease 
SEGA 
Subependymal giant cell astrocytoma 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half Life 
tmax 
Time to Maximum Concentration 
TSC 
Tuberous Sclerosis Complex 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
UNK 
Unknown 
UTI 
Urinary Tract Infection 
VEGF(R) 
Vascular Endothelial Growth Factor (Receptor) 
WBC 
Total White Blood Cell Count 
WHO 
World Health Organization 
Wks 
Weeks 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug. 
Investigational treatment 
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within 
approved indication/dosage. 
Medication number 
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study. 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures and not included in the investigational treatment. 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/healthy 
volunteer who enrolls in the study. 
Period 
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for safety, progression and/or survival. 
Stage (in cancer) 
The extent of a cancer in the body. Staging is usually based on the 
size of the tumor, whether lymph nodes contain cancer, and 
whether the cancer has spread from the original site to other parts 
of the body. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later. 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins, where 
applicable. 
Study treatment in this case refers to the investigational and non-
investigational treatments used in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment 
for any reason; may or may not also be the point/time of premature 
patient withdrawal. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points.

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Amendment 2 
Rationale for Amendment 2 
Everolimus has been approved in the US and in the European Union for the treatment of 
advanced breast cancer in combination with exemestane in In July 2012,  
This study was initiated in 2012 with the aim of confirming safety and efficacy data and 
facilitate treatment access to everolimus plus exemestane for HR-positive/Her-2-negative 
advanced breast cancer until commercial availability in participating countries and estimated 
to end by 31st December 2014. After that date, should the study drug not be accessible to 
patients in the respective country, Novartis should have implemented local transition or exit 
plan in order to ensure that all on-going patients will still have access to the study medication 
without any delay in their treatment 
As of June 30th 2014, 198 patients have been enrolled into the study.  
At this stage we deem appropriate to change the end of study “until everolimus is locally 
reimbursed or commercialized for this indication or until all patients have been discontinued 
from investigational treatment due to disease progression, unacceptable toxicity, death, 
consent withdrawal or any other reason”, in order to:  
• Facilitate treatment continuation at the single patient level in all participating countries 
• Continue data collection and further strengthen the final safety and efficacy data set 
The statistical plan was revised accordingly to take into account prolonged study duration and 
to ensure data will be analyzed will be mature enough to derive conclusive results. with 
primary efficacy and safety/tolerability analysis now planned at 15 months of median follow 
up time, i.e. at approximately two times the median PFS observed in the BOLERO-2 study. 
On the other hand, as the investigational drug will be commercially available in the majority 
of the participating countries by the end of 2014, recruitment will end in any case in all 
participating countries no later than on 31st of October 2014.  
Moreover, as substantial updates were included in the [Investigator’s Brochure] (version 13) 
recently released, relevant sessions of the protocol have been amendment accordingly, 
although this does not imply major changes in study implementation and conduction.  
Additional minor changes were included to amend negligible inconsistencies in the previous 
version, 
Changes to the background session: 
• Updated information about everolimus clinical efficacy and safety profile have been 
included. 
Changes to study design: 
• It is specified that enrollment will end in all participating countries by the time of 
registration/commercial availability of everolimus in the investigational indication and in 
any case no later than October 31st 2014.  

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• End of study has been amended to be in each participating country when everolimus is 
locally reimbursed or commercialized for this indication or when all patients have been 
discontinued from investigational treatment due to disease progression, unacceptable 
toxicity, death, consent withdrawal or any other reason. In those countries in which 
patients will be transitioned to locally reimbursed or commercialized drug supply, 
Novartis will have a local transition plan in order to ensure that all on-going patients will 
still have access to the study medication without 
Changes to dose references: 
• Publication fromYardley D. et al. 2014 is now included 
IRB/IEC 
A copy of this amended protocol must be sent to the applicable Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval/favorable opinion 
and any applicable health authority authorization 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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Amendment 1 
Amendment rationale 
As of November 18th 2013, 114 patients have been enrolled into the study. 
Need for more clarity about the phase IIIb nature vs ‘expanded treatment program’ of this 
study has been raised in multiple occasions during discussions with Health Authorities and for 
internal purposes. 
We thus deemed appropriate to bring more clarity about this aspect standardizing the relevant 
sessions of the protocol in line with the phase IIIb nature of this study, with the aim of 
confirming the safety and efficacy of everolimus plus exemestane for the treatment of HR-
positive/Her-2-negative advanced breast cancer in Emerging Growth Markets. 
Moreover, the management of selected adverse events will be updated and aligned across the 
everolimus program and with the last [Investigator’s Brochure] (version 12), specifically for 
the window of time permitted for temporary discontinuation of the treatment with everolimus 
upon the development of Grade 2 noninfectious pneumonitis (4 weeks in the original protocol, 
3 weeks in the amended version). 
Additional changes in inclusion/exclusion criteria include the removal of previous treatment 
with exemestane from exclusion criteria, in line with product SmPC, and the exclusion of 
patients with leptomeningeal metastasis, as evidence of efficacy of the investigational therapy 
in this patients is missing, being these patients excluded from the phase III registration study. 
Minor changes were introduced in the guidelines for screening and follow-up of bone disease 
to better standardize study procedures and correct some discrepancies in the original protocol. 
ER (endocrine receptor) has been amended with HR (hormone receptor) along the whole 
protocol for better consistency with inclusion criteria (admitting patients with both ER and/or 
PgR positive tumors) 
Changes to the title: 
• The term ‘expanded access’ has been removed from the title and along the whole 
document, in order to avoid confusion given the phase IIIb study design 
Changes to the rationale and study design: 
• Safety and tolerability is confirmed to be the primary endpoint of the study (no changes vs 
previous version). The objective of providing early access to the treatment before local 
registration/reimbursement has been moved to the end of the secondary endpoint list. 
Change to the inclusion – exclusion criteria: 
• Previous treatment with exemestane has been removed from exclusion criteria, in line with 
product SmPC 
• The exclusion of patients with leptomeningeal metastasis has been added, due to the lack 
of any evidence of efficacy of the investigational therapy in these patient subgroup 

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• It has been specified regarding HBV testing that all patients who currently live in (or have 
lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and 
Greece for more than 6 months should be tested for hepatitis B viral load and serologic 
markers. 
Changes to the treatment session: 
• It is now specified that enough tablets should be provided to cover administration until 
next scheduled visit 
• In the actions recommended base on hepatitis B screening results it is clarified that 
prophylaxis treatment, when needed, should be started at least 1 week prior to first dose of 
study drug 
• List of inhibitors or inducers of the isoenzyme CYP3A to be avoided during treatment 
with investigational drug has been updated, according to IB version 12. 
• It has been added that the storage temperature must be recorded at least 3 times per week 
in the temperature log, as per recent Novartis standard operating procedure updates. 
Changes to visit schedule and assessments: 
• MRI has been added as an alternative of CT when applicable 
• Regarding bone assessments, it has been clarified that bone scan/X-ray should be 
performed at screening and every 10 weeks if bone metastases are present at baseline. If 
bone metastases are not identified at baseline, bone scans will be performed as clinically 
indicated. In addition, CT/MRI will be required every 10 weeks until progression. If bone 
metastases are not identified at baseline, bone CT/MRI will be performed only to confirm 
potential findings identified by bone scans/X-rays. 
• The window of time to complete screening imaging assessments has been standardized to 
21 days along the whole document. For bone assessments this window has been now 
limited to 6 weeks prior to the Baseline visit/Treatment Day 1. 
 
 
 
• A typo in the definition of measurable lesions has been amended, confirming that all 
patients should have at least one lesion that can be accurately measured in at least one 
dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT as 
per RECIST 1.1 criteria 
• Table 7-2 has been added to better specify the imaging collection plan, including CT or 
MRI for any site of disease different than chest, abdomen, pelvis, bone and brain and skin 
color photography for skin lesions 
Changes to safety monitoring and reporting: 
• Hypophosphatemia, hypersensitivity, wound healing complications, increased 
creatinine/renal failure/proteinuria, cardiac failure have been added to the list of adverse 
events with special interest, in line with the most updated version of the risk management 
plan 

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Changes to Appendices: 
• Appendix 1 (Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1)) has been updated 
with the most recent version of the document (version 3.1). 
IRB/IEC 
A copy of this amended protocol must be sent to the applicable Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval/favorable opinion 
and any applicable health authority authorization 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 
CRAD001JIC06 
Title 
A phase IIIb, multicenter, open-label, study of everolimus (RAD001) in combination 
with exemestane in post-menopausal women with estrogen receptor positive, human 
epidermal growth factor receptor 2 negative locally advanced or metastatic breast 
cancer 
Brief title 
EVEREXES 
Sponsor and Clinical 
Phase 
Novartis 
Phase IIIb 
Investigation type 
Drug 
Study type 
Phase IIIb 
Purpose and rationale 
The present international, multi-center, open-label, single-arm study aims at 
collecting clinical safety, tolerability and efficacy data with the use of everolimus 
combined with exemestane in the Novartis Oncology EGM countries for the treatment 
of post-menopausal women with hormone receptor (HR) positive, human epidermal 
growth factor receptor 2 (HER2) negative locally advanced or metastatic breast 
cancer after documented recurrence or progression following a non-steroidal 
aromatase inhibitor (NSAI) therapy.  
 
The dose of everolimus is 10 mg daily orally and the recommended daily dose of 
exemestane is 25 mg via oral administration. Both drugs were shown to be safe and 
effective in the respective dose and regimens. 
 
The BOLERO-2 trial has demonstrated significant efficacy of the combinatorial 
treatment of everolimus and exemestane compared to an exemestane monotherapy 
in ER positive, HER2 negative women after failure of prior NSAI therapy. 
Primary Objective(s)  
To evaluate the safety and tolerability profile of everolimus in post-menopausal 
women with ER positive, HER2 negative locally advanced or metastatic breast 
cancer after documented recurrence or progression following a non-steroidal 
aromatase inhibitor therapy in EGM countries. 
 
The primary endpoints are safety and tolerability evaluations, assessed according to 
the Common Terminology Criteria (CTCAE), version 4.03. This includes the 
incidence of adverse events (AEs) by grade, incidence of serious adverse events 
(SAEs), changes from baseline in vital signs, as well as changes from baseline in 
laboratory results (hematology, blood chemistry, lipid profile, viral markers) qualifying 
as AEs. 
Secondary Objectives 
● To evaluate the efficacy of everolimus in post-menopausal women with ER 
positive, HER2 negative locally advanced or metastatic breast cancer after 
documented recurrence or progression following a non-steroidal aromatase inhibitor 
therapy in EGM countries. Efficacy will be assessed by the overall response rate 
(ORR), progression-free survival (PFS) rate and clinical benefit rate (CBR) as 
evaluated by RECIST 1.1 criteria over the study period. Efficacy endpoints will be 
derived using local (treating center’s) radiologist’s/ investigator’s assessment. 
 
● Additionally, changes from baseline in Eastern Cooperative Oncology Group 
(ECOG) performance status will be assessed. 
 
● To provide early access to everolimus for patients in post-menopausal women 
with ER positive, HER2 negative locally advanced or metastatic breast cancer after 
documented recurrence or progression following a non-steroidal aromatase inhibitor 
therapy in EGM countries. 
 
 

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Study design 
This is an international, multi-center, open-label, single arm, study designed to collect 
clinical safety, tolerability and efficacy data with the use of everolimus combined with 
exemestane in the Novartis Oncology EGM countries in post-menopausal women 
with HR positive, HER2 negative locally advanced or metastatic breast cancer after 
documented recurrence or progression following a non-steroidal aromatase inhibitor 
therapy. It is anticipated that up to 400 patients will be enrolled. 
 
The study comprises two periods: 
● Screening phase: 
Patients will grant informed consent to participate in the study. After eligibility is 
confirmed (all inclusion/exclusion criteria verified), patients can be enrolled. All 
screening evaluations should be completed within 21 days prior to Treatment Day 1. 
 
● Treatment phase: 
Patients will start study treatment on Day 1 with everolimus 10 mg daily p.o. (either 2 
x 5 mg or 1 x 10 mg tablets) in combination with exemestane 25 mg daily p.o. (25 mg 
tablets). Dose adjustment (reduction or interruption) will be allowed according to 
safety findings and dose adjustment guidelines. Study treatment will continue until 
progression, unacceptable toxicity or consent withdrawal. Further treatment after 
progression will be at the investigator’s discretion. 
 
During the study, visits will be performed at Screening, Baseline/Treatment Day 1 
(Treatment start), Week 4 (± 1 week), Week 10 (± 2 weeks), and then every 10 
weekly (± 2 weeks). Tumor evaluations through CT scan will be performed for 
Screening, at Week 10 (± 2 weeks) and thereafter every 10 weekly (± 2 weeks). All 
radiological evaluations and laboratory assessments will be performed locally, at the 
investigator’s facilities. Patients will be followed up for safety for 30 days (± 2 days) 
after the last dose of everolimus. AEs/SAEs with a suspected causality to the study 
drug must be reported beyond this 30 days safety interval. 
 
Patients will continue to be treated per protocol until documentation ofdisease 
progression, unacceptable toxicity, death, discontinuation due to any other reason. 
The present study will continue in each participating country until everolimus is locally 
reimbursed or commercialized for this indication or until all patients have been 
discontinued from investigational treatment due to disease progression, unacceptable 
toxicity, death, consent withdrawal or any other reason. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supplies, Novartis will have a local transition plan in order to 
ensure that all on-going patients will still have access to the study medication without 
any delay in their treatment. 
 
Population 
Eligible patients are postmenopausal women with hormone receptor positive locally 
advanced or metastatic breast cancer progressing following prior NSAI therapy as 
defined by: 
 
● Recurrence while on or after completion of an adjuvant treatment including 
letrozole or anastrozole, or 
 
● Progression while on or following the completion of letrozole or anastrozole 
treatment for locally advanced or metastatic breast cancer. 
 
Except for prior use of mTOR inhibitors, there are no restrictions as to the last 
anticancer treatment prior to enrolment. Patients must have documented evidence of 
recurrence or progression on last therapy prior to enrolment. 

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Main inclusion criteria 
● Postmenopausal women with metastatic, recurrent or locally advanced breast 
cancer not amenable to curative treatment by surgery or radiotherapy. 
● Histological or cytological confirmation of hormone-receptor positive (HR+)breast 
cancer. 
● Disease refractory to non-steroidal aromatase inhibitors, defined as: 
● 
Recurrence while on, or within 12 months (365 days) of completion of 
adjuvant therapy with letrozole or anastrozole, 
or 
● 
Progression while on, or within one month (30 days) of completion of 
letrozole or anastrozole treatment for locally advanced or metastatic breast 
cancer (ABC). 
 
Note: letrozole or anastrozole do not have to be the last treatment prior to inclusion in 
the study. Patients may have received one prior chemotherapy line for ABC, or have 
received other endocrine treatments such as tamoxifen, or fulvestrant. 
 
● Radiological or objective evidence of recurrence or progression on or after the 
last systemic therapy prior to enrolment. 
Note: the last line of therapy may be any other treatment than  mTOR inhibitors. 
Patients must have recovered to grade 1 or better from any adverse events (except 
alopecia) related to any previous therapy prior to enrolment. 
 
● Patients must have: 
● 
At least one lesion that can be accurately measured in at least one 
dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral 
CT or MRI, 
or 
● 
Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable 
disease as defined above. 
● Patients must have adequate bone marrow, coagulation, liver and renal function. 
Main exclusion criteria 
● Patients overexpressing HER2 by local laboratory testing (IHC 3+ staining or in 
situ hybridization positive). Patients with IHC 2+ must have a negative in situ 
hybridization test. 
 
● Patients with only non-measurable lesions other than bone metastasis (e.g. 
pleural effusion, ascites). 
 
● Patients with more than one prior chemotherapy line for ABC. A chemotherapy 
line is an anticancer regimen(s) that contains at least 1 cytotoxic chemotherapy 
agent, given for a minimum of 21 days. 
 
● Previous treatment with mTOR inhibitors. 
 
● Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin). 
 
● Patients with a known history of HIV seropositivity. Screening for HIV infection at 
baseline is not required. 
 
● Patient being treated with drugs recognized as being strong inhibitors or inducers 
of the isoenzyme CYP3A 
 
● History of brain or other CNS metastases, including leptomeningeal metastasis. 
Investigational drugs 
All patients will receive everolimus 10 mg/day once daily + exemestane 25 mg/day 
once daily by oral route. 

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Efficacy assessments 
● Overall Response Rate (ORR) over the study period, defined as the proportion of 
patients with best overall response of either complete response (CR) or partial 
response (PR) according to RECIST (version 1.1). 
 
● Progression Free Survival (PFS) rate over the study period, defined as the 
proportion of patients who have not had any documented progression or death due to 
any cause, according to RECIST (version 1.1). 
 
● Clinical Benefit Rate (CBR) over the study period, defined as the proportion of 
patients with best overall response of complete response (CR), partial response (PR) 
or stable disease (SD), with duration of 24 weeks or longer, according to RECIST 
(version 1.1). 
 
Efficacy endpoints based on radiological assessments of tumor burden will be 
derived using local radiologist’s/ investigator’s assessment.  
Safety and tolerability 
assessments 
● Incidence of adverse events (AEs) by grade, assessed according to the Common 
Terminology Criteria (CTCAE), version 4.03 
 
● Incidence of serious adverse events (SAEs), assessed according to the Common 
Terminology Criteria (CTCAE), version 4.03 
 
● Changes from baseline in laboratory results (hematology, blood chemistry, lipid 
profile, viral markers) qualifying as AEs 
 
● Changes from baseline in vital signs. 
Other assessments 
● Time to deterioration of ECOG performance status, from baseline 
 
Data analysis 
Analysis populations: 
The Full Analysis Set (FAS) consists of all patients to whom treatment was 
assigned and who received at least one dose of study drug. 
 
The Per-protocol Set (PP) consists of a subset of patients of the FAS who did not 
show major deviations from the protocol procedures that may have an impact on the 
study outcome. 
 
The Safety Set consists of all patients who received at least one dose of study drug 
and had at least one post-baseline safety assessment. The statement that a patient 
had no adverse events (on the Adverse Event CRF) constitutes a safety assessment. 
Patients who have received at least one dose of study drug but who have no post-
treatment safety data of any kind would be excluded from the safety population. 
 
Sample size: 
The proposed sample size (up to 400 patients) is a convenience sample The data will 
be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, and safety/tolerability observations and 
measurements. Primary efficacy and safety/tolerability analysis will be conducted at 
15 months of median follow up time, i.e. at approximately two times the median PFS 
reported in the BOLERO-2 study . 
Statistical methods: 
Demographic and other baseline characteristics will be summarized for the Full 
Analysis Set (FAS). Baseline characteristics include prior medication, past/current 
medical conditions and disease history. 
Concomitant medications and significant non-drug therapies prior to and after the 
start of the study drug will be coded according to the WHO Drug Reference List, and 

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summarized by ATC class and preferred term using frequency distributions. 
Duration (days) of exposure to study drugs will be summarized using descriptive 
statistics separately for everolimus and exemestane. 
 
Safety and tolerability 
● Data collected by AE CRFs will be coded using the MedDRA dictionary. The 
incidence of treatment-emergent adverse events (new or worsening from baseline) 
will be summarized by MedDRA system organ class and preferred term using 
frequency distributions. Additionally, AE will be summarized by maximum severity 
(based on CTCAE grades), and for AE with suspected drug relation, serious AE 
(SAE), and AE leading to permanent discontinuation of study drug. All information 
pertaining to AE noted during the study will be listed by patient, detailing the verbatim 
term given by the investigator, MedDRA preferred term and system organ class, 
start/end dates, severity, seriousness, relationship to study drug and action taken. 
● The AE onset will also be shown relative (in number of days) to the date of initial 
dose. AE starting more than 30 days after discontinuation of study drug will not be 
considered as treatment-emergent and will not be included in AE summary tables but 
listed only. 
● Data from other tests (e.g., electrocardiogram or vital signs) will be summarized 
descriptively as appropriate. Notable values will be flagged, and any other 
information collected will be listed as appropriate. 
Efficacy 
● Disease progression will be assessed based on radiological assessments of 
tumor burden will be derived using local radiologist’s/ investigator’s assessment. If a 
patient has not had an event at end of the study, his or her data will be censored at 
the date of last adequate tumor assessment. 
 
● The best overall response rate (ORR, according to RECIST 1.1) as well as 
individual response categories (CR, PR, SD, PD or unknown) will be summarized 
using frequency tables together with their associated two-sided exact 95% 
confidence intervals (Clopper-Pearson method). 
 
● The clinical benefit rate (CBR) is defined as the proportion of patients with best 
overall response of complete response (CR), partial response (PR) or stable disease 
(SD), with duration of 24 weeks or longer. The duration of best overall response is 
assessed as such: the start date is the date of first documented response (CR or PR) 
and the end date is the date of event defined as first documented progression 
disease or death due to underlying cancer. The CBR will be summarized using 
frequency tables together with its associated two-sided exact 95% confidence 
intervals (Clopper-Pearson method). 
 
● The progression-free survival (PFS) rate is defined as the proportion of patients 
who have not had any documented progression or death due to any cause, according 
to RECIST (version 1.1). If a patient has not had an event, progression-free survival 
is censored at the date of last adequate tumor assessment. PFS will be summarized 
using the Kaplan-Meier method. Percentiles (25%, median, 75%) of the event time 
distribution will be presented along with their two-sided 95% confidence interval. The 
Kaplan-Meier curve will be displayed graphically. 
 
Other assessments 
● The ECOG Performance Status will be summarized using frequency distributions 
by visit. Shifts from baseline value to worst post-baseline value will be summarized 
using frequency distributions. 
 
 
Key words 
Everolimus, Exemestane, mTor inhibitor, Advanced Breast Cancer, Metastatic Breast 
Cancer 

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1 
Background 
1.1 
Epidemiology, pathogenesis, and current treatments of 
advanced breast cancer 
Breast cancer is the most common form of malignancy in women, accounting globally for 
23% of all cancers in women and 14% of cancer deaths (Jemal 2011). Of the estimated 12.7 
million new cancer cases worldwide in 2008, 1.38 million were estimated to be new cases of 
breast cancer (Ferlay 2010). It was the most common cancer in women both in developed and 
developing regions with around 690,000 new cases estimated in each region (population ratio 
1:4) (GLOBOCAN 2008), and the most frequent cause of cancer death in women in both 
developing (269 000 deaths, 12.7% of total) and developed regions, where the estimated 189 
000 deaths is almost equal to the estimated number of deaths from lung cancer (188 000 
deaths). The incidence rates varied from 19.3 per 100,000 women in Eastern Africa to 89.7 
per 100,000 women in Western Europe, and were high (greater than 80 per 100,000) in 
developed regions of the world (except Japan) (GLOBOCAN 2008, Cancer Fact Sheet). 
However, although breast cancer is thought to be a disease of the developed world, a majority 
(69%) of all breast cancer deaths occurs in developing countries (WHO Global Burden of 
Disease 2004). 
The differences in breast cancer incidence between developed and developing countries can 
partly be explained by dietary effects combined with later first childbirth, lower parity, and 
shorter breastfeeding. The increasing adoption of western life-style in low- and middle-
income countries is an important determinant in the increase of breast cancer incidence in 
these countries (WHO Breast cancer risk factors). 
Approximately 40% of patients treated for early stage breast will eventually develop 
metastatic breast cancer (MBC). Median life expectancy after recurrence is between 24 to 30 
months or less (O’Shaughnessy 2005). Treatment goals for advanced breast cancer (ABC) are 
palliative in nature, primarily focused at reducing tumor size, slowing progression and 
metastasis and reducing complications such as fatigue, bone fracture and hypercalcemia. 
A number of breast carcinomas are dependent for their proliferation on 17 beta-oestradiol 
(E2), which can be synthesized from androstenedione through the action of aromatase, an 
enzyme of the cytochrome P450 superfamily. In premenopausal women, the expression of 
aromatase is found in the granulosa cells of ovarian follicles while in post-menopausal women, 
the expression of aromatase is in general derived from non-glandular tissue, such as 
subcutaneous fat. In breast carcinoma tissue of post-menopausal women, the concentration of 
estradiol is approximately 10 fold the concentration found in plasma (Thijssen 1989). 

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The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most 
important predictive and prognostic markers in human breast cancers. Approximately 70% of 
all invasive breast cancers are positive for ER and/or PgR expressions at the time of diagnosis. 
Consequently, anti-estrogen therapies that antagonize ER functions (such as tamoxifen) or 
inhibit estrogen production (e.g. aromatase inhibitors (AIs)) have been extensively developed 
in oncology (Smith 2003, Jensen 2003). Deprivation of estrogenic signaling with the anti-
estrogen tamoxifen has been the main form of hormonal treatment for over 30 years. Besides 
tamoxifen, progesterone analogues or progestins have been used for the treatment of breast 
cancer for almost 50 years. Although the exact mechanism of action of progestins has not 
been established, their effect on estrogen levels is thought to play a role. 
While therapies interfering with ER functions such as tamoxifen have significantly 
contributed to mortality reduction in advanced breast cancer patients, at best 50-60% of ER 
positive patients respond to anti-estrogen therapy. Aromatase inhibitors (AI) are a class of 
compounds that reduce peripheral estrogen synthesis by blocking the conversion of androgens 
to estrogens, which is the primary way estrogens are produced in post-menopausal women. 
Aminoglutethimide was the first non-steroidal (reversible-competitive) inhibitor of aromatase 
evaluated clinically for the treatment of ABC. More selective, less toxic, reversible AIs have 
been developed thereafter (Buzdar 2003, Mokbel 2002, Gligorov 2007), and the third 
generation AIs anastrozole, exemestane and letrozole are in current use in postmenopausal 
women with hormone receptor positive BC. 
Third-gerenation AIs can be broadly classified into two groups: non-steroidal aromatase 
inhibitors (NSAI), mainly letrozole (Femara®) and anastrozole (Arimidex®), and steroidal 
aromatase inactivators, represented by exemestane (Aromasin®). 
Letrozole and Anastrozole are both approved for use in the adjuvant setting and in the 
advanced breast cancer setting, based on comparisons to tamoxifen or megestrol acetate. 
Letrozole (Femara®, 2.5 mg tablets) has been approved for the following indications: 
• Adjuvant setting: 
• Adjuvant treatment (following surgery) of postmenopausal women with hormone 
receptor-positive early stage breast cancer. 
• Extended adjuvant treatment of postmenopausal women with early breast cancer who 
have received prior standard (5 years) adjuvant tamoxifen therapy. 
• ABC setting: 
• First-line treatment of postmenopausal women with hormone receptor-positive or 
unknown locally advanced or metastatic breast cancer. 
• Second-line treatment of postmenopausal women with hormone receptor-positive or 
unknown advanced breast cancer that is progressing after anti-estrogen therapy. 
The approved indications for anastrozole (Arimidex®, 1 mg tablets) are as follows: 
• Adjuvant setting: 
• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in 
postmenopausal women. 
• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in 
postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen. 

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• ABC setting: 
• First-line treatment of hormone receptor-positive advanced breast cancer in 
postmenopausal women. Superiority was shown for anastrozole vs. tamoxifen in the 
ITT population for disease free survival. 
• In the USA, it is also indicated for the treatment of advanced breast cancer in 
postmenopausal women with disease progression following tamoxifen therapy. 
NSAI (letrozole or anastrazole) are generally the treatment of choice for postmenopausal 
women with ER positive breast cancer. Following recurrence or progression on letrozole or 
anastrozole, the most commonly subsequent treatment includes exemestane and fulvestrant. In 
clinical practice, the use of chemotherapy is usually reserved for patients with high tumor 
burden or for patients that demonstrate an aggressive disease progression or symptomatic 
visceral disease. 
Exemestane (Aromasin®) is an irreversible steroidal aromatase inactivator that has 
demonstrated efficacy in the treatment of postmenopausal patients with advanced breast 
cancer. It is indicated for adjuvant treatment of postmenopausal women with ER positive 
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 hormonal therapy (HR 0.76 for 
disease-free survival in favor of exemestane vs. tamoxifen, 95% CI 0.66 to 0.88, p = 0.0001, 
4727 patients) (Coombes 2007). Exemestane is also indicated for the treatment of ABC in 
postmenopausal women whose disease has progressed following tamoxifen therapy (in the 
USA) or following antiestrogen therapy (in Europe). 
Fulvestrant (Faslodex®) an estrogen receptor antagonist, is also approved in this same setting, 
i.e., for the treatment of hormone receptor positive MBC in postmenopausal women with 
disease progression following antiestrogen therapy. In a clinical study comparing fulvestrant 
to anastrozole in treatment of ABC in patients whose disease progresses on prior endocrine 
treatment, there was no significant difference for time to progression between the two 
treatment groups (HR, 0.92; 95% CI 0.74 to 1.14; p = 0.43) (Osborne 2002). 
There are currently no treatments specifically approved for postmenopausal women with ER 
positive breast cancer after recurrence or progression on a NSAI (letrozole or anastrozole). To 
date, treatment of these patients remains an area of unmet medical need. 
The activity of exemestane in MBC after failure of NSAI was evaluated in a phase II trial. 
Exemestane 25 mg once daily was demonstrated to be safe and effective in postmenopausal 
patients with MBC following progression after treatment with a NSAI. Exemestane produced 
an objective clinical benefit rate (defined as CR+PR+SD for 24 weeks or longer) of 24.3 % in 
a population where 98 % of the patients received exemestane as a third or fourth line 
hormonal treatment (Lønning 2000). 

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Another trial assessed the efficacy and tolerability of exemestane administered as third-line 
hormonal therapy to postmenopausal women with metastatic breast cancer refractory to NSAI. 
Sixty postmenopausal women with stage IV hormone receptor positive breast cancer were 
enrolled. All patients had received two prior hormonal manipulations and had measurable or 
assessable disease. Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-
30.4). The overall clinical benefit was 38.3% (95% Cl, 21.2-49.3), and the median duration of 
objective tumor response was 20 months (range, 9-26). The median survival was 17.4 months 
(95% CI, 16.14-18.66) (Gennatas 2006). 
Fulvestrant and exemestane were compared in a double blind placebo controlled phase III trial 
in 693 postmenopausal women with ER+ BC after recurrence or progression on a NSAI (Chia 
2008). Fulvestrant was administered with a loading dose (500 mg d0, 250 mg d14 and d28) 
followed by the standard dose of 250 mg every 28 days. No differences were observed in 
terms of progression-free survival (3.7 month on both arms), response rate (7.4% vs. 6.7%, 
respectively) or disease control rate (32.2% vs. 31.5%, respectively). This modest level of 
activity emphasizes the need for new treatment options that are not solely targeting the 
estrogen receptor pathway. 
1.2 
Overview of investigational treatments 
1.2.1 
Overview of Everolimus 
Everolimus has been in clinical development since 1996 as 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®. From 2009, Afinitor has been 
approved for advanced renal cell carcinoma (RCC) worldwide. In 2010, Afinitor received US 
approval for patients with subependymal giant cell astrocytoma (SEGA) associated with 
tuberous sclerosis (TS). 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 and the EU. In July 2012, Afinitor® in combination with 
exemestane was approved for Advanced Breast Cancer in the US and in the EU. 
The following is a brief summary of the main characteristics of everolimus. More detailed 
information can be obtained from the everolimus Investigator’s Brochure. 
Everolimus 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 (Francesc 1999, Yu 1999, Lane 2009) and have 
antiangiogenic activity in vivo (Guba 2002, Tsutsumi 2004, Mabuchi 2007, Lane 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). 

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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 antiangiogenic 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 
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 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 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). 

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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). 
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]. 

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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 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 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. 
1.2.1.2.2 Everolimus in hormone receptor positive (HR+) breast cancer 
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 + advanced breast cancer (ABC) who had received prior hormonal 
therapy. In this trial, 19 of the 49 patients enrolled were ER-positive/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 2009). 

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Everolimus in combination with endocrine therapy 
The combination of everolimus with hormonal 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 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+ and HER2- breast cancer who had a recurrence or 
progression on letrozole or anastrozole (Baselga 2012). The study met its primary objective at 
the time of interim PFS analysis demonstrating 57% risk reduction in favor of treatment with 
everolimus plus exemestane (HR: 0.43; 95% CI: 0.35, 0.54; p<0.0001). The median PFS 
duration and corresponding 95% CI were 6.93 months (6.44, 8.05) for everolimus + 
exemestane and 2.83 months (2.76, 4.14) for placebo + exemestane arms respectively. The 
final PFS results were consistent with the interim analysis result (HR: 0.45; 95% CI: 0.38, 
0.54; p<0.0001). PFS medians were 7.82 and 3.19 months for everolimus + exemestane and 
placebo + exemestane arms respectively. All secondary efficacy endpoints (CBR, ORR, 
duration of response) as well as PFS analysis based on the central radiology review were 
supportive of the primary efficacy endpoint. This significant improvement was consistent 
across major demographic and prognostic subgroups.  
Results from the final OS analysis is also supportive of the clinical benefit demonstrated at the 
interim and final PFS analyses. Although the final analysis of OS was not statistically 
significant (results did not cross the boundary to declare statistical significance; one-sided 
pvalue from stratified log-rank test p=0.1426, HR from stratified Cox proportional hazard 
model: 0.89; 95% CI: 0.73, 1.10), the median OS showed a 4.43 months difference in favor of 
the everolimus arm. Median OS was 30.98 months (95% CI: 27.96, 34.56) in the everolimus 
plus exemestane arm and 26.55 months (95% CI: 22.57, 33.08) in the placebo plus 
exemestane arm. This 4.43-month median OS prolongation is consistent with the 4.6-month 
improvement seen in PFS, and is considered to be clinically meaningful. 
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 2012). Although the results of this phase II trial are encouraging, 
the small sample size may limit the impact of these results on clinical practice. 

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Safety profile of everolimus 
Overall, safety data available from completed, controlled and uncontrolled studies indicate 
that everolimus is generally well tolerated at weekly or daily dose schedules. The safety 
profile is characterized by manageable adverse events (AEs); mostly of grade 1 and 2 severity. 
These AEs are generally reversible and non-cumulative. 
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 BOLERO-2 phase III study (Study Y2301) 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 from the pooled 
of safety data were (in decreasing order), with an incidence ≥ 10%, reported in association 
with everolimus plus exemestane therapy (see Table 1-1) were consistent with what was 
previously reported: stomatitis, rash, fatigue, decreased appetite, diarrhea, infections, 
dysgeusia, nausea, pneumonitis, weight decreased, anemia, epistaxis, hyperglycemia, 
thrombocytopenia,  pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis and 
headache.  
The most common grade 3/4 ADRs (incidence ≥1/100 to <1/10 and suspected to be related to 
treatment by the investigator) were stomatitis, anemia, hyperglycemia, infections, fatigue, 
infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, 
lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate 
aminotransferase (AST) increased, and alanine aminotransferase (ALT) increased, and 
pneumonia. 
Further details related to everolimus safety can be found in the everolimus [Investigator’s 
Brochure]. 
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with 
serious cases of the following:  
• hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected 
event during periods of immunosuppression. 
• renal failure events (including fatal ones) and proteinuria. Monitoring of renal function is 
recommended. 
• amenorrhea (including secondary amenorrhea). 

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• pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome.  
• angioedema has been reported with and without concomitant use of everolimus mTOR 
and ACE inhibitors. 
Table 1-1 
Study Y2301 (BOLERO-2): Most common Adverse Events (equal or 
greater than 10% of patients) 
AE preferred term 
Everolimus + Exemestane 
(n=482), % 
Placebo + Exemestane 
(n=238), % 
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 
UTI 
10 
3 
7 
< 1 
0 
2 
< 1 
2 
0 
0 
GGT increase 
10 
2 
2 
5 
2 
9 
1 
1 
5 
2 
AST: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma glutamyltransferase; UTI: urinary 
tract infection 

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1.2.2 
Potential role of mTOR inhibition in the treatment of bone metastases 
The most common site of first cancer relapse is bone as more than 50% of the patients will 
develop bone metastases at time of first recurrence. About 80% of these bone metastases are 
osteolytic tumors leading to complication such as pathological fracture and hypercalcemia. 
Histological analyses of osteolytic primary and secondary bone tumors reveal that bone 
destruction is mediated by osteoclasts rather than by tumor cells themselves. 
Rapamycin and derivatives also influence bone tissues. Indeed, mTOR appears as an essential 
signaling pathway engaged in the stimulation of osteoclast survival and affects osteoblast 
differentiation (Ory 2007). Using primary osteoclast cultures, Kneissel et al have 
demonstrated that everolimus is a potent inhibitor of osteoclast formation and activity. 
Treatment of mouse osteoclast cultures with everolimus (0.3–100 nM) resulted in a 
concentration-dependent inhibition of osteoclast formation and activity. In human osteoclasts 
cultures, osteoclast formation and activity were completely inhibited at 30 and 10 nM, 
respectively. Everolimus appeared also to directly inhibit bone resorption, detected by the 
inhibition of mRNA and protein expression of cathepsin K; the main collagen-degrading 
protease in osteoclasts. In vivo data suggest that the overall impact of everolimus on bone in a 
classical model of bone loss is dominated by osteoclast inhibitory activity. Everolimus 
directly inhibits bone resorption by osteoclasts and thus could at least be neutral or protective 
for bone in vivo (Kneissel 2004). 
1.2.3 
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 ER+ early breast cancer 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 hormonal therapy. It is also indicated for the treatment of advanced breast cancer 
(ABC) in postmenopausal women whose disease has progressed following tamoxifen therapy 
(in the USA) or following antiestrogen 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, 2011). 

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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 1993, Plourde 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 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. 
2 
Rationale 
2.1 
Study rationale and purpose 
This study is proposed in the light of the need for new treatment options, such as everolimus, 
in emergent growth market (EGM) countries until it is approved or reimbursed. Therefore, the 
study is conducted to collect clinical safety, tolerability and efficacy data with the use of 
everolimus combined with exemestane in the Novartis Oncology EGM countries. 
2.2 
Rationale for the study design 
The present international, multi-center, open-label, single-arm study aims at collecting clinical 
safety, tolerability and efficacy data with the use of everolimus combined with exemestane in 
post-menopausal women with HR positive, HER2 negative locally advanced or metastatic 
breast cancer after documented recurrence or progression following a non-steroidal aromatase 
inhibitor therapy, in EGM countries. 

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Everolimus in combination of exemestane has been approved in the US and in the European 
Union in July 2012 for the treatment of post-menopausal women with advanced hormone 
receptor-positive, HER2-negative breast cancer (advanced HR+ BC) after failure of treatment 
with a non-steroidal aromatase inhibitor therapy. Novartis has also filed a NDA in many EGM 
countries. This study is proposed in the light of the need for new treatment options, such as 
everolimus, in EGM countries until it is approved or reimbursed.  
2.3 
Rationale for dose and regimen selection 
The dose of everolimus is 10 mg daily orally and the recommended daily dose of exemestane 
is 25 mg via oral administration. Both drugs were shown to be safe and effective in the 
respective dose and regimens. 
Exemestane is indicated for adjuvant treatment of postmenopausal women with hormone 
receptor positive (HR+) 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 
hormonal therapy. It is also indicated for the treatment of advanced breast cancer (ABC) in 
postmenopausal women whose disease has progressed following tamoxifen therapy (in the 
USA) or following antiestrogen therapy (in Europe). 
The BOLERO-2 trial (Study Y2301) has demonstrated significant efficacy (improvement of 
the PFS) of the combinatorial treatment of everolimus and exemestane compared to placebo 
plus exemestane in ER positive HER2 negative women after failure of prior NSAI therapy. 
Thus the benefit of the combination treatment versus exemestane monotherapy was shown in 
a defined patient population under controlled conditions. 
3 
Objectives and endpoints 
3.1 
Primary objectives 
To evaluate the safety and tolerability profile of everolimus in post-menopausal women with 
HR positive, HER2 negative locally advanced or metastatic breast cancer after documented 
recurrence or progression following a non-steroidal aromatase inhibitor therapy in Novartis 
Oncology EGM countries. 
3.1.1 
Primary endpoints 
The primary endpoints are safety and tolerability evaluations, assessed according to the 
Common Terminology Criteria (CTCAE), version 4.03. This includes the incidence of 
adverse events (AEs) by grade, incidence of serious adverse events (SAEs), changes from 
baseline in vital signs, as well as changes from baseline in laboratory results (hematology, 
blood chemistry, lipid profile, viral markers) qualifying as AEs. 
3.2 
Secondary objectives 
• To evaluate the efficacy of everolimus in post-menopausal women with HR positive, 
HER2 negative locally advanced or metastatic breast cancer after documented recurrence 
or progression following a non-steroidal aromatase inhibitor therapy in EGM countries. 

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• To assess changes from baseline in Eastern Cooperative Oncology Group (ECOG) 
performance status during treatment with everolimus plus exemestane 
• To provide early access to everolimus for post-menopausal women with HR positive, 
HER2 negative locally advanced or metastatic breast cancer after documented recurrence 
or progression following a non-steroidal aromatase inhibitor therapy in EGM countries. 
3.2.1 
Secondary endpoints 
Efficacy endpoints based on radiological (and photographical when applicable) assessments 
of tumor burden will be derived using local (treating center’s) radiologist’s/ investigator’s 
assessment. 
For patients without event at the end of the study, data will be censored at the date of last 
adequate tumor assessment. 
• Overall Response Rate (ORR) over the study period: 
• Overall response rate (ORR) is defined as the proportion of patients with best overall 
response of either complete response (CR) or partial response (PR) according to 
RECIST (version 1.1). 
• Progression Free Survival (PFS) rate over the study period: 
• PFS rate is defined as the proportion of patients who have not had any documented 
progression or death due to any cause, according to RECIST (version 1.1). 
• Clinical Benefit Rate (CBR) over the study period: 
• CBR rate is defined as the proportion of patients with best overall response of 
complete response (CR), partial response (PR) or stable disease (SD), with duration of 
24 weeks or longer, according to RECIST (version 1.1). 
For these three outcomes, in patients with non-measurable disease (bone metastases), the 
following is considered a disease progression: appearance of one or more new bone lytic 
lesions; appearance of one or more lesions outside of bone; unequivocal progression of 
existing bone lesions. Pathological fracture, new compression fracture, or complications of 
bone metastases will not be considered as evidence of disease progression unless one of the 
above criteria is fulfilled. 
Changes from baseline in ECOG performance status will be described. Time to deterioration 
of ECOG performance status, from baseline will be assessed. 

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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
To evaluate the safety and tolerability profile of 
everolimus in post-menopausal women with HR 
positive, 
HER2 
negative 
locally 
advanced 
or 
metastatic breast cancer after documented recurrence 
or progression following a non-steroidal aromatase 
inhibitor therapy in Novartis Oncology EGM countries. 
 
Incidence of adverse events (AEs) by grade, serious 
adverse events (SAEs), changes from baseline in vital 
signs and laboratory results (hematology, blood 
chemistry, lipid profile) qualifying as AEs. All AEs will 
be assessed according to the Common Terminology 
Criteria (CTCAE), version 4.03. 
Refer to Section 10.5 
Key secondary 
- To evaluate the efficacy of everolimus in post-
menopausal women with HR positive, HER2 negative 
locally advanced or metastatic breast cancer after 
documented recurrence or progression following a 
non-steroidal aromatase inhibitor therapy in EGM 
countries. 
 
● ORR 
● PFS rate 
● CBR 
 
 
Other secondary 
- To assess changes from baseline in Eastern 
Cooperative Oncology Group (ECOG) performance 
status over the study period. 
 
- To evaluate the efficacy of provide early access to 
everolimus infor post-menopausal women with HR 
positive, HER2 negative locally advanced or 
metastatic breast cancer after documented recurrence 
or progression following a non-steroidal aromatase 
inhibitor therapy in EGM countries. 
● Time to deterioration of ECOG performance status, 
from baseline 
 
● Number of patients enrolled per study and per 
country 
Refer to Section 10.6.1 

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4 
Study design 
4.1 
Description of study design 
This is an international, multi-center, open-label, single arm, phase IIIb study designed to 
collect clinical safety, tolerability and efficacy data with the use of everolimus combined with 
exemestane in post-menopausal women with HR positive, HER2 negative locally advanced or 
metastatic breast cancer after documented recurrence or progression following a non-steroidal 
aromatase inhibitor therapy, with no prior treatment by mTOR inhibitors, in the EGM 
countries. Enrollment will end in all participating countries by the time of 
registration/commercial availability of everolimus for the investigational indication or in any 
case no later than October 31st 2014. It is anticipated that up to 400 patients will be enrolled 
from a set of EGM countries of Novartis Oncology by this date. 
In each participating country, the study will start after approvals are being obtained from the 
respective local authority and IRB and will end when everolimus is locally reimbursed or 
commercialized for this indication or when all patients have been discontinued from 
investigational treatment due to disease progression, unacceptable toxicity, death, consent 
withdrawal or any other reason. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supply , Novartis will have a local transition plan in order to ensure that 
all on-going patients will still have access to the study medication without any delay in their 
treatment. 
Data derived from the study will be collected, according to ICH GCP and any international 
and local regulations, to evaluate the safety, tolerability and efficacy of the combination of 
everolimus (10 mg daily) and exemestane (25 mg daily) in eligible patients. 
The study comprises two periods: 
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. 
After eligibility is confirmed (all inclusion/exclusion criteria verified), patients can be 
enrolled. All screening evaluations (including screening for hepatitis B and C) should be 
completed within 21 days prior to the first dose of the study drugs (Treatment Day 1). 
Screening for hepatitis B 
During the screening period, the following three categories of patients should be tested for 
hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBsAb, and HBcAb: 
1. All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal, and Greece for more than 6 months. 

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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. 
Patients with positive HBV-DNA of HBsAg at screening must initiate prophylaxis with 
appropriate antiviral medication at least one week prior to treatment start (Treatment Day 1). 
The management guidelines are provided according to the results of the baseline assessment 
of viral load and serological markers for hepatitis B (see Section 6.3.3.1). 
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, 
• Additional patients at the discretion of the investigator. 
The management guidelines are provided according to the results of the baseline assessment 
of hepatitis C viral load (see Section 6.3.3.2). 
Enrolment in the study will be confirmed by completing the Enrolment form on the electronic 
case report form (eCRF). Information collected for screening failures include date of informed 
consent, inclusion/exclusion criteria, and serious adverse events (SAE) where relevant. 

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Treatment phase 
Patients will start study treatment on Day 1 with everolimus 10 mg daily p.o. (either 2 x 5 mg 
or 1 x 10 mg tablets) in combination with exemestane 25 mg daily p.o. (25 mg tablets). Dose 
adjustment (reduction or interruption) will be allowed according to safety findings and dose 
adjustment guidelines. Study treatment will continue until disease progression, unacceptable 
toxicity, death, consent withdrawal or any other reason. Further treatment after progression 
will be at the investigator’s discretion. 
During the study, visits will be performed at Screening, Baseline/Treatment Day 1 (Treatment 
start), Week 4 (± 1 week), Week 10 (± 2 weeks), and then every 10-weekly (± 2 weeks) till 
end of treatment. 
Tumor evaluations through CT scan/MRI will be performed for Screening, at Week 10, and 
10 weekly thereafter. All radiological evaluations and laboratory assessments will be 
performed locally, at the center level. Patients will be followed up for safety for 30 days (± 2 
days) after the last dose of everolimus. AEs/SAEs with a suspected causality to the study drug 
must be reported beyond this 30 days safety interval. 
Figure 4-1 
Study design 
 
4.2 
Definition of end of the study 
In each participating country, the study will start after approvals are being obtained from the 
respective local authority and IRB and will end when everolimus is locally reimbursed or 
commercialized for this indication or when all patients have been discontinued from 
investigational treatment due to disease progression, unacceptable toxicity, death, consent 
withdrawal or any other reason. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supplies, Novartis will have a local transition plan in order to ensure that 
all on-going patients will still have access to the study medication without any delay in their 
treatment. 
Patients will be followed up for safety purposes for 30 days (± 2 days) after the last dose of 
study drug. At the end of the study, the progression status of all participating patients will be 
updated and recorded in the electronic case report form (eCRF). 
Enrolled 
Until 

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4.3 
Early study termination 
Novartis can terminate the study at any time for reasons stipulated in the clinical trial 
agreement. Should this be necessary, the patient should be seen as soon as possible for the 
final visit and the same assessments should be performed as planned 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 the IRBs and/or Ethic 
Committees of the early termination of the trial. 
5 
Population 
Enrollment will end in all participating countries by the time of registration/commercial 
availability of everolimus for this investigational indication or in any case no later than 
October 31st 2014. It is anticipated that up to 400 patients will be enrolled from a set of EGM 
countries of Novartis Oncology by this date. 
Eligible patients are postmenopausal women with HR positive, HER2 negative locally 
advanced or metastatic breast cancer progressing following prior therapy with nonsteroidal 
aromatase inhibitors (NSAI) as defined by either of the following: 
• Recurrence while on or after completion  of an adjuvant treatment including letrozole or 
anastrozole, or 
• Progression while on or following the completion of letrozole or anastrozole treatment for 
locally advanced or metastatic breast cancer. 
Patients must not have been treated by mTOR inhibitors prior to enrolment. With this 
exception, there are no restrictions as to the last anticancer treatment prior to enrolment. 
Patients must have documented evidence of recurrence or progression on last therapy prior to 
enrolment. 
Written informed consent must be obtained prior to any screening procedures. The 
investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered enrolment in the study. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Adult women (≥ 18 years of age) with metastatic, recurrent or locally advanced breast 
cancer not amenable to curative treatment by surgery or radiotherapy. 
2. Histological or cytological confirmation of hormone receptor positive (HR+) breast cancer. 
3. Postmenopausal women. Ovarian radiation or treatment with a luteinizing hormone-
releasing hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) does not 
satisfy this inclusion criterion. Postmenopausal status is defined by one of the following: 
• Age ≥ 55 years and one year or more of amenorrhea 
• Age < 55 years and one year or more of amenorrhea, with estradiol assay < 20 pg/ml 
and/or post-menopausal levels of FSH and LH per local institutional standards 

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• Prior hysterectomy, with estradiol assay < 20 pg/ml and/or post-menopausal levels of 
FSH and LH per local institutional standards 
• Surgical menopause with bilateral oophorectomy. 
4. Disease refractory to non-steroidal aromatase inhibitors (NSAI), defined as: 
• Recurrence while on, or within 12 months (365 days) of completion of adjuvant 
therapy with letrozole or anastrozole, 
or 
• Progression while on, or within one month (30 days) of completion of letrozole or 
anastrozole treatment for ABC. 
• Notes: Letrozole or anastrozole do not have to be the last treatment prior to study 
baseline. Patients may have received one prior chemotherapy line for ABC, or 
have received other endocrine treatments such as tamoxifen, or fulvestrant and 
including exemestane monotherapy. 
5. Radiological or objective evidence of recurrence or progression on or after the last 
systemic therapy prior to enrolment. 
• Notes: The last line of therapy may be any other treatment than mTOR inhibitors. 
Patients must have recovered to grade 1 or better from any adverse events related to 
previous therapy (except alopecia) prior to enrolment. 
6. Patients must have: 
• Measurable disease defined as at least one lesion that can be accurately measured in at 
least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with 
spiral CT or MRI, 
or 
• Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as 
defined above. 
Note: Lymph nodes must be ≥ 15 mm in the short axis to be considered measurable 
Patients with bone lesions and at least one measurable lesion are considered as having 
measurable disease  
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 the 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. 
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. 

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10. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × 
ULN. Treatment with statins may be initiated or adjusted as needed to meet these values 
before enrolment. 
11.  ECOG Performance Status ≤ 2. 
12. Adequate organ function at the discretion of the investigator. 
13. Patients with positive HBV-DNA and/or HBsAg at screening must initiate prophylaxis 
with appropriate antiviral medication at least one week prior to treatment start. 
14. Signed informed consent obtained before any trial related activity and according to local 
guidelines. 
5.2 
Exclusion criteria 
Patients eligible for participation in this study must not meet any of the following criteria: 
1. Patients overexpressing HER2 by local laboratory testing (IHC 3+ staining or in situ 
hybridization positive), based on the most recent test. Patients with IHC 2+ must have a 
negative in situ hybridization test. 
2. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, 
ascites). 
3. Patients with more than one prior chemotherapy line for treating metastatic breast cancer. 
A chemotherapy line is an anticancer regimen(s) that contains at least 1 cytotoxic 
chemotherapy agent, given for a minimum of 21 days. A cytotoxic chemotherapy regimen 
that lasted less than 21 days and was discontinued for a reason other than disease 
progression is not accounted as a "prior line of chemotherapy". 
4. Previous treatment with mTOR inhibitors. 
5. Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin). 
6. Any other malignancy within 5 years prior to enrolment, with the exception of adequately 
treated in-situ carcinoma of the cervix uteri, basal or squamous skin cell carcinoma, or 
non-melanoma skin cancer. 
7. Radiotherapy within four weeks prior to enrolment, except radiotherapy to the bone for 
analgesic purpose or for lytic lesions at risk of fracture. Patients must have recovered from 
radiotherapy toxicities prior to enrolment. 
8. Patient receiving hormone replacement therapy (HRT). Patient may be enrolled after 
discontinuation of HRT. 
9. History of brain or other CNS metastases, including leptomeningeal metastasis. 

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10. Treatment with immunosuppressive agents or chronic corticosteroids, with the following 
exceptions: 
• Patients on stable low dose of systemic corticosteroids for at least two weeks before 
enrolment 
• Corticosteroids used in topical applications (e.g. cream), inhaled sprays, eye drops or 
local (e.g. intra-articular) injections. 
11. Bilateral diffuse lymphangitic carcinomatosis. 
12. Patients with a known history of HIV seropositivity. Screening for HIV infection at 
baseline is not required. 
13. Active, bleeding diathesis. Patients treated with anti-vitamin K medication, LMWH, or 
anti-platelet medication must have an INR ≤ 2.0. 
14. Any severe and / or uncontrolled medical conditions such as: 
a. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
≤6 months prior to enrolment, serious uncontrolled cardiac arrhythmia 
b. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN 
c. Acute and chronic, active infectious disorders (except for Hep B and Hep C positive 
patients) and non-malignant medical illnesses that are uncontrolled or whose control 
may be jeopardized by the complications of this study therapy 
d. Impairment of gastrointestinal function or who have gastrointestinal disease that may 
significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome) 
e. Active skin, mucosa, ocular or gastro-intestinal disorders of Grade > 1 
f. Significant symptomatic deterioration of lung function. If clinically indicated, 
pulmonary function tests including measures of predicted lung volumes, DLco, O2 
saturation at rest on room air should be considered to exclude restrictive pulmonary 
disease, pneumonitis or pulmonary infiltrates. 
15. Patients being treated with drugs recognized as being strong inhibitors or inducers of the 
isoenzyme CYP3A at enrolment (rifabutin, rifampicin, clarithromycin, ketoconazole, 
itraconazole, letroconazole, voriconazole, ritonavir, telithromycin) continuously for at 
least 7 days during any time period in the last 2 weeks prior to enrolment (clinically 
relevant drug interaction are listed in Section 6.4.1). 
16. Patients unwilling to or unable to comply with the protocol. 
17.  Patients enrolled in another investigational drug or device study. 
18. Patients who have discontinued this study may not be re-enrolled. 
6 
Treatments 
6.1 
Study treatments 
This is a non-randomized, single-arm, open-label study. The investigational drugs used in the 
course of this trial are everolimus in combination with exemestane. All patients will be 
assigned to treatment with everolimus and exemestane. 

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6.1.1 
Everolimus 
Everolimus is formulated as tablets of 10 and 5 mg strength for oral administration. The dose 
is 10 mg once daily (as one tablet of 10 mg or two tablets of 5 mg at a time) per oral route. 
6.1.2 
Exemestane 
Commercially available exemestane will be supplied as tablets of 25 mg strength for oral 
administration. The dose is 25 mg once daily (one tablet) per oral route. 
Complete guidelines for management and administration of exemestane can be found in the 
package insert. 
6.1.3 
Dosing regimen 
All patients will receive everolimus + exemestane. All patients will take everolimus 10 mg 
orally per day. All patients will also take one 25 mg tablet of exemestane once daily (Table 6-
1). 
Table 6-1 
Starting dose and treatment schedule 
Study drugs 
Pharmaceutical form, 
route of administration 
Dose 
Frequency 
Everolimus (RAD0001) 
Tablets for oral use 
1 tablet of 10 mg 
or 2 tablets of 5 mg* 
Daily 
Exemestane 
Tablets for oral use 
25 mg 
Daily 
*: Choice will be made at each participating country level 
Patients will be provided with study treatment for self administration at home, starting on 
Treatment Day 1. Enough tablets should be provided to cover administration until next 
scheduled visit. 
Everolimus and exemestane will be dosed starting on Treatment Day 1 (Visit 2). 
Patients will be instructed to take one 10 mg tablet of everolimus or 2 tablets of 5 mg at a time 
per oral route with a large glass of water at the same time every day with or without food. The 
tablets should not be chewed or crushed. 
Similarly, patients will be instructed to take one 25 mg tablet of exemestane orally with a 
large glass of water at the same time every day. Package insert instructions should be 
followed. 
Everolimus should be swallowed whole with a glass of water and the tablets should not be 
chewed or crushed and grapefruit or citrus juices must be avoided for everolimus 
administration. If the tablets cannot be swallowed, the tablets should be disintegrated in 
approximately 30 ml of water. Immediately prior to administration, the contents should be 
stirred gently until the tablets have disintegrated into a suspension. The patient should then 
drink the contents. Afterwards, the glass should be rinsed with an additional 30 ml of liquid 
and drunk by the patient. If vomiting occurs no attempt should be made to replace the dose. 
Everolimus and exemestane will be taken daily from Visit 2, Day 1 until disease progression, 
unacceptable toxicity, death, and withdrawal from the study for any other reason. 

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The End of Treatment (EOT) is defined as the last date that the patient has taken the study 
drug everolimus, excluding an everolimus interruption for < 4 weeks. A Follow-up visit 30 
days (± 2 days) after the last date that the patient has taken the study drug will be conducted to 
report any adverse events during this period. 
The investigator should promote compliance by instructing the patient to take the study drugs 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if she is 
unable for any reason to take the study drug as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
6.1.4 
Treatment duration 
Patients will be treated with everolimus and exemestane until progression of disease, 
unacceptable toxicity, death, consent withdrawal, or discontinuation for any other reason. 
6.2 
Dose modifications 
6.2.1 
Dose adjustment and interruption 
Treatment with everolimus and exemestane should continue as long as clinical benefit is 
observed or until unacceptable toxicity occurs. The management of severe and/or intolerable 
suspected adverse events may require temporary dose interruption (with or without dose 
reduction) or discontinuation of everolimus therapy. 
Dose adjustments are permitted for any adverse event suspected to be related to everolimus in 
those patients unable to tolerate their individual once daily oral dose. If dose reduction is 
required, the suggested dose is approximately 50% lower than the daily dose previously 
administered (see Table 6-2). 
If administration of everolimus must be interrupted because of unacceptable toxicity, 
everolimus dosing should be interrupted or modified according to the guidelines presented in 
Table 6-2, Table 6-3, and Table 6-4. 
Table 6-2 
Everolimus dose reduction steps 
Dose level 
Dose and schedule 
0 = starting dose 
10 mg daily 
-1 dose level 
5 mg daily 
-2 dose level 
5 mg every other day 
In addition, if any surgery is planned, everolimus dosing should be interrupted one week prior 
to surgery and should be re-started as soon as possible after wound healing. 

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Table 6-3 and Table 6-4 provide the procedure to be followed in the event of toxicities 
suspected to be related to the everolimus treatment. Included are also instructions for re-
initiation of everolimus dosing once sufficient recovery of toxicity is seen. If everolimus 
dosing is interrupted due to toxicity, everolimus should not be resumed unless recovery to 
grade ≤ 1 is achieved in less than 4 weeks. Then everolimus could be reintroduced at the 
initial dose or a lower dose level depending on the toxicity type and grade (see Table 6-3 and 
Table 6-4). 
If a patient has already decreased everolimus intake by 2 dose levels, no further dose 
reduction is permitted. Patients requiring an additional everolimus dose reduction will be 
required to discontinue study treatment. Patients who interrupt everolimus therapy for more 
than 4 weeks must be discontinued from the study. 
All study drugs, i.e. everolimus and exemestane, interruptions or dose modifications must be 
recorded on the Dosage Administration Record page of the CRF. 
Table 6-3 
Everolimus: 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 treatment. 
Physicians should always manage patients according to their medical judgment based on the particular clinical 
circumstances. 

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Table 6-4 
Everolimus: dose modification guidelines for non-hematologic 
toxicities 
Adverse drug reaction 
Severity 
Everolimus dose adjustment 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 ADL 
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 
weeks. 
Grade 3 
Symptomatic, interfering 
with ADL; O2 indicated 
Interrupt everolimus until symptoms resolve to ≤ 
grade 1. 
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 
Consider treatment with corticosteroids. 
Stomatitisa 
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). 
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) 
Grade 4 
Symptoms associated with 
life-threatening 
consequences 
Discontinue everolimus and treat with appropriate 
medical therapy. 
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. 

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Adverse drug reaction 
Severity 
Everolimus dose adjustment and management 
recommendations 
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 everolimus at a lower dose. 
Manage with appropriate medical therapy and 
monitor. 
Grade 4  
Discontinue everolimus and treat with appropriate 
medical therapy. 
Toxicity requiring 
interruption for > 4 weeks 
 
Permanently discontinue treatment 
ADL: activities of daily living 
O2: oxygen 
a: Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as 
they may worsen mouth ulcers. 
Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-
threatening symptoms. 
If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously 
administered. 
6.2.2 
Follow-up for toxicities 
Patients whose everolimus treatment is interrupted or permanently discontinued due to an 
adverse event or abnormal laboratory value suspected to be related to study treatment must be 
followed at least weekly until the adverse event or abnormal laboratory values resolves or 
returns to grade 1. 
If a patient requires a dose delay of > 4 weeks from the intended day of the next scheduled 
dose for either everolimus or exemestane, then the patient must be discontinued from the 
study. 
6.3 
Known undesirable effects of the study drugs 
The most frequently observed adverse events (AEs) with everolimus are rash, stomatitis /oral 
mucositis, non-infectious pneumonitis, fatigue, headache, anorexia, nausea, vomiting, 
diarrhea, and infections. Overall, the most frequently observed laboratory abnormalities 
include neutropenia, thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia. 
The majority of these AEs have been of mild to moderate severity (NCI CTC grade 1-2). 
Recommendations for dose adjustments, should any of these treatment-related adverse events 
occur, are given in Table 6-2, Table 6-3, and Table 6-4. 

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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 leg oedema. 
Thrombocytopenia and leucopenia have been reported occasionally. Reductions in bone 
mineral density can occur with long-term use of exemestane (Motzer 2008). 
Please refer to the package insert of the local supply of exemestane for more details. 
6.3.1 
Non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed. 
A diagnosis of non-infectious pneumonitis should be considered in patients presenting with 
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or 
dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Opportunistic infections such as PJP should 
be considered ruled out in the differential diagnosis of non-infectious pneumonitis. Patients 
should be advised to report promptly any new or worsening respiratory symptoms. 
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration. If symptoms 
are moderate (grade 2), consideration should be given to interruption of therapy until 
symptoms improve. The use of corticosteroids may be indicated.Everolimus may be 
reintroduced at a daily dose approximately 50% lower than the dose previously administered. 
For cases of grade 3 non-infectious pneumonitis, interrupt everolimus until resolution to less 
than or equal to grade 1. Everolimus may be re-initiated at a daily dose approximately 50% 
lower than the dose previously administered depending on the individual clinical 
circumstances. If toxicity recurs at grade 3, consider discontinuation of everolimus. For cases 
of grade 4 noninfectious pneumonitis, everolimus therapy should be discontinued. 
Corticosteroids may be indicated until clinical symptoms resolve. 
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 
prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be considered. 
Guidelines for management of non-infectious pneumonitis suspected to be associated with 
everolimus and dose modification instructions have been provided in Table 6-4. 
6.3.2 
Infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis, or candidiasis, or pneumocystis jirovecii pneumonia 
(PJP) and viral infections including reactivation of hepatitis B virus, have been described in 
patients taking everolimus. Some of these infections have been severe (e.g. leading to sepsis, 
respiratory or hepatic failure) and occasionally have had a fatal outcome. 

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Physicians and patients should be aware of the increased risk of infection with everolimus. 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
everolimus. 
Patients with positive results of HBV-DNA and/or HBsAg at screening should begin a 
prophylaxis treatment for 1-2 week prior to beginning everolimus therapy. Patients should 
have HBV-DNA monitored frequently throughout the course of everolimus therapy for signs 
of hepatitis reactivation. 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy. 
Cases of Pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have been 
reported in patients who received everolimus. PJP may be associated with concomitant use of 
corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered 
when concomitant use of corticosteroids or other immunosuppressive agents are required. 
6.3.3 
Management of Hepatitis reactivation/flare 
6.3.3.1 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 6-5 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 prior to enrolment in the study. 
Table 6-5 
Actions recommended base on hepatitis B screening results 
 
Result 
HBV-DNA  
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
- 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior 
HBV 
vaccination 
+ or - 
- or + 
with prior HBV 
vaccination 
HBcAb 
 
 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be 
started at least 1 week prior to 
first dose of study drug. 
Monitor HBV-DNA approximately
every 6 weeks 
(from Visit 2 and onwards) 
No prophylaxis 
 
Monitor HBV-DNA 
approximately 
every 3 weeks 
(from Visit 2 and onwards) 
No specific action 

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Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug. 
The first HBV-DNA result would be regarded as screen visit. 
For hepatitis B reactivation, definition and management guidelines, see Table 6-6 Guidelines 
for management of hepatitis B. 
Table 6-6 
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 6-2- 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. 
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 v 3.0 Metabolic Laboratory/Other: Viral 
Re-activation), unless considered life threatening by the investigator; in which case they should be recorded as 
grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on 
which the rise or reappearance of HBV- DNA was recorded. 
6.3.3.2 
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 6-7. 

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Table 6-7 
Guidelines for management of hepatitis C 
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 3.0 Metabolic Laboratory/Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4 (CTCAE 
v 3.0 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. 
6.4 
Concomitant medication 
In addition to receiving everolimus and exemestane, all patients should receive best 
supportive care (BSC), as per standard local practice for the treatment of pre-existing medical 
conditions or adverse events that may arise during the study. BSC is defined as drug or 
nondrug therapies, nutritional support, physical therapy or any other treatment alternative that 
the investigator believes to be in the patient’s best interest, but excluding other antineoplastic 
treatments. 
All medications and non-drug therapies taken within 30 days prior to starting the study 
treatment should be reported on the Concomitant Medication/Significant Non-drug Therapy 
Prior to Start of Study Drug CRF. The patient should notify the investigational site about any 
new medications (including over-the-counter products and herbal/alternative medications) 
taken during the study. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy and blood transfusions) administered during the study 
and for up to 30 days after study drug discontinuation must be listed on the Concomitant 
Medications or the Procedures and Significant Non-Drug Therapies CRF pages, respectively. 
The use of live vaccines and close contact with those who have received live vaccines should 
be avoided during treatment with everolimus. Examples of live vaccines are: intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a 
typhoid vaccines. 
Information regarding drug-to-drug interactions for everolimus is provided in Section 6.4.1. 

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6.4.1 
Prohibited concomitant therapy 
Local radiotherapy for analgesic purpose or for lytic lesions at risk of fracture should have 
been completed two weeks prior to enrolment. Patients must have recovered from 
radiotherapy toxicities prior to enrolment in the study. 
Everolimus may affect the response to vaccinations making it less effective. Live vaccines 
must be avoided during treatment with everolimus. Examples of live vaccines are: intranasal 
influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, 
varicella, and TY21a typhoid vaccines. 
Administration of the following treatments is prohibited during the study period: 
• Investigational or commercial anticancer agents, such as chemotherapy, immunotherapy, 
targeted therapy, biological response modifiers, or endocrine therapy other than 
exemestane (including steroids) 
• Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (e.g. raloxifene). 
Treatment with topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways 
diseases), eye drops or local injections (e.g. intra-articular) of corticosteroids is allowed. 
Chronic low dose therapy with systemic corticosteroids, i.e. ≤ 10 mg/day prednisolone 
equivalent, is also allowed. 
Hematopoietic growth factors (e.g. erythropoietin, G-CSF and GM-CSF) are not to be 
administered prophylactically. Their use must be reserved to cases of Grade 3 or 4 
neutropenia and anemia as per the labeling of these agents. 
Where possible, it is recommended to avoid drugs or substances known to be inhibitors or 
inducers of the isoenzyme CYP3A as systemic therapy in association with everolimus as these 
can alter its metabolism: 
• Co-administration of everolimus with strong CYP3A inhibitors (e.g. ketoconazole, 
itraconazole, ritonavir, clarithromycin and telythromycin), and strong inducers (e.g. 
rifampin, rifabutin) should be avoided. 
• Co-administration of everolimus with moderate CYP3A inhibitors (e.g. erythromycin, 
fluconazole, calcium channel blockers, benzodiazepines, verapamil, diltiazem, amprenavir, 
fosamprenavir or aprepitant) and PgP inhibitors should also be used with caution (e.g. 
increased frequency of safety monitoring). 
• Co-administration of everolimus with strong CYP3A4 inducers (e.g. phenytoin, 
carbamazepin, rifampin, rifabutin, Phenobarbital, St John’s wort) should be avoided. 
• Sevilla orange, grapefruit and grapefruit juice affect cytochrome P450 and PgP activity 
and must therefore be avoided during study drug intake. 
Clinically relevant inducers, inhibitors and substrates of CYP3A and PgP are listed in Table 
6-8 and Table 6-9. 

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Table 6-8 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A 
Inducers 
Strong inducers: 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. 
John's wort 
(hypericum perforatum) 
Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, 
tipranavir 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, 
Echinacea, 
garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, 
oxcarbazepine, 
pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, 
terbinafine, 
topiramate, [troglitazone] , vinblastine 
Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, 
lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole (Krishna et al 2009), ritonavir, 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 

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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, everolimus 
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, rifampin, 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, 
2011,29-Oct-2012 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. 
6.5 
Discontinuation of the study drugs 
Study drug interruption refers to a patient stopping either study drug during the course of the 
study, but then re-starting it at a later time in the study. If either everolimus or exemestane are 
interrupted for more than 4 weeks, the patient will be permanently discontinued from the 
study. 
If the administration of everolimus must be interrupted because of an unacceptable toxicity, 
everolimus dosing will be interrupted or modified according to rules described in Section 
6.2.1. All study drug interruptions must be recorded on the appropriate Dosage 
Administration CRF. 
A patient who requires everolimus dose interruption (regardless of the reason for the 
interruption) lasting >28 days (counting from the first day when a dose was missed) must 
discontinue everolimus. 
Study discontinuation refers to a patient’s withdrawal from everolimus. The reason for 
discontinuation from treatment must be recorded on the End of treatment CRF. 
Everolimus will be discontinued for any of the following reasons: 
• Disease progression 
• Consent withdrawal 
• Unacceptable adverse events 
• Everolimus dose interruption of >4 weeks 
• Intercurrent illness that prevent further administration of everolimus treatment 
• Need for any other types of anticancer therapy, except for palliative radiotherapy for bone 
lesions 
• General or specific changes in the patient’s condition which render the patient 
unacceptable for further everolimus treatment at the discretion of the investigator 

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• Death. 
If a patient has discontinued both study treatments due to an unacceptable adverse drug 
reaction or an abnormal laboratory value, she should not have withdrawal of consent recorded 
as the reason for discontinuation. Instead, the reason for discontinuation must be recorded as 
due to adverse drug reaction or an abnormal laboratory value. 
Patients who discontinue everolimus should be scheduled for an End of Treatment Visit, as 
soon as possible, after discontinuing everolimus, at which time all of the assessments listed 
for the End of Treatment Visit will be performed. The date and reason for stopping the study 
everolimus treatment should be recorded on the CRF. 
If everolimus is permanently discontinued, the patient will be considered to have completed 
study treatment. All patients must have safety evaluations for 30 days (± 2 days) after the last 
dose of everolimus. Once the last dose of everolimus is taken, no further AEs/SAEs will be 
collected on this protocol beyond the 30 days follow-up safety interval. 
After discontinuation of everolimus, the patient will be treated at the investigator’s discretion. 
6.6 
Patient numbering 
Each patient is uniquely identified in the study by a combination of her center number and 
patient number in the center. 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; patients are numbered consecutively, starting with patient 1. Patient numbers 
will not be re-used. If the patient fails to be started on treatment for any reason, the reason for 
not being started on treatment will be entered on the Screening Log. 
6.7 
Study drug preparation and dispensation 
6.7.1 
Packaging and labeling 
All study medication will be packaged into blister packs. The blisters should be opened only 
at the time of administration, as the drugs are both hygroscopic and light sensitive. All blisters 
will conform to all local regulatory requirements. 
Everolimus will be supplied to study sites by Novartis as commercial drug re-labeled for 
clinical trial use. Medication labels will be in the local language and comply with the legal 
requirements of each country. They will include storage conditions for the drug and the 
medication number but no information about the patient. 
6.7.2 
Drug supply and storage 
Everolimus and exemestane tablets including instructions for administration will be dispensed 
by the pharmacist or other authorized site personnel at the investigator’s institution on an 
outpatient basis. 

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Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, the study drug should be stored according to 
the instructions specified on the drug labels. As long as both drugs are supplied by Novartis, 
they are to be stored below 30°C room temperature in dry and secured space. The storage 
temperature must be recorded at least 3 times per week in the temperature log. 
An authorized person at the investigator’s site throughout the entire study must record receipt 
and dispensing of supplied study drugs. Clinical supplies are to be dispensed only in 
accordance with the protocol. 
In each participating country, everolimus and exemestane will be provided to participating 
centers by Novartis until everolimus is locally reimbursed or commercialized for this 
indication or when all patients have been discontinued from investigational treatment due to 
disease progression, unacceptable toxicity, death, consent withdrawal or any other reason. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supplies, Novartis will have a local transition plan in order to ensure that 
all on-going patients will still have access to the study medication without any delay in their 
treatment. 
6.7.3 
Study drug compliance 
The investigator and/or study personnel will assess compliance at each patient visit. To 
accurately determine the patient’s drug exposure throughout the study, the following 
information must be reported on the Drug Administration Record CRF for both everolimus 
and exemestane pages and in the source document: 
• Planned dose administration 
• Actual total daily dose administered 
• Start and end date of drug administration 
• Dose change (no or yes) 
• Reason for dose change (e.g. adverse event, dosing error, lab test abnormality etc.). 
6.7.4 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drugs supplied by Novartis in a drug accountability log. Drug accountability will be 
noted by the field monitor during site visits and at the completion of the trial. Patients will be 
asked to return all unused Novartis-supplied study drugs and packaging on an ongoing basis 
or at the time of study drug discontinuation. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supplies, the investigator will return all used and unused Novartis 
supplied everolimus and exemestane 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. 

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6.7.5 
Disposal and destruction 
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate. Destruction at the site is allowed only if permitted by local regulations 
and authorized by Novartis. 
7 
Visit schedule and assessments 
7.1 
Study flow and visits schedule 
Table 7-1 lists all study assessments by visit. All data obtained from these assessments must 
be supported in the patient’s source documentation. All assessments will be captured in the 
CRF, with the only exception of safety laboratory tests and ECG, which will remain only in 
the patient’s source documents. 
Tests, procedures and visits should occur on schedule as far as possible. 

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Table 7-1 
Schedule of assessments 
 
Screening  
Day -21 to 
-1 
Baseline 
Day 1 
Week 
4 
± 1 
week 
Week 
10 
± 2 
weeks 
Week 20 
± 2 weeks 
Week 30 
± 2 weeks 
Week 
40 
± 2 
weeks 
Week 50 
± 2 weeks/ 
EOT 
Following visits
(each 10 ± 2 
weeks) 
EOT
Follow-up 
EOT + 30 
days (± 2 
days) 
 
 
 
 
 
 
 
Visit N° 
1 
2 
3 
4 
5 
6 
7 
8 
N 
EOT
F-up 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history, 
current medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of breast 
cancer 
X 
 
 
 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapies 
X 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs, 
ECOG status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drugs 
dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CT scan/MRI 
chest, abdomen, 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 

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Screening  
Day -21 to 
-1 
Baseline 
Day 1 
Week 
4 
± 1 
week 
Week 
10 
± 2 
weeks 
Week 20 
± 2 weeks 
Week 30 
± 2 weeks 
Week 
40 
± 2 
weeks 
Week 50 
± 2 weeks/ 
EOT 
Following visits
(each 10 ± 2 
weeks) 
EOT
Follow-up 
EOT + 30 
days (± 2 
days) 
 
 
 
 
 
 
 
Visit N° 
1 
2 
3 
4 
5 
6 
7 
8 
N 
EOT
F-up 
pelvis (1) 
Brain CT scan or 
MRI (2) 
X 
 
 
As clinically indicated 
 
 
 
 
 
 
 
 
 
 
Bone scan/ X-ray 
(3) 
X 
If bone metastases are present at baseline, a bone scan or skeletal survey is required every 10 weeks. If bone 
metastases are not identified at baseline, bone scans will be performed as clinically indicated 
 
Bone CT/MRI (3) 
X  
If bone metastases are present at baseline, a bone scan or 
 skeletal survey is required every 10 weeks. If bone metastases are not 
 identified at baseline, bone CT/MRI will be performed only to confirm potential findings identified by bone scans/X-
rays. 
 
 
 
Hematology, 
chemistry, lipid 
profile (5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B viral 
load and markers 
X 
Monitor approximately every 3-6 weeks when required. 
 
 
 
Hepatitis C viral 
load and markers 
X 
Monitor approximately every 6 weeks when required. 
 
ECG, 
coagulation, 
urinalysis 
X 
As clinically indicated 
 
BAL and 
pulmonary 
 
As clinically indicated 
 

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Screening  
Day -21 to 
-1 
Baseline 
Day 1 
Week 
4 
± 1 
week 
Week 
10 
± 2 
weeks 
Week 20 
± 2 weeks 
Week 30 
± 2 weeks 
Week 
40 
± 2 
weeks 
Week 50 
± 2 weeks/ 
EOT 
Following visits
(each 10 ± 2 
weeks) 
EOT
Follow-up 
EOT + 30 
days (± 2 
days) 
 
 
 
 
 
 
 
Visit N° 
1 
2 
3 
4 
5 
6 
7 
8 
N 
EOT
F-up 
function tests 
Final progression 
status 
 
 
 
 
 
 
 
 
 
 
X 
(1): A RECIST evaluation must be performed and documented in the CRF for CT scans/MRI, including those performed routinely outside the study schedule. 
 
(2): A brain CT scan or MRI will be performed at baseline ≤ 21 days prior to the first dose of the study treatment, and as clinically indicated if the patient develops 
symptoms or signs of CNS involvement. 
 
(3): A bone scan or a skeletal survey will be performed at baseline ≤ 21 days prior to the first dose of the treatment. If clinically indicated, any abnormalities (i.e. hotspots) 
identified on the bone scan/X-rays must be confirmed by CT scan or MRI. Bone lesions (non-target) identified at baseline by CT scan or MRI will be followed using the 
same method according to radiological assessment schedule. If there are not bone metastases identified at baseline, additional bone scans or skeletal surveys should be 
performed as clinically indicated until disease progression or discontinuation from study treatment for any other reason. Abnormalities found on subsequent bone scans 
may also be confirmed by CT scan or MRI. 
 
 
 
(5): Safety laboratory tests are performed according to routine clinical practice, and at least for each safety visit. Safety laboratory tests include hematology (complete 
blood count, white blood count, differential count, red blood cell count, hemoglobin, hematocrit, platelet count), serum chemistry (urea/BUN, uric acid, creatinine, 
electrolytes, total protein, LDH, total bilirubin, gamma-GT, albumin, alkaline phosphatase, AST and ALT, fasting glucose), and serum fasting lipid profile (total cholesterol 
and triglycerides). 

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7.1.1 
Screening period 
The baseline visit/Treatment Day 1 will occur no later than 21 days after the screening visit. 
All assessments requested at the screening visit should be completed before Treatment Day 1. 
The following assessments and procedures will be performed at the screening visit or 
requested at the screening visit to be completed within the screening period: 
• Obtain patient’s written informed consent form prior to any study-specific assessment 
• General demographics including age and gender 
• Medical history/current medical conditions (including prior concomitant medications 
within the last 4 weeks prior to Day 1) 
• 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 therapies: date start, date end, setting (neoadjuvant, adjuvant, 
metastatic), best response, reason for treatment discontinuation. 
• Physical examination, height and weight 
• Vital signs including blood pressure and heart rate 
• ECOG performance status 
• Hepatitis B viral load and markers, hepatitis C viral load (see Section 6.3.3.1 and Section 
6.3.3.2). 
The other safety laboratory assessments, including hematology, biochemistry, serum lipid 
profile, coagulation and urinalysis should be performed locally at the investigator’s discretion 
and are not captured on the CRF. However, laboratory results that are out of range and 
clinically significant should be captured on the medical history/current medical conditions 
CRF. 
The following radiological tumor assessments should be performed within the 21-day 
screening period prior to the start of study treatment: 
• CT scan/MRI for chest, abdomen, and pelvis. CT scan/MRI with contrast media should be 
used except for patients who are allergic/sensitive to the radiographic contrast media. 
• Brain: CT or MRI if CNS metastases are present 
• Bone Scan and CT or X-ray to confirm existing bone lesions (according to local practice), 
unless performed within 6 weeks prior to the Baseline visit/Treatment Day 1. 
Patients eligible to the study with positive HBV-DNA of HBsAg at screening must initiate 
prophylaxis with appropriate antiviral medication at least one week prior to treatment start 
(Treatment Day 1). 
7.1.1.1 
Screening failures 
Patient must provide a signed Informed Consent Form (ICF) prior to any study specific 
screening evaluations. The investigator must review inclusion/exclusion criteria and document 
the patient’s eligibility in the patient record. Patients who do not meet all entry criteria will be 
considered to be screening failures. The reason for not being started will be entered in the 
site’s screening failure log. 

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The following data will be collected for all screening failures: 
• Date of informed consent signature 
• Inclusion/exclusion criteria 
• SAE data (where applicable). 
7.1.1.2 
Enrolment in the study 
Enrolment in the study will be confirmed by completion of the Enrolment form on the eCRF. 
7.1.2 
Treatment period 
Patients will start study treatment on Baseline/Treatment Day 1 with everolimus 10 mg daily 
p.o. (either 2 x 5 mg or 1 x 10 mg tablets) in combination with exemestane 25 mg daily p.o. 
(25 mg tablets). Dose adjustment (reduction or interruption) will be allowed according to 
safety findings and dose adjustment guidelines. Study treatment will continue until disease 
progression, unacceptable toxicity, death, consent withdrawal or any other reason. Further 
treatment after progression will be at the investigator’s discretion. 
During the treatment period, visits will be performed at Week 4 (± 1 week), and then on 
weeks 10 (± 2 weeks), 20 (± 2 weeks), 30 (± 2 weeks), 40 (± 2 weeks), and Week 50/End of 
treatment (± 2 weeks). 
Tumor evaluations through CT scan/MRI will be performed for Screening, at Week 10, Week 
20, Week 30, Week 40 and Week 50/EOT visits. All radiological evaluations and laboratory 
assessments will be performed locally, at the center level. Patients will be followed up for 
safety for 30 days (± 2 days) after the last dose of everolimus. AEs/SAEs with a suspected 
causality to the study drug must be reported beyond this 30 days safety interval. 
7.1.3 
Treatment exposure and compliance 
Compliance with the study treatments 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 both drugs 
(everolimus and exemestane). 
To accurately record the administration of study treatments, the following information must 
be recorded on the DAR CRF throughout the study: 
• Planned dose administration 
• Actual total dose administered 
• Regimen 
• Start/End date of drug administration 
• Dose change or delay and reason for modification. 
7.1.4 
Discontinuation of the study drugs 
Study discontinuation refers to a patient’s withdrawal from everolimus. The reason for 
discontinuation from treatment must be recorded on the End of treatment CRF. 
Everolimus will be discontinued for any of the following reasons: 

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• Disease progression 
• Consent withdrawal 
• Unacceptable adverse events 
• Everolimus dose interruption of > 4 weeks 
• Intercurrent illness that prevent further administration of everolimus treatment 
• Need for any other types of anticancer therapy, except for palliative radiotherapy for bone 
lesions 
• General or specific changes in the patient’s condition which render the patient 
unacceptable for further everolimus treatment at the discretion of the investigator 
• Death. 
If a patient has discontinued both study treatments due to an unacceptable adverse drug 
reaction or an abnormal laboratory value, she should not have withdrawal of consent recorded 
as the reason for discontinuation. Instead, the reason for discontinuation must be recorded as 
due to adverse drug reaction or an abnormal laboratory value. 
If everolimus or exemestane is permanently discontinued, the patient will be considered to 
have completed study treatment. All patients must have safety evaluations for 30 days (± 2 
days) after the last dose of everolimus. 
Patients who discontinue everolimus should be scheduled for an End of Treatment Visit, as 
soon as possible, after discontinuing everolimus, at which time all of the assessments listed 
for the End of Treatment Visit will be performed. The date and reason for stopping the study 
everolimus treatment should be recorded on the CRF. 
Once the last dose of everolimus is taken, no further AEs/SAEs will be collected on this 
protocol beyond the 30 day follow-up safety interval. 
7.1.5 
End of the study 
In each participating country, the study will end when everolimus is locally reimbursed or 
commercialized for this indication or when all patients have been discontinued from 
investigational treatment due to disease progression, unacceptable toxicity, death, consent 
withdrawal or any other reason. 
Patients will be followed up for safety purposes for 30 days (± 2 days) after the last dose of 
study drug. 
At the end of the study, the progression status of all participating patients will be updated and 
recorded in the CRF. 
In those countries in which patients will be transitioned to locally reimbursed or 
commercialized drug supplies, Novartis will have a local transition plan in order to ensure that 
all on-going patients will still have access to the study medication without any delay in their 
treatment. 

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7.2 
Safety and tolerability assessments 
Safety and tolerability will be monitored by assessing all adverse events, including serious 
adverse events, the regular monitoring of hematology, blood chemistry, lipid profile, hepatitis 
B and C markers, vital signs, ECOG performance status and physical examination. Adverse 
events will be evaluated continuously throughout the study period. The other assessments 
should be performed based on the scheduled day of assessment (Refer to Table 7-1). 
Toxicity will be assessed using the NCI-CTCAE Common Terminology Criteria for Adverse 
Events, version 4.03 (CTCAEv4.03). AE/SAE collection and reporting is detailed in Section 8. 
7.2.1 
Physical examination, height and weight 
Physical examination must comprise a total body examination (general appearance, skin, neck, 
including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes and 
extremities). 
Physical examination will be performed at screening, on treatment Day 1 (prior to 
administration of the study drug, unless physical examination in screening was done less than 
7 days before Day 1), as well as at Week 4, Week 10, Week 20, Week 30, Week 40, and 
Week 50 or End of treatment visit. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
documented on the Medical History / Current medical Conditions CRF. Significant findings 
made after the start of study drug, which meet the definition of an adverse event, must be 
recorded on the Adverse Event CRF. 
Height and weight will be measured at the screening visit. 
7.2.2 
Vital signs 
Vital signs will be recorded on the appropriate CRF pages at each visit. Heart rate and blood 
pressure will be measured according to normal medical practice. 
The particular clinical findings seen before taking study drug must be documented in the 
Relevant Medical History CRF. The findings that are compatible with adverse events after 
taking study drug must be documented in the Adverse Event CRF. 
7.2.3 
Laboratory evaluations 
Laboratory evaluations should be performed locally at every protocol required visit (Table 7-1) 
or as frequently as clinically indicated. The patient should be in a fasting state for 12 hours at 
the time of blood sampling. 
All scheduled laboratory evaluations must be obtained according to the specified visit window 
in Table 7.1, whether or not study treatment is administered. Screening examinations 
performed ≤ 7 days of the first dose of study treatment do not need to be repeated on Day 1. 

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Laboratory values will be recorded in the patient’s source documents and must not be 
documented in the CRF. However, any particular clinically significant findings seen before 
taking study drugs must be documented in the Relevant Medical History/Current Medical 
Conditions CRF. 
Abnormal laboratory parameters that are considered clinically significant, induce clinical 
signs or symptoms, require concomitant therapy (e.g. hematologic abnormality that requires 
transfusion or hematological stem cell support), or require changes in study treatment, or 
require changes in study drug(s) constitute adverse events in their own right and must 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 AE (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 and is still, by definition, an adverse event. 
7.2.3.1 
Hematology 
Hematology tests include a complete blood count (CBC): a total white blood cell count 
(WBC), differential count, red blood cell count (RBC), hemoglobin (Hb), hematocrit and a 
platelet count. 
Hematological tests will be performed at screening, on Day 1 (repeated prior to administration 
of the study drug, if performed more than 7 days prior to Day 1), Week 4, Week 10, Week 20, 
Week 30, Week 40, and Week 50 or End of treatment visit. 
In the event of Grade 2, Grade 3 or Grade 4 hematological toxicities that require study drug 
dose modifications or interruptions, hematological tests should be repeated weekly until 
recovery to the baseline value or Grade 1. 
7.2.3.2 
Blood chemistry 
Serum chemistry tests should include urea/BUN, creatinine, LDH, total protein, electrolytes 
(sodium, potassium and calcium), total bilirubin, GGT, albumin, alkaline phosphatase, 
AST/SGOT, ALT/SGPT, uric acid and fasting glucose. Patients should fast for 12 hours prior 
to blood sampling. 
Serum chemistry should be performed at screening, on Day 1 (repeated prior to administration 
of the study drug, if performed more than 7 days prior to Day 1), Week 4, Week 10, Week 20, 
Week 30, Week 40, and Week 50 or End of treatment visit. 

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In the event of Grade 2, Grade 3 or Grade 4 non-hematological toxicities that require study 
drug dose modifications or interruptions, biochemistry tests should be repeated weekly until 
recovery to the baseline value or Grade 1. 
7.2.3.3 
Serum lipid profile 
A serum lipid profile assessment should be performed at screening, on Day 1 (repeated prior 
to administration of the study drug, if performed more than 7 days prior to Day 1), Week 4, 
Week 10, Week 20, Week 30, Week 40, and Week 50 or End of treatment visit. Patients 
should fast for 12 hours prior to blood sampling. 
In the event of Grade 2, Grade 3 or Grade 4 toxicities serum lipid tests should be repeated 
weekly until recovery to the baseline value or Grade 1. 
7.2.3.4 
Other laboratory tests 
Coagulation assessments such as international normalized ratio (INR) or activated partial 
thromboplastin time (aPTT) should be performed at screening/baseline and repeated if 
clinically indicated. 
A urinalysis assessment according to local routine will be performed only at 
screening/baseline. 
7.2.3.5 
Hepatitis B viral load and markers, hepatitis C viral load 
HBV-DNA, HBsAg, HBsAb, HBcAb and HCV-RNA will be measured at screening. 
Significant findings must be recorded as Relevant Medical History / Current Medical 
Conditions. 
These assessments will be repeated every 3-6 weeks during the treatment period when 
required. Results will be recorded in the CRF. Hepatitis reactivation or flare will be managed 
according to guidelines presented in Section 6.3.3, and will be recorded on the Adverse 
Events CRF. 
7.2.3.6 
ECG 
A standard 12-lead ECG should be performed at screening/baseline. Tracings must be dated 
and signed by the investigator (or his/her designee) and filed with the patient’s source 
documentation. Significant findings must be recorded as Relevant Medical History / Current 
Medical Conditions (if present before treatment). 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 recorded on the Adverse Events CRF. 
7.2.4 
Pulmonary function tests (PFTs) 
Pneumonitis is a known adverse event associated with the use of rapamycin and its analogues. 
Bronchoscopy with biopsy, broncho-alveolar lavage (BAL) and pulmonary function tests 
(PFTs) should be performed during the trial if clinically indicated and if warranted to exclude 
or manage non-infection pneumonitis. Significant findings must be recorded on the Adverse 
Events CRF. 

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7.3 
Efficacy assessments 
Tumor assessments are summarized in Table 7-2. 
Tumor response will be evaluated according to RECIST (Version 1.1) (See Appendix 1). 
All patients should have at least one lesion that can be accurately measured in at least one 
dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT as per 
RECIST 1.1 criteria, or in the absence of measurable disease have at least one lytic or mixed 
(lytic + blastic) bone lesion. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline for each study tumor assessment after start of study 
treatment. 
For patients with measurable disease at baseline, tumor progression will be evaluated at each 
assessment according to the RECIST 1.1 criteria (see Appendix 1 for details). All patients 
being discontinued from the study for disease progression must have their progression 
documented using the RECIST 1.1 criteria. 
A CT scan/MRI of the chest, abdomen and pelvis will be performed at screening and repeated 
at Week 10, Week 20, Week 30, Week 40, and Week 50/EOT. CT scan with contrast media 
should be used except for patients who are allergic/sensitive to the radiographic contrast 
media. Response will be assessed by local radiology review. The decision regarding patient 
management will remain with the local investigator. The same radiologist/physician should 
perform the evaluation for the entire duration of the study. 
Bone scans/skeletal survey by X-ray must be performed at baseline within 6 weeks before 
enrolment. Positive areas on bone scans/X-ray must be assessed by MRI or CT scan with bone 
windows, prior to enrolment and should continue to be assessed using the same modality 
(MRI or CT scan) at Weeks 10, 20, 30, 40, and Week 50 or End of Treatment. Additional 
bone scans/X-ray should be performed if clinically indicated. Abnormalities found on 
subsequent bone scans/X-ray must be confirmed by MRI or CT scan. 
In the absence of measurable disease at baseline, the following will be considered progression 
among patients with lytic or mixed (lytic + blastic) bone lesions: 
• Appearance of one or more new lytic lesions in bone 
• 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. 

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Table 7-2 
Imaging collection plan 
Procedure 
Screening: 
Day -21 to -1 
Treatment phase 
End of treatment 
CT or MRI (chest, 
abdomen, pelvis) 
Mandated 
Every 10 weeks from  
treatment start until 
progression or end of study
Mandated 
CT or MRI for any site of 
disease 
Mandated if suspected 
lesion at screening 
If lesion at screening: 
every 10 weeks from 
treatment start until 
progression or end of study
Mandated if lesion at 
screening 
Brain CT or MRI 
Mandated at 
screening only if 
existing or suspected 
brain metastases 
 
As clinically indicated 
As clinically indicated 
Bone scan/X-ray 
Mandated 
 
As clinically indicated 
As clinically indicated 
Bone CT or MRI 
Mandated at 
screening only if 
skeletal abnormalities 
identified by bone 
scan/X-ray at 
screening 
 
If bone lesion at screening: 
every 10 weeks from 
treatment start  until 
progression or end of study
Mandated only if bone 
lesion at screening 
Skin color photography 
Mandated if skin 
lesions at screening 
If skin lesions at screening: 
every 10 weeks from 
treatment start  until 
progression or end of study
Mandated if skin lesions at 
screening 
7.4 
ECOG Performance Status 
The performance status will be scored using the ECOG Performance Status Scale (Oken, 
1982), as described in Table 7-3. 
ECOG Performance Status will be assessed and recorded at screening, on Day 1, and at each 
follow-up visit. Assessment of ECOG Performance Status should be performed on the 
scheduled day, even if study medication is being held. Time to deterioration of ECOG 
performance status, from baseline will be assessed 
Table 7-3 
ECOG Performance Status 
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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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, 
require therapy (e.g. hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study drug(s). 
Except for 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 Medical History/Current Medical 
Conditions CRF. Adverse event monitoring should be continued for at least 30 days (± 2 days) 
following the last dose of everolimus. Adverse events (including laboratory 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 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through a Death form. 

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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 
during the screening process or between visits, or through physical examination, laboratory 
test, or other assessments. 
Progression of malignancy (including fatal outcomes), if documented by use of RECIST 
(version 1.1) will 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 study 
drugs. 
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) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
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. 
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. 

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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 
The adverse events of special interest associated with mTOR inhibition include: 
• Stomatitis 
• Non-infectious pneumonitis 
• Infections 
• Hyperglycemia 
• Hyperlipidemia 
• Hypophosphatemia 
• Skin Rash 
• Hypersensitivity 
• Wound healing complications 
• Increased creatinine/renal failure/proteinuria 
• Cardiac failure 
8.2 
Serious adverse events 
8.2.1 
Definitions 
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 
• 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: 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, if any 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 

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• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Note: 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 
Every SAE, regardless of suspected causality, occurring after the patient has provided 
informed consent and until 30 days after the patient has stopped study treatment/participation 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAE experienced after this 30-day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new 
event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study drug, 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, and whether the patient continued the study 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 drug, 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 European Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 

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8.3 
Emergency unblinding of treatment assignment 
Not applicable, this is an open label study. 
8.4 
Pregnancies 
Not applicable; this study will enroll post-menopausal women only. 
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. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
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. 

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9.2 
Site monitoring 
Before study initiation, Novartis personnel (or designated CRO) will review the protocol and 
CRFs with the investigators and their staff at a site initiation visit. During the study, the field 
monitor will visit the site regularly to check the completeness of patient records, the accuracy 
of entries on the eCRFs, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrolment, and to ensure that study drug 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 on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF 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 
eCRFs are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
Novartis will supply the investigator site with an Electronic Data Capture (EDC) system that 
has been fully validated and conforms to 21 CFR Part 11 requirements. 
Novartis (or designated CRO) will train designated investigator site staff on the EDC system. 
Investigator site staff will not be given access to the EDC system until they have been trained. 
The investigator will notify Novartis and the CRO of any changes in study personnel 
responsible for entering study related data into the EDC system. Once notified, Novartis (or 
designated CRO) will ensure that the new site personnel are adequately trained, understand 
the study protocol requirements and can properly use the EDC system. 
Designated investigator staff will enter the data required by the protocol into the eCRFs 
through the EDC system. Automatic validation programs check for data discrepancies in the 
eCRFs and, by generating appropriate error messages, allow modification or verification of 
the entered data by the investigator staff before transfer to Novartis via a secure Virtual 
Private Network. If applicable, the investigator must certify that the data are complete and 
accurate by signing a memo prior to database lock. 
The principal investigator is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entries and updates are performed in a timely manner. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site. 

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9.4 
Database management and quality control 
Data recorded on the eCRFs will be reviewed by a designated CRO staff for completeness and 
accuracy following their own internal standard operating procedures that have been reviewed 
and approved by Novartis. 
Site personnel will be instructed to make any required corrections or additions. Obvious errors 
are corrected by CRO Data Management staff. Queries are sent to the investigational site 
using an electronic data query system. The designated investigator site staff is required to 
respond to the query and make any necessary changes to the data within a reasonable 
timeframe. If the electronic query system is not used, a paper Data Query Form will be faxed 
to the site. Site personnel will complete and sign the faxed copy. This copy will then be faxed 
back to the CRO Data Management staff that will make the correction to the database. The 
signed copy of the Data Query Form is kept at the investigator site. 
Concomitant 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 may be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the database has been declared to be complete and accurate, 
the database will be locked and made available for data analysis. Any changes to the database 
after that time can only be made by joint written agreement between the Global Head of 
Biostatistics and Statistical Reporting and the Global Therapeutic Area Head. 
10 
Statistical methods and data analysis 
The study is designed as an open-label, single-arm, phase IIIB trial to assess the safety, 
tolerability and efficacy of everolimus plus exemestane in postmenopausal women with 
hormone receptor positive breast cancer progressing following prior therapy with non-
steroidal aromatase inhibitors. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. The data will be analyzed by 
Novartis and/or designated CRO. Any data analysis carried out independently by the 
investigator should be submitted to Novartis before publication or presentation. 
10.1 
Analysis sets 
The Full Analysis Set (FAS) consists of all patients to whom treatment was assigned and 
who received at least one dose of study drug. 

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The Per-protocol Set (PP) consists of a subset of patients of the FAS who did not show 
major deviations from the protocol procedures that may have an impact on the study outcome. 
Criteria that are assumed to have such an impact will be defined in the Protocol Deviations 
Module of the Validation and Planning (VAP) documentation, and assessed before database 
lock during the blinded review meeting. 
The Safety Set consists of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment. The statement that a patient had no adverse events 
(on the Adverse Event CRF) constitutes a safety assessment. Patients who have received at 
least one dose of study drug but who have no post-treatment safety data of any kind would be 
excluded from the safety population. 
10.2 
General statistical methods 
The data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, and safety observations and measurements. Primary 
efficacy and safety/tolerability analysis will be conducted at 15 months of median follow up 
time, i.e. at approximately two times the median PFS reported in the BOLERO-2 study 
(Baselga et al. 2012; Yardley D. et al. 2014).Categorical variables will be summarized by 
absolute and relative frequencies. Continuous variables will be summarized by descriptive 
statistics (number of valid and missing observations, mean, standard deviation, median, 
minimum, and maximum). 
Time to event data including rates of affected patients will be assessed using the Kaplan-
Meier method. Two-sided 95% confidence intervals will be provided for the main statistical 
estimators. 
10.3 
Patient demographics and baseline characteristics 
Demographic and other baseline characteristics will be summarized for the Full Analysis Set 
(FAS). Baseline characteristics include prior medication, past/current medical conditions and 
disease history. 
Medical history will be coded using MedDRA and will be presented by MedDRA system 
organ class, preferred term and treatment group. Separate tables will be provided for past 
medical conditions and current medical conditions. Prior medications and significant non-
drug therapies will be coded according to the WHO Drug Reference List, and summarized by 
ATC class and preferred term using frequency distributions. 
10.4 
Treatments (study drugs, concomitant therapies) 
Duration (days) of drug exposure will be summarized using descriptive statistics separately 
for everolimus and exemestane. 

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Duration of drug exposure will be calculated as the difference between the last and first day of 
drug application +1. Dosage averages will be calculated including and excluding zero doses 
for periods of temporary interruption of treatment, regardless of whether this was due to 
safety/tolerability reasons or patients’ non-compliance. Average daily dose levels will be 
summarized descriptively. Frequencies of the number of patients with any dose reduction 
(including temporary dose interruption) as well as the number of dose reductions by reason 
will be given. These analyses will be performed on the Safety Set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be coded according to the WHO Drug Reference List, and summarized by 
ATC class and preferred term using frequency distributions. 
10.5 
Primary objective 
The primary objective is to evaluate the safety and tolerability profile of everolimus in post-
menopausal women with ER positive, HER2 negative locally advanced or metastatic breast 
cancer after documented recurrence or progression following a non-steroidal aromatase 
inhibitor therapy in emergent growth markets (EGM). 
The assessment of safety and tolerability will be based mainly on the frequency of adverse 
events, including the laboratory values that qualify as adverse events. Other safety data (e.g. 
vital signs, and special tests) will be considered as appropriate. The analysis will be 
descriptive. For all safety/tolerability analyses, the safety set will be used. 
Data collected by AE CRFs will be coded using the MedDRA dictionary. The incidence of 
treatment-emergent adverse events (new or worsening from baseline) will be summarized by 
MedDRA system organ class and preferred term using frequency distributions. Additionally, 
AE will be summarized by maximum severity (based on CTCAE grades), and for AE with 
suspected drug relation, serious AE (SAE), and AE leading to permanent discontinuation of 
study drug. All information pertaining to AE noted during the study will be listed by patient, 
detailing the verbatim term given by the investigator, MedDRA preferred term and system 
organ class, start/end dates, severity, seriousness, relationship to study drug and action taken. 
The AE onset will also be shown relative (in number of days) to the date of initial dose. AE 
starting more than 30 days after discontinuation of study drug will not be considered as 
treatment-emergent and will not be included in AE summary tables but listed only. 
Data from other tests (e.g., electrocardiogram or vital signs) will be summarized descriptively 
as appropriate. Notable values will be flagged, and any other information collected will be 
listed as appropriate. 
10.6 
Secondary objectives 
10.6.1 
Efficacy endpoints 
Efficacy endpoints will be analyzed on the Full Analysis Set (primary analysis) and on the Per 
Protocol Set (supportive analysis). 

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Efficacy endpoints based on radiological assessments of tumor burden will be derived using 
local radiologist’s/ investigator’s assessment. If a patient has not had an event before exiting 
the study, his or her data will be censored at the date of last adequate tumor assessment. 
10.6.1.1 Overall response rate 
The Overall response rate (ORR) will be provided over the study period. The ORR is the 
proportion of patients with a best overall response of confirmed complete (CR) or partial (PR) 
response at those time points. The best overall response for each patient is determined from 
the sequence of investigator overall lesion responses according to RECIST 1.1. To be 
assigned a best overall response of CR at least two determinations of CR at least 4 weeks 
apart before progression are required. To be assigned a best overall response of PR at least 
two determinations of PR or better at least 4 weeks apart before progression (and not 
qualifying for a CR) are required. 
The ORR (best overall response of CR or PR) as well as individual response categories (CR, 
PR, SD, PD or unknown) measured at approximately week 20 and week 50 will be 
summarized using frequency tables together with their associated two-sided exact 95% 
confidence intervals (Clopper-Pearson method). 
10.6.1.2  Clinical benefit rate 
The clinical benefit rate (CBR) will be provided over the study period. CBR rate is defined as 
the proportion of patients with best overall response of complete response (CR), partial 
response (PR) or stable disease (SD), with duration of 24 weeks or longer, according to 
RECIST 1.1. The best overall response for each patient is determined from the sequence of 
investigator overall lesion responses according to RECIST 1.1. To be assigned a best overall 
response of CR or PR, two determinations of CR at least 4 weeks apart before progression are 
required. 
The duration of best overall response is assessed as such: the start date is the date of first 
documented response (CR or PR) and the end date is the date of event defined as first 
documented progression disease or death due to underlying cancer. 
The CBR measured at approximately week 20 and week 50 will be summarized using 
frequency tables together with its associated two-sided exact 95% confidence intervals 
(Clopper-Pearson method). 
10.6.1.3 Progression-free survival 
Progression-free survival (PFS) is the time from date of 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. 
Disease progression will be assessed using the local (treating center’s radiologist’s) 
investigator’s tumor assessment. PFS will be summarized using the Kaplan-Meier method. 
Percentiles (25%, median, 75%) of the event time distribution will be presented along with 
their two-sided 95% confidence interval. The Kaplan-Meier curve will be displayed 
graphically. 

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10.6.1.4 Handling of missing data 
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 (see Post-text 
supplement 1). 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. Patients with a best overall response assessment of unknown (UNK) will not be 
regarded as ‘responders’ but will be included in the denominator for the calculation of the 
ORR for the FAS. 
10.6.2 
Other endpoints 
10.6.2.1 ECOG Performance Status 
The ECOG Performance Status will be summarized using frequency distributions by visit. 
Shifts from baseline value to worst post-baseline value will be summarized using frequency 
distributions. 
10.7 
Sample size calculation 
No hypothesis testing will be performed in this study, which is descriptive in purpose. 
The proposed sample size is up to 400 patients. The study recruitment will be globally 
competitive and end by October 31st 2014 at latest. 
The actual sample size may differ from this plan. 
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. 

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Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. The date when a subject’s Informed Consent was actually obtained will be 
captured in their eCRFs. 
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 trial agreement. Specific conditions for terminating the study are outlined in Section 
4.3. 
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. 

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Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
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 
enrolment 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. 

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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 
trial 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/REB at/of 
the study site should be informed according to local regulations, but not later than 10 working 
days. 

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13 
References (available upon request) 
Aromasin® prescribing information, Pfizer-Pharmacia, 2011. 
Bachelot T, Bourgier C, Cropet C, et al. 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 2012; 30: 2718-24. 
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor 
positive advanced breast cancer. N Engl J Med 2012; 366: 520-29. 
Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant 
everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen 
receptor-positive breast cancer. J Clin Oncol 2009; 27: 2630-37. 
Buzdar A, Jonat W, Howell A, et al. for the Arimidex Study Group (1998) Anastrozole versus 
megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma. 
Results of a survival update based on a combined analysis of data from two mature Phase III 
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Buzdar A. Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors. 
Clinical Cancer Research 2003; 9 (Suppl.): 468s-472s. 
Chia S, Gradishar W, Mauriac L et al. Double-blind, randomized placebo controlled trial of 
fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in 
postmenopausal women with hormone receptor–positive, advanced breast cancer: Results 
From EFECT. J. Clin. Oncol 2008; 26: 1664-70. 
Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus 
tamoxifen after 2-3 year’s tamoxifen treatment (Intergroup Exemestane Study): a randomized 
controlled trial. Lancet 2007; 369: 559-570. 
Crowe A and Lemaire M. In vitro and in situ absorption of SDZ-RAD using a human 
intestinal cell line (Caco-2) and a single pass perfusion model in rats: Comparison with 
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Demers, LM, Lipton A, Harvey HA, et al. The efficacy of CGS 20267 in suppressing estrogen 
biosynthesis in patients with advanced stage breast cancer. J Steroid Biochem Mol Biol 1993; 
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Ellard SL, Clemons M, Gelmon KA, et al. Randomized phase II study comparing two 
schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical 
Trials Group IND.163. J Clin Oncol. 2009; 27: 4536-41. 
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: 
GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-917. 
Francesc V, Chambard JC, Pouysségur J. p70 S6 Kinase-mediated protein synthesis is a 
critical step for vascular endothelial cell proliferation. J Biol Chem 1999; 274: 26776-82. 

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Gennatas C, Michalaki V, Carvounis E, et al. Third-line hormonal treatment with exemestane 
in postmenopausal patients with advanced breast cancer progressing on letrozole or 
anastrozole. A phase II trial conducted by the hellenic group of oncology (HELGO). Tumori 
2006; 92: 13-17. 
Gligorov J, Pritchard K, Goss P. Adjuvant and extended adjuvant use of aromatase inhibitors: 
Reducing the risk of recurrence and distant metastasis. Breast 2007, 16 (suppl 3): 1-9. 
GLOBOCAN 2008. Available from: http://globocan.iarc.fr/ 
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic 
tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat 
Med 2002; 8: 128-35. 
Hortobagyi GN. Commentary: role of bone-modifying agents in metastatic breast cancer. J 
Oncol Pract 2011; 7: 121–23. 
Hutson PR, Love R, Havighurst T, et al. Effect of Exemestane on tamoxifen pharmacokinetics 
in postmenopausal women treated for breast cancer. Clin Cancer Res 2005; 11: 8722-27. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-
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Jensen E, Jordan C. The estrogen receptor: a model for molecular medicine. Clin Cancer Res 
2003; 9: 1980–89. 
Kneissel M, Luong-Nguyen NH, Baptist M, et al. Everolimus suppresses cancellous bone lose, 
bone resorption, and catherpsin K expression by osteoclasts. Bone 2004; 35: 1144-56. 
Kuhn B, Jacobsen W, Christians U, et al. Metabolism of sirolimus and its derivative 
everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and 
quantum chemical calculations. J Med Chem. 2001; 44: 2027-34. 
Lane HA, Wood JM, McSheehy PM, et al. mTOR inhibitor RAD001 (everolimus) has 
antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin 
Cancer Res 2009; 15: 1612-22. 
Laplante A, Demeule M, Murphy GF, Béliveau R. Interaction of immunosuppressive agents 
rapamycin and its analogue SDZ-RAD with endothelial P-gp. Transplant Proc. 2002; 34: 
3393-95 
Lønning P, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer after 
failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Onc 2000; 18: 2234-44. 
Mabuchi S, Altomare DA, Cheung M, et al. (2007b). RAD001 inhibits human ovarian cancer 
cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian 
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Mabuchi S, Altomare DA, Connolly DC, et al. (2007a). RAD001 (Everolimus) delays tumor 
onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res 2007; 67: 
2408-13. 
Marangoni E, Vincent-Salomon A, Auger N, et al. A new model of patient tumor-derived 
breast cancer xenografts for preclinical assays. Clin Cancer Res. 2007; 13: 3989-98. 
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Motzer RJ, Escudier B, Oudard S, et al. (2008) Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372: 
449-456. 
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Oncologist 2005; 10 (suppl 3): 20-29. 
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Ory B, Moriceau G, Rendini F, et al. mTOR inhibitors (rapamycin and its derivatives) and 
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Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy 
and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced 
breast cancer progressing on prior endocrine therapy: Results of a North American trial. J Clin 
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Plourde PV, Dyroff M, Dowsett M, et al. ARIMIDEX: a new oral, once-a-day aromatase 
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Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348: 2431-
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Thijssen JH, Blankenstein MA. Endogenous oestrogens and androgens in normal and 
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Tsutsumi N, Yonemitsu Y, Shikada Y, et al. Essential role of PDGFRalpha-p70S6K signaling 
in mesenchymal cells during therapeutic and tumor angiogenesis in vivo: role of PDGFRalpha 
during angiogenesis. Circ Res 2004; 94: 1186-94. 
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http://who.int/cancer/detection/breastcancer/en/index2.html. Consulted on 17 September 2012. 
World Health Organization. Global Burden of Disease, 2004. 
Yardley DA, Nogushi S, Pritchard KI, et al. Everolimus Plus Exemestane in Postmenopausal 
Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis. Adv 
Ther. 2013;30:870-84. 
Yu Y, Sato JD (1999) MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase 
mediate the mitogenic response of human endothelial cells to vascular endothelial growth 
factor. J Cell Physiol 1999; 178: 235-46. 

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14 
Appendices 
14.1 
Appendix 1: Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1) 
Harmonization of efficacy analysis of solid tumor studies RECIST version 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 
List of Contributors 
 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
Authors (Version 2): 
 
Authors (Version 1): 
 
 
 

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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
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 
TTF 
Time to treatment failure 
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 14.1.2 and the definition of best response in 
14.1.16 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 14.1.17 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 14.1.27 
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 
14.1.3.1 Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 14.1.25. 

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Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
≥10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
14.1.4 
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 14.1.25. 
14.1.5 
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: 

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• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during followup. 
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. 
14.1.6 
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 14.1.3.1. 
• Nodal target: See Section 14.1.3.1. 

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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 e-CRF. 
14.1.7 
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. 
14.1.8 
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. 
14.1.9 
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. 
14.1.10 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. 
14.1.11 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 14.1.5. 
 

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Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance  
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the 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. 

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• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
14.1.12 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) 
Partial Response (PR): 
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). 

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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 14.1.11 for assigning PD following a CR for the non-target lesion response in the 
presence of non-target lesions nodal lesions should be applied. 
14.1.13 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 14.1.14). 
• 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 14.1.5. 
14.1.14 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. 

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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 14.1.7. 
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. 
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. 
14.1.15 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.25 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
14.1.16 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. 

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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 
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. 

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If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
• The best overall response for a patient is always calculated, based on the sequence of 
overall lesion responses. However, the overall lesion response at a given assessment may 
be provided from different sources: Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD. 
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 within8 
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). 

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14.1.17 Time to event variables 
14.1.18 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. 
14.1.19 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. 
14.1.20 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. 
14.1.21 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment. 

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14.1.22 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 rate 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in Ellis et al (2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis). 
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. 
14.1.23 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. 

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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 14.4.22. 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. 
14.1.24 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 of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 

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• 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 
postbaseline 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 14.1.25). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.1.25 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 

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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 14.1.7. 
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 
nonmeasurable disease. 
14.1.26 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 14.1.24, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:  

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Table 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 14.1.24 
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. 
• (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. 

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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. 
14.1.27 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). 
14.1.28 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
14.1.29 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 7 days of the 
last study treatment. 

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Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
14.1.30 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 

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14.1.31 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 
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. 
14.1.32 Programming rules 
The following should be used for programming of efficacy results: 
14.1.33 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. 
14.1.34 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 14.1.24). 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. 

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14.1.35 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. 
14.1.36 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)’. 
14.1.37 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.38 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 14.1.24. 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). 

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• 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 
anticancer 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. 
14.1.39 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