Clinical trial NCT01698918
Conditions: Hormone Receptor Positive Breast Cancer
Keywords: Metastatic breast cancer Locally advanced breast cancer HER2- ER+ Everolimus Afinitor
Sponsor: Novartis Pharmaceuticals
Start date: 2013-03-07; Completion date: 2021-01-13
Enrollment: 202 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer.

Moreover, the study also aimed to investigate the efficacy and safety of second line treatment with everolumus plus examestane in participants whose disease progressed during everolimus plus letrozole therapy.

Detailed description:
This was an open-label, phase II, multicenter, international, single-arm study for postmenopausal women with ER+/HER2- metastatic or locally advanced breast cancer.

This study was comprised of 2 phases:

\- Core Phase: from first participant first visit to 24 months after enrollment of the last participant (and upon approval of amendment 5 dated 14-Feb-2017), up to approximately 4 years. The main purpose of the amendment 5 was to implement an Extension Phase up to 3 years.

During the core phase, all enrolled participants received everolimus in combination with letrozole in the first line setting until disease progression or any other reason for which the participant might be discontinued. Only those participants who had disease progression in the first line setting were offered second line treatment (everolimus in combination with exemestane). Participants who discontinued first line treatment due to reasons other than disease progression were not eligible for second line treatment. The participants who were treated in the second line setting continued treatment until disease progression, unacceptable toxicity or withdrawal of consent.

\- Extension Phase: Participants that were still benefiting from everolimus at the end of the Core Phase (and upon approval of amendment 5 dated 14-Feb-2017) were transitioned to the Extension phase of the study. Participants were continued on their existing line of treatment (everolimus plus letrozole or everolimus plus exemestane) in the extension, up to 3 years or until progression or any other reason for which the participant might be discontinued. Participants entering the Extension Phase on first line treatment and deemed to no longer be clinically benefiting were not offered second line treatment in the context of the study

This study included a randomized, open-label sub-study for participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event: at the first onset of symptoms suggestive of stomatitis, participants were to contact the study site and based on preliminary confirmation of diagnosis, participants were asked to visit the study site within 24 hours. Upon confirmation of stomatitis, participants in countries where the alcohol-free 0.5 mg/5 mL dexamethasone oral solution was commercially available (US sites only) were randomly assigned in a 1:1 ratio to take either 0.5 mg/5 mL dexamethasone mouth rinse or the standard of care used to treat stomatitis at the participant's center.

All participants who experienced stomatitis (regardless of inclusion in the sub-study) were instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the participant recovered. For subsequent episodes of stomatitis, participants were instructed to contact the physician. If part of the randomized set upon telephone confirmation, they were instructed to utilize the same treatment they were assigned to after the first episode and complete the OSDQ booklet.

Arms: arm 1: Participants received everolimus in combination with letrozole as first-line treatment. Only participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane)
Interventions: intervention 1: Everolimus intervention 2: Letrozole intervention 3: Exemestane intervention 4: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study) intervention 5: Standard of care to treat stomatitis (Stomatitis sub-study)
Intervention descriptions: intervention 1: Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent. intervention 2: 1st line study treatment: Letrozole was self administered as a daily dose of 2.5mg continuously until disease progression or any other reason for which the patient might be discontinued intervention 3: 2nd Line Study Treatment: Exemestane was self administered as a daily dose of 25mg taken orally continuously until disease progression or any other reason for which the patient might be discontinued intervention 4: Alcohol-free 0.5mg/5ml dexamethasone oral solution was self-administered at a daily dose of 10ml 3 times per day (participants with confirmed stomatitis who entered the stomatitis sub-study). intervention 5: Standard of care used to treat stomatitis at the patient's center (participants with confirmed stomatitis who entered the stomatitis sub-study).

Protocol documents:
Prot_000.pdf: 
Clinical Development and Medical Affairs
RAD001/Everolimus
Protocol CRAD001Y24135 / NCT01698918
An open-label, phase II, single-arm study of everolimus in 
combination with letrozole in the treatment of 
postmenopausal women with estrogen receptor positive 
HER2 negative metastatic or locally advanced breast 
cancer
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-003065-17
Version number
05 (Clean)
Development phase
II
Document status
Final
Release date
14-Feb-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Amendment 5 (14-Feb-2017)............................................................................................12
Amendment 4 ....................................................................................................................15
Amendment 3 ....................................................................................................................17
Amendment 2 ....................................................................................................................19
Amendment 1 ....................................................................................................................22
Protocol summary:.............................................................................................................24
1
Background........................................................................................................................28
1.1
Overview of disease pathogenesis, epidemiology and current endocrine 
treatment options ...................................................................................................28
1.2
Introduction to investigational treatment(s) and other study treatment(s).............29
1.2.1
Overview of everolimus........................................................................29
2
Rationale............................................................................................................................38
2.1
Study rationale and purpose...................................................................................38
2.2
Rationale for the study design ...............................................................................39
2.2.1
Stomatitis therapeutic intervention .......................................................39
2.3
Rationale for dose and regimen selection..............................................................40
2.4
Rationale for choice of combination drugs............................................................40
3
Objectives and endpoints...................................................................................................40
4
Study design ......................................................................................................................42
4.1
Description of study design ...................................................................................42
4.2
Early study termination..........................................................................................45
4.3
Definition of end of study......................................................................................45
5
Population..........................................................................................................................45
5.1
Patient population..................................................................................................45
5.2
Inclusion criteria ....................................................................................................46
5.3
Exclusion criteria...................................................................................................47
6
Treatment...........................................................................................................................48
6.1
Study treatment......................................................................................................48
6.1.1
Dosing regimen.....................................................................................49
6.1.2
Treatment duration................................................................................49


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6.1.3
Prohibited concomitant therapy ............................................................50
6.2
Dose modifications and known undesirable effects of study drug/treatment........53
6.2.1
Everolimus ............................................................................................53
6.2.2
Management of specific everolimus-related toxicities .........................54
6.3
Patient numbering, treatment assignment or randomization .................................64
6.3.1
Patient numbering .................................................................................64
6.3.2
Treatment assignment for oral stomatitis therapy.................................65
6.3.3
Treatment blinding................................................................................65
6.4
Study drug preparation and dispensation...............................................................65
6.4.1
Study drug packaging and labeling.......................................................65
6.4.2
Drug supply and storage........................................................................66
6.4.3
Study drug compliance and accountability ...........................................66
6.4.4
Disposal and destruction .......................................................................67
7
Visit schedule and assessments .........................................................................................67
7.1
Study flow and visit schedule................................................................................67
7.1.1
Screening procedures ............................................................................77
7.1.2
Treatment period...................................................................................79
7.1.3
Second line treatment............................................................................80
7.1.4
Extension Phase ....................................................................................81
7.1.5
End of treatment visit including study completion and premature 
withdrawal.............................................................................................82
7.1.6
Follow up period ...................................................................................83
7.2
Assessment types...................................................................................................84
7.2.1
Efficacy assessments.............................................................................84
7.2.2
Safety and tolerability assessments.......................................................85
89
89
90
7.2.6
Patient reported outcomes.....................................................................90
8
Safety monitoring and reporting........................................................................................91
8.1
Adverse events.......................................................................................................91
8.1.1
Definitions and reporting ......................................................................91
8.1.2
Laboratory test abnormalities................................................................92
8.2
Serious adverse events...........................................................................................93
8.2.1
Definitions.............................................................................................93
8.2.2
Reporting...............................................................................................93


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8.3
Pregnancies............................................................................................................94
8.4
Warnings and precautions......................................................................................94
8.5
Data Monitoring Committee..................................................................................94
8.6
Steering Committee ...............................................................................................95
9
Data collection and management.......................................................................................95
9.1
Data confidentiality ...............................................................................................95
9.2
Site monitoring ......................................................................................................95
9.3
Data collection.......................................................................................................96
9.4
Database management and quality control............................................................96
10 Statistical methods and data analysis ................................................................................96
10.1
Analysis sets ..........................................................................................................97
10.1.1
Full Analysis Set ...................................................................................97
10.1.2
Safety Set ..............................................................................................97
10.2
Patient demographics/other baseline characteristics .............................................97
10.3
Treatments (study drug, concomitant therapies, compliance)...............................97
10.3.1
Study medication...................................................................................97
10.3.2
Concomitant therapies...........................................................................97
10.4
Primary objective...................................................................................................98
10.4.1
Variable.................................................................................................98
10.4.2
Statistical hypothesis, model, and method of analysis..........................98
10.4.3
Handling of missing values/censoring/discontinuations.......................98
10.5
Secondary objectives .............................................................................................98
10.5.1
Overall response rate and clinical benefit rate in first line....................99
10.5.2
Progression free survival in second line................................................99
10.5.3
Overall response rate and clinical benefit rate in second line...............99
10.5.4
Overall survival (OS)............................................................................99
10.5.5
Other secondary objective.....................................................................99
101
101
101
10.7
Interim analysis....................................................................................................101
10.8
Sample size calculation........................................................................................102
11 Ethical considerations and administrative procedures ....................................................102
11.1
Regulatory and ethical compliance......................................................................102
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................102
11.3
Informed consent procedures...............................................................................102


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11.4
Discontinuation of the study................................................................................103
11.5
Publication of study protocol and results.............................................................103
11.6
Study documentation, record keeping and retention of documents.....................103
11.7
Confidentiality of study documents and patient records .....................................104
11.8
Audits and inspections.........................................................................................104
11.9
Financial disclosures............................................................................................104
12 Protocol adherence ..........................................................................................................104
12.1
Amendments to the protocol................................................................................104
13 References (available upon request)................................................................................105
14 Appendices ......................................................................................................................111
14.1
Appendix 1: Oral Stomatitis Daily Questionnaire (OSDQ) ................................111
14.2
Appendix 2: Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST version 1.0).113
14.2.1
Introduction.........................................................................................115
14.2.2
Efficacy assessments...........................................................................115
14.2.3
Eligibility.............................................................................................115
14.2.4
Methods of tumor measurement..........................................................116
14.2.5
Baseline documentation of target and non-target lesions ...................117
14.2.6
Evaluation of target and non-target lesions.........................................118
14.2.7
Evaluation of overall lesion response .................................................119
14.2.8
Efficacy definitions .............................................................................120
14.2.9
Best overall response...........................................................................120
14.2.10
Time to event variables .......................................................................122
14.2.11
Progression-free survival ....................................................................122
14.2.12
Overall survival...................................................................................123
14.2.13
Time to progression.............................................................................123
14.2.14
Time to treatment failure.....................................................................123
14.2.15
Duration of response ...........................................................................123
14.2.16
Time to response .................................................................................124
14.2.17
Definition of start and end dates for time to event variables ..............124
14.2.18
Sensitivity analyses .............................................................................126
14.2.19
Data handling and programming rules................................................127
14.2.20
Study/project specific decisions..........................................................128
14.2.21
Treatment and study completion CRFs...............................................128
14.2.22
Medical validation of programmed overall lesion response ...............129
14.2.23
Programming rules..............................................................................130


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14.2.24
Calculation of ‘time to event’ variables..............................................130
14.2.25
Incomplete assessment dates...............................................................130
14.2.26
Incomplete dates for last contact or death...........................................130
14.2.27
Non-target lesion response..................................................................130
14.2.28
Study/project specific programming...................................................130
14.2.29
Censoring reason.................................................................................130
14.2.30
References (available upon request) ...................................................131
List of tables
Table 1-1
Everolimus - Drug substance ................................................................32
Table 3-1
Objectives and related endpoints ..........................................................41
Table 6-1
Dose and treatment schedule (first line setting & Extension Phase) ....49
Table 6-2
Dose and treatment schedule (second line setting & Extension 
Phase)....................................................................................................49
Table 6-3
Dose and treatment schedule for oral stomatitis ...................................49
Table 6-4
Clinically relevant drug interactions: inducers and inhibitors of 
isoenzyme CYP3A................................................................................52
Table 6-5
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors ...............................53
Table 6-6
Action to be taken for positive baseline hepatitis B results ..................56
Table 6-7
Guidelines for management of hepatitis B reactivation........................57
Table 6-8
Guidelines for management of hepatitis C flare ...................................58
Table 6-9
Dose reduction steps for everolimus.....................................................60
Table 6-10
Dosing guidelines for study drug-related non-hematologic 
toxicities................................................................................................61
Table 6-11
Dosing guidelines for study drug-related hematologic toxicities .........64
Table 6-12
Preparation and dispensing ...................................................................65
Table 6-13
Packaging and labeling .........................................................................66
Table 6-14
Supply and storage of study treatments ................................................66
Table 7-1
Visit evaluation schedule (Core Phase: First line treatment)................68
Table 7-2
Visit evaluation schedule (Core Phase: Second-line treatment) ...........73
Table 7-3
Visit evaluation schedule (Extension Phase) ........................................76
Table 7-4
Imaging collection plan during Core Phase ..........................................85
Table 7-5
ECOG Performance Status Scale..........................................................86
Table 7-6
Local clinical laboratory parameters collection plan ............................87
Table 14-1
Oral Stomatitis Daily Questionnaire...................................................111
Table 14-2
Response criteria for target lesions .....................................................118


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Table 14-3
Response criteria for non-target lesions..............................................119
Table 14-4
Overall lesion response at each assessment ........................................120
Table 14-5
Options for event dates used in PFS, TTP, duration of response........126
List of figures
Figure 1-1
Chemical structure of everolimus .........................................................32
Figure 4-1
Study design..........................................................................................44


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List of abbreviations
ABC
Advanced Breast Cancer
AE
Adverse Event
AI
Aromatase Inhibitor
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BC
Breast Cancer
BUN
Blood Urea Nitrogen
CBR
Clinical Benefit Rate
CDP
Clinical Development Plan
Cmax
Maximum blood concentration
CMO&PS
Chief Medical Office and Patient Safety
CPK
Creatine phosphokinase
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR
CV
Coefficient of variation
CYP3A4
Cytochrome P450 3A4
ECG
Electrocardiogram
ER
Estrogen Receptor
FAS
Full Analysis Set
HER-2
Human Epidermal Growth Factor Receptor 2
HMG
3-hydroxy-3-methyl-glutaryl
HR
Hormone Receptor
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response 
System and Interactive Web Response System
IV
Intravenous(ly)
IVRS
Interactive Voice Response System
LHRH
Luteinizing hormone-release hormone
LLLT
Low Level Laser Therapy
MBC
Metastatic Breast Cancer
MTD
Maximum Tolerated Dose


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mTOR
mammalian Target Of Rapamycin
NCCN
National Comprehensive Cancer Network
NSAI
Non-steroidal Aromatase Inhibitor
ORR
Overall Response Rate
OS
Overall Survival
OSDQ
Oral Stomatitis Daily Questionnaire
PFS
Progression Free Survival
PgP
P-glycoprotein
PgR
Progesterone Receptor
PHI
Protected Health Information
pNET
Pancreatic Neuroendocrine Tumor
PRO
Patient Reported Outcome
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
RCC
Renal Cell Carcinoma
REB
Research Ethics Board
S6K
S6 ribosomal protein kinase
SAE
Serious Adverse Event
SEGA
Subependymal Giant Cell Astrocytoma
SOC
Standard of Care
Tmax
Time to maximum concentration
TS
Tuberous Sclerosis
TSC
Tuberous Sclerosis Complex
TTP
Time To Progression
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
First line setting
Everolimus plus letrozole as first line treatment for patients with 
metastatic or locally advanced unresectable breast cancer
Second line setting
Everolimus plus exemestane treatment following progression on first 
line therapy with everolimus plus letrozole
Investigational drug
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Patient No.
A unique identifying number assigned to each patient/subject/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 progression and/or survival
Randomization number
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the 
size of the tumor, whether lymph nodes contain cancer, and whether 
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Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
Treatment group
A treatment group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. Cohorts are not expanded, new 
cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints


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Amendment 5 (14-Feb-2017)
Amendment rationale
The main purpose of the amendment is to add an Extension Phase for up to three years to 
continue to monitor safety and provide access to treatment for patients who are continuing to 
benefit from treatment with everolimus following the overall survival cutoff which is 24 
months post last patient first visit (LPFV) of the core study phase. The first line combination 
treatment (everolimus + letrozole) is not approved in label for any country and for the second 
line combination (everolimus + exemestane) some countries mandate that the treatment be 
provided without cost to patients and some countries have limited availability of supply. For 
these reasons, treatment will continue to be provided to patients receiving treatment at the 
time of implementation of this amendment. Treatment will be provided for the respective line 
of treatment (first or second) that the patients are currently receiving at the time of starting the 
Extension Phase. This new amendment will continue safety monitoring however supersede 
the previous amendment (Amendment 4) with regard to the method of access to treatment. In 
the previous amendment, the method of access to treatment was planned by offering patients 
participation in a rollover study, however the Novartis rollover studies are not approved for 
the combination therapies of this trial.
During the Extension Phase, patients will be evaluated as per institution’s standard of care to 
determine clinical benefit and safety will continue to be monitored as per the protocol 
requirements. The purpose of the extension is to continue safety monitoring and provide 
access to treatment; the only efficacy assessment to be collected will be the physician’s 
determination of whether or not the patient is continuing to clinically benefit from the study 
treatment. Note: Efficacy assessments will continue to be collected as per protocol until 
approval of this amendment and patients have transitioned to the Extension Phase.
To date, enrollment in the study is closed. LPFV was achieved on 17-Dec-2014. A total of 
two hundred and two patients were enrolled in the study. At the time of the data cut-off of the
17-Jun-2016 (18 months after the last patient’s recruitment), 64 patients were ongoing in the 
1st line treatment setting and 19 patients were ongoing in the 2nd line treatment setting. The 
study closure will occur once the last patient last visit (LPLV) in the study has been 
documented.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions
The changes to the protocol are as follows:
Section
Change
List of Abbreviations
Updated list of abbreviations to reflect those present in this protocol version
Protocol Summary
Added text in reference to Extension Phase


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Protocol Summary
4.1
6.1
6.1.2
7.1.3
7.1.4
7.1.5
Throughout protocol made consistent the reference for the reasons for 
discontinuation.
1.1
Updated references and everolimus information
1.2.1
1.2.1.1
6.1.3.1
6.2.1
6.2.2
6.2.2.1
6.2.2.2
6.2.2.5
6.2.2.6
6.2.2.10
Updated text to current IB (27-Apr-2016) / Program standard language 
(Aug2016)
1.2.1.4
Updated references and everolimus information
1.2.1.5
1.2.1.6
2.1
2.3
2.4
Updated references
3
Added objectives for the Extension Phase under Secondary Objectives (Table 
3-1)
4.1
Added text to describe the addition of the Extension Phase. Updated text to 
distinguish aspects that are different in the Extension phase compared to the 
Core Phase. Removed reference to the rollover study (from previous 
amendment, Amendment 4). Clarified the overall survival cutoff. Updated 
Study Design figure (Figure 4-1) to include Extension Phase
4.3 (new)
Added Section Definition of end of study (not in previous version) to clarify 
end of study
5.1
Clarified that patients in the Core Phase that progress can be offered second 
line treatment
6.1
Clarified that when patients on first line treatment in the Extension Phase they 
will not be offered second line treatment and that the OSDQ will not be 
administered during the Extension Phase
6.1.1
6.1.2
Updated to reflect addition of Extension Phase
6.3.2
Added text regarding that during the Extension Phase, standard of care at the 
patient’s site as recommended by the investigator to treat stomatitis will be 
followed
7.1
Updated the visit schedules as a result of adding the Extension Phase


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7.1.3
Clarified that when patients progress while on first line treatment in the 
Extension Phase they will not be offered second line treatment and clarified 
that “documented disease progression” refers to the image scan that 
determined disease progression
7.1.4 (new)
Added new section to detail Extension Phase procedures
7.1.5 (previously 
7.1.4)
Clarified the EOT eCRFs that will be used in the main study phase and the 
Extension Phase. Removed reference to rollover (from previous amendment, 
Amendment 4)
7.1.6
(previously 7.1.5)
7.1.6.1
(previously 7.1.5.1.1)
Removed reference to rollover (from previous amendment, Amendment 4)
7.1.6.2
Clarified cutoff for overall survival.
7.2.1
7.2.2
7.2.2.1
7.2.2.2
7.2.2.3
7.2.2.4
7.2.2.6.1
Add text regarding assessments not required during Extension Phase.
7.2.6
Clarified that OSDQ will not be administered during the Extension Phase.
8.2.2
 
 
10.2
10.3.1
10.3.2
10.5
10.5.5.1
10.5.5.2
10.5.5.2.1
10.5.5.2.2
10.5.5.2.3
10.5.5.3 (new)
Updated statistical section to reflect changes made due to the addition of the 
Extension Phase.
13
Updated references
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 4
Amendment rationale
The main purpose of the amendment is to clarify that patients who are benefiting from 
treatment with Afinitor at the time of overall survival analysis may discontinue this study and 
transition to commercial Afinitor or to a rollover study. The study closure will occur once the 
last patient last visit (LPLV) in the study has been documented.
A rollover study allows patients to continue to be treated from multiple protocols in one 
program spanning multiple indications. Patients will be evaluated as per institution’s 
standards and safety will continue to be monitored as per rollover protocol requirements.
Several Novartis rollover studies are available such as the global rollover study: 
CRAD001C2X01B or local studies (e.g. CRAD001C1X01B in Japan, CRAD001C2XB in 
Thailand). Choice of rollover studies will be depending on the country/site location. These 
studies have reduced scheduled assessments for the patients, reduced data collection, queries 
and monitoring frequencies.
Patients may also transition to commercially available treatments, where possible as per local 
regulations. Patients will be evaluated as per institution’s standards and safety will continue to 
be monitored as per prescribing information.
In addition, the amendment clarifies the timing of the analysis of progression free survival for 
second line treatment. This analysis will be performed 18 months after last patient first visit 
(LPFV) only if there is adequate number of patients in second line treatment at that time. 
Otherwise, the analysis will be performed 24 months after LPFV at the same time as the 
overall survival analysis.
To date, enrollment in the study is closed. Last patient first visit was achieved on 17th of 
December 2014. A total of two hundred and two patients were enrolled in the study. At the 
release date of this amendment, 127 patients were ongoing in the 1st line treatment setting and 
11 patients were ongoing in the 2nd line treatment setting. A total of 20 patients were 
randomized in the stomatitis therapeutic intervention sub-study.
As mentioned in protocol Section 10.5.4, the overall survival analysis will be performed 24 
months after LPFV which occurred on 17th of December 2014.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions
The changes to the protocol are as follows:

Section 4.1 Description of study design:
Specific language added indicating that patients still benefiting from Afinitor at time of 
overall survival analysis may discontinue the study and transition to a rollover study, where 
possible or to commercial supply of Afinitor. Only patients transitioning to a rollover study 


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will not need a 28 day follow up safety visit since their safety will be evaluated as part of the 
rollover study.
The end of study was defined by adding the following sentence: “The end of study is planned 
to be 24 months after last patient’s recruitment when the overall survival analysis will be 
performed. Patients who are benefiting from treatment with Afinitor at that time may 
discontinue this study and transition to commercial Afinitor or to a rollover study. The study 
will be closed once the last patient last visit (LPLV) in the study has been documented”.
Text was also added to clarify the timing of the analysis of progression free survival (PFS) for 
second line treatment. This analysis will be performed 18 months after the last patient’s 
recruitment provided that the number of patients in second line treatment is adequate for a 
reliable PFS analysis. Otherwise, this analysis will be performed 24 months after the last 
patient’s recruitment.

Section 7.1.4 End of treatment visit including study completion and premature withdrawal:
Reason for end of treatment: “Treatment duration completed as per protocol” has been added. 
This reason will be chosen when patient ends treatment to transition to a rollover study or to 
commercial Afinitor. Language around the 28 days follow-up and study evaluation 
completion visit has been added.

Section 7.1.5 Follow-up period:
Text added to mention that the 28-day follow-up is not applicable to the patients transitioning 
to the rollover study. Instead, these patients will have their safety follow-up performed and 
included in the study report of the rollover study.

Section 7.1.5.1.1 Study evaluation completion:
Language added to indicate that patients transitioning to a rollover study or to commercial 
supply of Afinitor will not need to complete the Study Evaluation Completion visit.

Section 10.4.3 Handling of missing values/censoring/discontinuations
Text added to clarify the timing of the analysis of progression free survival (PFS) for second 
line treatment. This analysis will be performed 18 months after the last patient’s recruitment
provided that the number of patients in second line treatment is adequate for a reliable PFS 
analysis. Otherwise, this analysis will be performed 24 months after the last patient’s 
recruitment.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 3
Amendment rationale
The main purpose of the amendment is to describe the process for implementing a centralized 
key eligibility check prior to enrollment of patients to the study.
The total number of patients that currently have been treated with everolimus, in either 
Novartis-sponsored clinical studies, individual patient supply programs or investigator 
sponsored clinical studies, as of 30-Sep-2013 was also updated.
The management of data from Oral Stomatitis Daily Questionnaires (OSDQ) has also been 
clarified since the data from the questionnaires are not being entered in a separate electronic 
database by a designated CRO. Indeed, the data from the OSDQ are being entered in the study 
database by the investigational staff.
In addition, the calculation of the clinical benefit rate was clarified to mention that patients 
with non-measurable disease only at baseline will be included into the numerator of CBR, if 
they achieve a complete response or stable disease lasting 24 weeks or longer. The wording 
used to describe the censoring rule for PFS was also clarified. These changes are only to add 
clarity and will not impact the statistical analysis.
As of 17th of March 2014, fifty six patients have been enrolled in the study.
The changes proposed by this amendment will not influence the population, design, treatment, 
assessments, safety monitoring, data review, statistical methods, or analysis of the primary 
endpoint of this study.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Changes to the protocol
The changes to the protocol are as follows:

Section 1.2.1 Overview of everolimus and Section 6.2.1 Everolimus:
The total number of patients that currently have been treated with the study treatment as of 
30-Sep-2013 has been updated to 30,582

Section 7.1.1.1 Screening:
The eligibility checklist has been added.

Table 7-1 Visit Evaluation Schedule (First-line treatment):

The eligibility checklist has been added.

Section 9.4 Database management and quality control
The management of data from Oral Stomatitis Daily Questionnaires has been corrected to 
reflect the current practice.

Section 10.4.3 Handling of missing values/censoring/discontinuations


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The wording used to describe the censoring rule for PFS was clarified.

Section 10.5.1 overall response rate and clinical benefit rate
Calculation of the clinical benefit rate was clarified to mention that patients with non-
measurable disease only at baseline will be included into the numerator of CBR, if they 
achieve a complete response or stable disease lasting 24 weeks or longer.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, if required according to 
local regulations.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 2
Amendment rationale
The main purpose of the amendment is to clarify that the dexamethasone therapeutic 
investigation will only be conducted in countries where an alcohol-free 0.5mg/5ml 
dexamethasone solution is commercially available. The availability of alcohol-free 
dexamethasone solution at the dosage specified in the protocol is geographically limited and 
this clarification would allow all countries to participate in the trial to investigate the activity 
of everolimus in combination with letrozole in first line and in combination with exemestane 
in second line even though they cannot participate in the stomatitis assessment part.
The amendment also includes the following changes:
The title and other sections of the document were corrected to follow the patient population 
definition in the inclusion criteria.
The efficacy assessment radiologic specifications were amended to allow more flexibility in 
practice at study sites.
The definition of Clinical Benefit Rate (CBR) is provided
The start date to calculate progression-free survival in the first-line setting is clarified
The language to define study drug and investigational therapy is updated
Recent updates regarding Afinitor approvals and IB are included
Changes to the protocol
The changes to the protocol are as follows:

Locally advanced, HER2 negative breast cancer patients:

The title has been updated to include locally advanced, HER2 negative breast cancer 
patients as defined in inclusion criteria #1

Throughout the entire document, relevant sections have been updated to include 
HER2 negative, locally advanced breast cancer patients in line with inclusion criteria 
#1

Objectives and endpoints:

Table 3-1 was updated to include ORR to be in line with secondary endpoints 
described in Section 10.5.3

Radiology:

Table 7-1 was updated to include CT or MRI for brain as clinically indicated, during 
the study

Section 7.2.1 changed ‘Each center must have a designated radiologist who is 
responsible for the interpretation of CT or MRI’ to ‘If possible, each center should
have a designated radiologist responsible for the interpretation of CT or MRI scans
and the evaluation according to RECIST version 1.0 criteria (see Appendix 2 for 
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
Section 7.2.1: +/- 1 week was added as a window for tumor assessments

Table 7-3: +/- 1 week was added as a window for CT and MRI procedures and bone 
scan or skeletal surveys

Throughout the document references to RECIST have been updated to reflect 
RECIST version 1.0 used in this trial

Visit assessment:

Visit assessment window of +/- 3 days has been added (except for on-study imaging 
assessments for which window is +/- 1 week)

Clinical Benefit Rate:

The protocol summary section and Section 10.5.1 have been updated to include the 
definition of clinical benefit rate

CBR defined as the proportion of patients with best overall response of CR, PR or SD 
with a duration of 24 weeks or longer according to RECIST version 1.0

Sections 10.5.1 and 10.5.3 have been corrected to include CBR to be in line with 
secondary endpoints.

Section 10.5.3 has been updated to correct a typo to replace ‘median PFS’ by ‘ORR 
and CBR’

Start date for progression Free Survival and Overall survival

In Section 10.4.1, starting date for PFS in the first-line setting has been corrected to 
‘date of enrollment’ to be in line with the definition provided in the protocol summary 
and the definition of the Full Analysis Set

Similarly in Section 10.5.4, starting date for OS has been corrected to ‘date of 
enrollment’

Dexamethasone therapeutic intervention:

Throughout the entire document clarification has been added to references to the 
dexamethasone therapeutic intervention to specify that it will only be conducted in 
countries where an alcohol-free 0.5mg/5ml dexamethasone oral solution is 
commercially available

Study Drug:

Section 6 has been updated to clarify the source of study drug and study treatments

Section 6 has been updated to include the definition of study drug and investigational 
therapy for this trial

Section 7.1.2 has been updated to reflect all methods of study drug compliance

Afinitor approvals:

Section 1.2.1 has been updated to include recent Afinitor approvals

Section 6.2.1 has been updated based on investigator brochure edition 11
Throughout the protocol typographical errors have been corrected. At the time of this 
amendment one patient has been enrolled to the study. Changes to specific sections of the 
protocol are shown in the track changes version of the protocol using strike through red font 
for deletions and red underlined for insertions.


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IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 1
Amendment rationale
The purpose of the amendment is to correct the dosage strength of the oral dexamethasone 
mouth rinse to be administered in the stomatitis therapeutic intervention; to add that patients 
who discontinue study treatment for any reason other than disease progression or consent 
withdrawal will continue to have tumor assessments until disease progression or until new 
anti-cancer therapy is initiated; to add that the ratio for randomization in the stomatitis 
therapeutic intervention will be 1:1 and to remove progesterone receptor from the population 
description.
The changes to the protocol are as follows:
1. Concentration of dexamethasone
a. The concentration of the dexamethasone oral solution has been corrected from 5% to 
0.5mg/5ml throughout the document.
2. Schedule of tumor assessments
a. All patients who discontinue study treatment for any reason (i.e., an adverse event, 
administrative reasons etc) other than disease progression or consent withdrawal will 
continue to have tumor assessments per the schedule until disease progression or until 
new anti-cancer therapy is initiated.
b. The visit evaluation schedule has been updated to include additional Post treatment 
evaluations for consistency with the schedule of tumor assessments.
3. Proportions for randomization in the stomatitis substudy
a. Patients who develop stomatitis will be randomized in a 1:1 ratio to receive either 
0.5mg/5ml solution dexamethasone mouth rinse or standard of care at the patient’s 
center.
4. Estrogen receptor positive patients
a. The patient population includes estrogen receptor positive only. Reference to 
progesterone receptor has been removed.
This amendment will also correct typographical errors in the inclusion criteria numbering and 
throughout the document. The Local clinical lab parameters collection plan and the Guideline 
for hepatitis B reactivation tables have been updated for consistency with the eCRF and the 
global hepatitis guidance. There are also minor editorial changes throughout the document. At 
the time of this amendment, enrollment has not yet been initiated.
Changes to the protocol
The following has been changed:

Throughout the entire document 5% has been changed to 0.5mg/5ml

Protocol Summary: Removed and/or progesterone receptor

Section 5.1: Removed and/or progesterone receptor

Section 7.2.6: Added the following: All patients who discontinue study treatment for any 
reason (i.e., an adverse event, administrative reasons etc) other than disease progression or 


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consent withdrawal will continue to have tumor assessments per the schedule until disease 
progression or until new anti-cancer therapy is initiated.

Section 6.3.2 changed randomly assigned to randomized in 1:1 ratio

Table 7-5 updated for consistency with Section 7.2.2.5

Table 6-7 updated for consistency with global hepatitis guidance

Table 7-1 and 7-2: added column for post treatment evaluations
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Protocol summary:
Protocol number
CRAD001Y24135
Title
An open-label, phase II, single-arm study of everolimus in combination 
with letrozole in the treatment of postmenopausal women with estrogen 
receptor positive HER2 negative metastatic or locally advanced breast 
cancer
Brief title
Study of efficacy and safety of everolimus and letrozole in estrogen 
receptor positive HER2 negative metastatic or locally advanced breast 
cancer patients.
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
There is growing evidence to support close interaction between the mTOR 
pathway and ER signaling. mTOR forms two different protein complexes, 
mTOR-raptor signal transduction complexes 1 and 2 (mTORC1 and 
mTORC2) (Guertin and Sabatini 2007). A substrate of mTORC1, p70 
ribosomal S6 kinase (S9K1), directly phosphorylates the activation domain 
AF-1 of the ER, responsible for ligand-independent receptor activation 
(Yamnik et al 2009, Yamnik and Holz 2010). Preclinical studies suggest 
that in breast cancer cells with upregulated Akt signaling, sensitivity to 
hormonal therapy may be restored by treatment with everolimus or other 
mTOR inhibitors (Baselga 2009). mTOR inhibitors given in combination 
with aromatase inhibitors (AIs) in preclinical models result in synergistic 
inhibition of proliferation and induction of apoptosis (Boulay et al 2005).
This extensive preclinical work suggests that co-targeting the mTOR 
pathway and ER signaling may improve the effectiveness of endocrine 
therapy. In addition, endocrine-resistant breast cancer cells demonstrate 
hyperactivation of the PI3K/mTOR pathway, and treatment with mTOR 
inhibitors including rapamycin analogs reverses this resistance (Miller et al 
2010).
Results from recent clinical studies support these findings. Combining 
everolimus with letrozole (Baselga et al 2009) in the neoadjuvant setting 
induced higher response rates than with letrozole alone in 
postmenopausal women with ER-positive breast cancer. The combination 
of everolimus with tamoxifen was also associated with prolonged PFS and 
improved overall survival (OS) in a phase II randomized study in patients 
progressing after prior AI treatment compared with tamoxifen alone 
(Bachelot et al 2012). An ongoing trial combining everolimus with 
fulvestrant in postmenopausal women with ER positive breast cancer has 
also shown encouraging activity (Badin et al 2010). In a recent pivotal 
phase III, randomized, double-blind, placebo-controlled trial, BOLERO-2, 
of everolimus plus exemestane versus exemestane plus placebo in ER 
positive postmenopausal women with locally advanced or metastatic 
disease refractory to letrozole or anastrozole, the addition of everolimus to 
exemestane prolonged median progression free survival from 3.2 to 7.8 
months based on local assessment (hazard ratio, 0.45; 95% confidence 
interval 0.38-0.54; p< 0.0001) and 4.1 to 11 months based on central 
radiology review (hazard ratio, 0.38; 95% confidence interval 0.31-0.48; p< 
0.0001) (Piccart-Gebhart et al 2012).
Taken together, the above data support the activity of everolimus both in 


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patients progressing after initial endocrine treatment and in patients who 
have not received prior treatment in the neoadjuvant setting. However, to 
date the efficacy of everolimus plus endocrine therapy has not been 
explored for first line therapy of patients with metastatic disease. 
Preclinical studies have shown that inhibition of the PI3K/mTOR pathway 
can prevent the emergence of hormone-independent cells, suggesting that 
early intervention with combined endocrine therapy and mTOR inhibition 
may prevent or delay endocrine resistance (Miller et al 2010). It is also of 
interest to investigate whether continued mTOR inhibition with sequential 
endocrine therapy may provide clinical benefit. The proposed trial will 
assess the efficacy of everolimus plus letrozole in the first line treatment of 
patients with metastatic or locally advanced breast cancer and explore the 
efficacy of continued treatment with everolimus plus exemestane after 
initial progression.
Primary Objective
The primary objective is to estimate progression-free survival in patients 
treated with everolimus + letrozole in the first line setting.
Secondary Objectives
Determine the overall response rate and clinical benefit rate of everolimus 
+ letrozole in the first line setting
Determine the progression free survival and clinical benefit rate of 
everolimus + exemestane in the second line setting
Evaluate the safety of everolimus + letrozole in the first line setting
Evaluate the safety of everolimus + exemestane in the second line setting
Estimate the overall survival of patients treated with everolimus + letrozole 
in the first line setting
Evaluate a therapeutic intervention to reduce the severity and duration of 
stomatitis
Evaluate clinical benefit as assessed by the investigator during the 
Extension Phase
Evaluate long term safety data
Study design
This is an open-label, phase II, multicenter, international, single-arm trial 
for patients with ER+, HER2- metastatic or locally advanced unresectable 
breast cancer. Patients will receive everolimus in combination with 
letrozole until disease progression (primary study endpoint).
The study will be comprised of 2 phases:

Core Phase: from FPFV to 24 months after LPFV and upon approval 
of amendment 5; safety and efficacy data (including PROs in selected 
subset) will be collected.

Extension Phase: from the end of the Core Phase (upon approval of 
amendment 5) to LPLV of the extension phase for patients that are still 
deriving benefit at the end of the Core Phase. Patients may be 
transitioned to the Extension Phase and continue to receive the drugs 
up to 3 years or until disease progression or for any other reason the 
patient may be discontinued (refer to Section 7.1.5). Note: Only safety 
and clinical benefit as assessed by investigator will be collected.
In the Core Phase, following initial progression, patients will be offered 
everolimus in combination with exemestane until disease progression 
(secondary study endpoint). In countries where the alcohol-free 0.5mg/5ml 


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dexamethasone oral solution is commercially available, patients 
developing oral stomatitis will be randomized to take a 0.5mg/5ml 
dexamethasone mouth rinse (3 times/day) or the best supportive care 
normally used at each participating center (secondary study endpoint).
Patients still benefiting from everolimus following the overall survival cutoff 
and following approval of Amendment 5 may continue treatment in an 
Extension Phase of the study up to 3 years. Patients may continue on their 
existing line of treatment (1st or 2nd) in the extension and they will 
participate in the study until disease progression as deemed by 
physician judgement or other reason the patient may be discontinued 
(refer to Section 7.1.5). Those patients entering the Extension Phase on 
1st line setting will not be offered to move on to 2nd line treatment if 
deemed no longer clinically benefiting in that setting. Rather, these 
patients can start other standard treatment(s) or approved everolimus 
combination after exiting the study.
Population
Postmenopausal women with estrogen receptor positive HER2 negative 
metastatic or locally advanced unresectable breast cancer.
Patients enrolled in this study are not permitted to participate in additional 
parallel investigational drug or device studies.
Number of Patients
200
Inclusion criteria
Refer to Section 5.2 for the complete list and more details on inclusion 
criteria
Adult women (>18 years of age) with metastatic or locally advanced, 
unresectable breast cancer not amenable to curative treatment by surgery 
or radiotherapy
Histological or cytological confirmation of estrogen-receptor positive (ER+) 
human epidermal growth factor receptor 2 negative (HER2-) breast cancer
Postmenopausal women. Postmenopausal status is defined in Section 5.2.
No prior treatment for metastatic breast cancer
Patients must either have at least one lesion that can be accurately 
measured in at least one dimension >20mm with conventional imaging 
techniques or >10mm with spiral CT or MRI OR Bone lesions: lytic or 
mixed (lytic + sclerotic) in the absence of measurable disease as defined 
above.
Willingness to complete a daily diary quality-of- life questionnaire 
throughout the study
Exclusion criteria
Refer to Section 5.3 for complete list and more details on exclusion criteria
Patients with only non-measurable lesions other than bone metastases as 
defined above (e.g., pleural effusion, ascites, etc)
Patients who have received prior hormonal or any other systemic therapy 
for metastatic breast cancer.
Patients may have received prior neoadjuvant or adjuvant endocrine 
therapy. In the case of neoadjuvant or adjuvant NSAI 
(letrozole/anastrozole) therapy patients must have completed therapy at 
least 1 year prior to study enrollment.
Previous treatment with mTOR inhibitors.
Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin).
Currently receiving hormone replacement therapy, unless discontinued 
prior to enrollment.
Patients receiving chronic treatment with systemic immunosuppressive 
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Investigational and 
reference therapy
Everolimus
Letrozole
Exemestane
Efficacy assessments
The primary endpoint in this study (Core Phase) is progression-free 
survival (PFS), defined as the time from date of enrollment to the date of 
first documented progression or death due to any cause in the first line 
treatment. If a patient has not had an event, PFS will be censored at the 
date of last adequate tumor assessment. See RECIST version 1.0 
(Appendix 2). Disease progression for primary efficacy endpoint derivation 
will be based on the local radiologist’s/investigator’s tumor assessment. 
Overall response rate, a secondary endpoint in this study, is defined as the 
proportion of patients whose best overall response is either complete 
response (CR) or partial response (PR) according to RECIST. Clinical 
benefit rate (CBR), another secondary endpoint in this study, is defined as 
the proportion of patients with best overall response of CR, PR or stable 
disease (SD) with a duration of 24 weeks or longer according to RECIST 
version 1.0.
During the Extension Phase, there will be no efficacy assessments other 
than the physician’s determination of whether or not the patient is 
continuing to clinically benefit from the study treatment.
Safety assessments
Safety assessments will consist of monitoring and recording all adverse 
(AEs), including serious adverse events (SAE), the regular monitoring of 
hematology, serum chemistry, routine monitoring of vital signs (heart rate, 
blood pressure, and body temperature), weight, ECOG performance 
status, chest CT scans and physical condition.
Toxicity will be assessed using the NCI-CTC Common Terminology 
Criteria for Adverse Events, version 4.0 (CTCAEv4.0).
In the Extension Phase, safety assessments will consist of monitoring and 
recording all adverse (AEs), including serious adverse events (SAE)
Other assessments
An assessment of Patient reported outcomes (PRO) is planned in this trial 
using Oral Stomatitis Daily Questionnaire (OSDQ); OSDQ questionnaires 
will not be administered during the Extension Phase.
Data analysis
The primary efficacy endpoint, PFS, will be analyzed based on the data 
from FAS. The median PFS as well as the 25th and 75th quartile will be 
estimated using the Kaplan-Meier method and presented along with 95% 
confidence intervals.
Key words
Estrogen receptor positive, HER-2 negative, metastatic or locally 
advanced breast cancer, everolimus in combination with letrozole, 
exemestane, oral stomatitis


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
endocrine treatment options
Breast cancer is the most common form of malignancy occurring in women. In the US, it is 
estimated that approximately 231,840 new cases of invasive breast cancer (BC) were 
diagnosed in 2015. In that same year, about 40,290 women would die from their disease 
(American Cancer Society 2015-2016). Worldwide breast cancer was responsible for over 
500,000 deaths in 2004. Approximately 30-40% of diagnosed breast cancer patients will 
eventually develop metastatic breast cancer (MBC) (American Cancer Society 2015-2016). 
Treatment for MBC is palliative and median life expectancy after recurrence is between 24 
and 30 months or less (World Health Organization Facts and Figures 2007, Piccart 2014).
The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most 
important prognostic and predictive markers in human breast cancers. Patients with hormone 
receptor-positive disease have a more favorable prognosis compared with those who are 
hormone receptor-negative. In addition, hormone receptor positivity predicts for 
responsiveness to treatment with endocrine therapy (NCCN 2016). Approximately 70% of all 
invasive breast cancers are positive for ER and/or PgR expression at the time of diagnosis. 
Consequently, anti-estrogen therapies that antagonize ER function (such as tamoxifen) or 
inhibit estrogen production (e.g. aromatase inhibitors [AIs]) have been extensively developed 
in oncology (Smith and Dowsett 2003, Jensen and Jordan 2003). Deprivation of estrogenic 
signaling with the anti-estrogen tamoxifen has been the main form of hormonal treatment for 
30 years. Tamoxifen is indicated for treatment across the whole continuum of breast cancer, 
ranging from risk reduction for women with increased risk of breast cancer, as an adjuvant 
treatment and also for metastatic disease. Besides tamoxifen, progesterone analogues or 
progestins have been used for the treatment of breast cancer for almost 50 years. Once the 
standard second-line therapy after tamoxifen, progestins are now mainly used for patients 
whose cancer does not respond well to other hormonal treatments (NCCN 2016).
While tamoxifen has significantly contributed to the mortality reduction in patients with early 
breast cancer, a significant number of patients experience relapse, and up to 50% of ER-
positive patients with advanced breast cancer (ABC) do not respond to tamoxifen therapy. 
Consequently, new approaches have been investigated. A number of aromatase inhibitors (AIs) 
that reduce peripheral estrogen synthesis have been developed for the treatment of ABC. The 
AIs block the conversion of androgens to estrogen, which is the primary way estrogens are 
produced in postmenopausal women (Mouridsen et al 2003).
At present, third generation aromatase inhibitors are the accepted standard of care for adjuvant 
therapy in postmenopausal women and the accepted standard of care for first line treatment of 
metastatic disease in postmenopausal women. The third generation AIs can be broadly 
classified into two groups: non-steroidal aromatase inhibitors (NSAI), such as letrozole 
(Femara®) and anastrozole (Arimidex®) and the steroidal aromatase inactivator, exemestane 
(Aromasin®) (NCCN 2016).


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Letrozole (Femara®) is indicated for the adjuvant treatment of postmenopausal women with 
hormone receptor positive early breast cancer, for the extended adjuvant treatment of early 
breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen 
therapy, for neoadjuvant use in Europe and for the first line treatment of postmenopausal 
women with hormone receptor positive locally advanced or metastatic breast cancer.
Anastrozole (Arimidex®) is indicated for adjuvant treatment of postmenopausal women with 
hormone receptor positive early breast cancer. In Europe it is indicated for adjuvant treatment 
of hormone receptor-positive early invasive breast cancer in postmenopausal women who 
have received 2 to 3 years of adjuvant tamoxifen. It is also indicated for the first line treatment 
of postmenopausal women with hormone receptor positive locally advanced or metastatic 
breast cancer and in the US for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following tamoxifen therapy.
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 estrogen 
receptor positive early breast cancer who have received two to three years of tamoxifen and 
are switched to exemestane for completion of adjuvant hormonal therapy and for the 
treatment of ABC in postmenopausal women whose disease has progressed following 
tamoxifen therapy (in US) or following anti-estrogen therapy (in Europe).
Fulvestrant (Faslodex®) an estrogen receptor antagonist, is indicated for the treatment of 
hormone receptor positive MBC as monotherapy or in combination with palbociclib (in US) 
in postmenopausal women with disease progression following antiestrogen therapy 
(AstraZeneca prescribing information, 2016) or for disease relapse on or after adjuvant anti-
estrogen therapy, or disease progression on therapy with an anti-estrogen (in Europe 2016).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of everolimus
Organ transplantation
Everolimus was initially developed for the prophylaxis of organ transplant rejection. It was 
originally approved in Europe on 3-Dec-2003 under the trade name Certican® for the 
prophylaxis of allograft rejection following renal or cardiac transplantation, in a combination 
immunosuppressive regimen with cyclosporine and corticosteroid therapy, and has since been 
granted approval in 106 countries worldwide. In the United States (US), everolimus was 
approved by the Food and Drug Administration (FDA) on 20-Apr-2010 under the trade name 
Zortress® (NDA 21-560) for prophylaxis of organ rejection in adult patients at low-moderate 
immunologic risk receiving a kidney transplant. Certican®/Zortress® is also approved for the 
prophylaxis of organ rejection in adult patients receiving a liver transplant in 78 countries 
worldwide (approval in Europe received 17-October-2012 and FDA approval on 15-February-
2013). Additional registrations for use of Certican® in organ transplantation are pending in 
Africa, South America, Middle East, and Asia-Pacific region.


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Oncology
Everolimus first entered clinical development for one of numerous oncology indications in 
2002.
It was approved by the FDA on 30-Mar-2009 under the trade name Afinitor® for the treatment 
of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib 
or sorafenib. The European Commission (EC) approved Afinitor® on 03-Aug-2009 for the 
treatment of patients with advanced RCC, whose disease has progressed on or after treatment 
with vascular endothelial growth factor (VEGF)-targeted therapy. Everolimus has been 
approved in 122 countries worldwide for the treatment of patients with advanced RCC.
On 05-May-2011, FDA approved Afinitor® for the treatment of progressive neuroendocrine 
tumors of pancreatic origin (pNET) in patients with unresectable, locally advanced or 
metastatic disease. The EC approved Afinitor® on 24-Aug-2011 for the treatment of 
unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumors of 
pancreatic origin in adults with progressive disease. Everolimus has been approved in 112 
countries worldwide for the treatment of patients with advanced pNET/NET.
On 26-Feb-2016, FDA approved Afinitor®
for advanced non-functional NET of 
gastrointestinal (GI) or lung origin based on the results of Phase III study T2302. The EC 
approved Afinitor® on 26-May-2016 for the treatment of unresectable or metastatic, well-
differentiated (Grade 1 or Grade 2) non-functional NET of GI or lung origin in adults with 
progressive disease. Other health authority reviews are ongoing.
On 20-Jul-2012, FDA approved Afinitor® for the treatment of postmenopausal women with 
advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2 
negative (HER2-) breast cancer in combination with exemestane, after failure of treatment 
with letrozole or anastrozole. The EC approved Afinitor® on 23-Jul-2012 for the treatment of 
HR+, HER2- advanced breast cancer, in combination with exemestane, in postmenopausal 
women without symptomatic visceral disease after recurrence or progression following a non-
steroidal aromatase inhibitor. Everolimus has been approved in 115 countries worldwide for 
the treatment of patients with advanced HR+, HER2- breast cancer.
Tuberous sclerosis
Everolimus received accelerated approval from FDA on 29-Oct-2010 for the treatment of 
patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis 
that require therapeutic intervention but are not candidates for curative surgical resection. 
Subsequently on 26-Apr-2012, the indication was slightly revised by FDA to “Afinitor® is 
indicated for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA 
associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are 
not candidates for curative surgical resection”. The EC conditionally approved everolimus on 
02-Sep-2011 under the trade name Votubia® for the treatment of patients aged 3 years and 
older with SEGA associated with TSC who require therapeutic intervention but are not 
amenable to surgery.
On 29-Aug-2012, FDA revised the indication to “Afinitor® Tablets and Afinitor® Disperz are 
indicated in pediatric and adult patients with TSC for the treatment of SEGA that requires 
therapeutic intervention but cannot be curatively resected”.


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Under the trade name of Votubia®, on 15-Nov-2013, based on M2301 study, the indication 
was revised with the removal of the age restriction to “Votubia is indicated for the treatment 
of patients with SEGA associate with TSC who require therapeutic intervention but are not 
amendable to surgery”.
The follow-up data from studies C2485 and M2301 demonstrated sustained efficacy and
safety of everolimus in this patient population. In 2015/2016, these data allowed the 
conversion of the conditional marketing authorization to full approval in the EU and 
fulfillment of post-marketing requirements by the FDA
Everolimus has been approved in 100 countries worldwide for the treatment of patients with 
TSC who have SEGA.
Everolimus received accelerated approval from FDA on 26-Apr-2012 for the treatment of 
adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. On 31-
Oct-2012, the EC granted a decision for Votubia® for the treatment of adult patients with renal 
angiomyolipoma associated with TSC who are at risk of complications (based on factors such 
as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do 
not require immediate surgery. Everolimus has been approved in 95 countries for the 
treatment of renal angiomyolipoma associated with TSC.
Approximately 35801 patients (excluding those patients who received marketed 
Afinitor®/Votubia®, those on planned and roll over studies as well as investigator-sponsored 
studies) have been enrolled in studies with everolimus as of 31-Mar-216:

33761 patient in Novartis-sponsored clinical trials

2,040 patients in the individual patient program
The following is a brief summary of the main characteristics of Everolimus. More complete 
information can be obtained from the everolimus investigator’s brochure (IB).
1.2.1.1
Mechanism of action
Everolimus is a derivative of rapamycin that acts as a signal transduction inhibitor (Table 1-1, 
Figure 1-1). Everolimus selectively inhibits mammalian target of rapamycin (mTOR), 
specifically targeting the mTOR-raptor signal transduction complex. mTOR is a key serine-
threonine kinase in the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling 
cascade, which is known to be dysregulated in a wide spectrum of human cancers (Boulay and 
Lane 2007).
Everolimus is being investigated as an anticancer agent based on its potential to act

directly tumor cells by inhibiting growth and proliferation

indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF production and VEGF-induced proliferation of endothelial 
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Table 1-1
Everolimus - Drug substance
Chemical name
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-
dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-
aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-
pentaone
International non-
proprietary name
Everolimus
Figure 1-1
Chemical structure of everolimus
N
O
OH
C
H3
O
O
CH3
CH3
OH
C
H3
O
O
O
O
H
C
H3
O
CH3
O
C
H3
O
O
CH3
CH3
O
C
H3
1.2.1.2
Everolimus pharmacokinetics
Everolimus is rapidly absorbed after oral administration, with a median time to peak blood 
levels (tmax) of 1-2 hours post dose. The extent of absorptions is estimated at about 11%. The 
area under the blood concentration-time curve (AUC) is dose-proportional over the dose range 
tested with maximum blood concentration (Cmax) appears to plateau at dose levels higher than 
20mg. The elimination half-life in cancer patients averaged 30 hours, which is similar to that 
in healthy subjects. Inter-patient variability is moderate with the coefficient of variation (CV) 
of approximately 50%. In healthy subjects, high fat meals reduced systemic exposure to 
everolimus 10mg (as measured by AUC 0-∞) by 22% and peak plasma concentration Cmax by 
54%. Light fat meals reduced AUC0-∞by 32% and Cmax by 42%. Food, however, had no 
apparent effect on the post absorption phase concentration-time profile (Everolimus (RAD001) 
Investigator Brochure, Clinical Study Report [RAD001C2120]).
Steady-state trough levels are highly predictive of AUC, with a coefficient of determination of 
0.96, as has been reported in renal transplantation patients (Kovarik 2001).
Everolimus is mainly metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4) in the 
liver and to some extent in the intestinal wall. Everolimus is also a substrate of P-glycoprotein 
(P-gp). Therefore, the absorption and subsequent elimination of systematically absorbed 
everolimus may be influenced by medicinal products that interact with CYP3A4 and/or P-gp. 
Strong CYP3A inhibitors (such as ketoconazole, itraconazole, ritonavir) and inducers (such as 
rifampicin, rifabutin) should be avoided. In study [RAD001C2108], everolimus, at a daily 
dose of either 5mg or 10mg, was added to the daily letrozole regimen of 2.5mg in breast 


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cancer patients. Metabolism of letrozole is mainly mediated by CYP3A4 and CYP2A6 with 
minor contribution of renal clearance. Due to the low affinity of letrozole to CYP3A4, the 
potential for pharmacokinetic interaction is remote. Pharmacokinetic profiles of letrozole 
were investigated before addition of everolimus and after everolimus reached steady state 
(day 15). Data suggested that, indeed, co-administration of everolimus with 2.5mg/day 
letrozole did not influence the pharmacokinetics of letrozole. The exposure of everolimus in 
the presence of letrozole was similar to the historical data obtained from the amended study 
[C2102] CP report (Everolimus (RAD001) [Investigator Brochure], Clinical Study Report 
[RAD001C2102] and 2108).
1.2.1.3
mTOR and breast cancer
Activation of the mTOR pathway is a key adaptive change driving endocrine resistance in 
patients with breast cancer. Research into the mechanisms of resistance has shown that 
various signal transduction pathways are activated to escape the effect of endocrine therapy. 
For example, the PI3 kinase/Akt/mTOR pathway is constitutively activated in aromatase 
inhibitor resistant and long-term estrogen deprivation BC cells (Campbell 2001, Santen 2005, 
Tokunaga 2006). The selective inhibitor of mTOR, sirolimus or rapamycin, demonstrated a 
significant growth inhibition particularly in long-term estrogen deprivation BC cells (Yue 
2007).
1.2.1.4
Everolimus in breast cancer
Everolimus was studied in a randomized phase II study comparing two schedules of 
everolimus (10mg daily and 70mg weekly) in patients with recurrent/metastatic breast cancer 
(Ellard 2009). The results demonstrated that in general, adverse effects were those predicted 
from preclinical and early clinical studies (O’Donnell 2008, Tabernero 2008) including 
hyperglycemia and hyperlipidemia (generally in patients with preexisting abnormalities), and 
were reversible. The most common grade 3 or 4 adverse events were fatigue, non-infectious 
pneumonitis and neutropenia. Pneumonitis occurred more frequently than anticipated, but was 
reversible in all affected patients and in general, manageable, although some patients required
discontinuation. None of the 16 patients recruited to the weekly 70mg arm responded, with 
four patients with a stable disease. Among the 33 patients treated in the daily 10mg arm, 
response was evaluable in 30 patients; one patient had a complete response, three patients had 
a partial response and 15 patients had stable disease. The four responding patients were ER+ 
and the HER2 status was normal in 3 patients and unknown in one. Ellard et al. suggested that 
continuous daily dosing of everolimus, but not weekly dosing, has single agent activity in this 
disease setting. While ER positive and HER-2 normal status appeared to be predictive for 
response and/or prolonged stable disease, no associations were noted between molecular 
markers and efficacy (Ellard 2009).
There is growing evidence to support close interaction between the mTOR pathway and ER 
signaling. mTOR forms two different protein complexes, mTOR-raptor signal transduction 
complexes 1 and 2 (mTORC1 and mTORC2) (Guertin and Sabatini 2007). A substrate of 
mTORC1, p70 ribosomal S6 kinase (S6K1), directly phosphorylates the activation domain 
AF-1 of the ER, responsible for ligand-independent receptor activation (Yamnik et al 2009, 
Yamnik and Holz 2010). Preclinical studies suggest that sensitivity to hormonal therapy may 


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be restored by treatment with everolimus or other mTOR inhibitors in breast cancer cells with 
upregulated Akt signaling (Baselga 2009). mTOR inhibitors given in combination with 
aromatase inhibitors (AIs) in preclinical models result in synergistic inhibition of proliferation 
and induction of apoptosis (Boulay et al 2005).
In particular, the combination of everolimus and letrozole synergistically inhibits proliferation 
in breast cancer cells (Miller et al 2010). This combination letrozole (2.5mg daily) and 
everolimus (10mg daily) (L-R) was evaluated in a randomized double blind phase II trial 
against letrozole + placebo (L-P) as a 4-month neoadjuvant treatment for postmenopausal 
women with early BC. 270 patients were enrolled in this trial (138 L-R vs. 132 L-P). 
Response rates on L-R and L-P were 68% vs. 59% (palpation, p = 0.0062) and 58% vs. 47% 
(ultrasound, p = 0.0021) respectively. Pharmacodynamic changes in each treatment arm were 
observed. Marked downregulation in progesterone receptor and cyclin D1 were seen in 
response to letrozole. Phospho-S6 levels showed dramatic down-regulation only in response 
to everolimus. Cell cycle response, as defined by the proportion of patients with < 2.7% Ki67+
tumor cells at day 15, was also significantly higher in the everolimus + letrozole arm (57% 
everolimus treated patients vs. 30% placebo treated patients were cell cycle responder at day 
15, p<0.01). Baselga et al concluded that everolimus significantly increased the efficacy of 
letrozole in newly diagnosed ER+ BC, with regard to both clinical and cell cycle response. 
The increased cell cycle response rate on everolimus was found in all subsets of tumors, 
including PTEN-positive PI3KCA wild-type tumors. The most common grade 3 / 4 adverse 
events in the L-R arm were hyperglycemia (5%), stomatitis (2%), pneumonitis (2%), and 
infections (2%). The trial demonstrated that mTOR inhibition provides additional efficacy to 
long term estrogen deprivation and has an acceptable level of tolerability in the neoadjuvant 
setting (Baselga 2008).
The Tamoxifen-RAD001 (TAMRAD) trial was designed to evaluate the role of everolimus in 
combination with endocrine therapy in patients with hormone resistant disease. It was a 
randomized, open-label phase II trial evaluating tamoxifen (20 mg daily) and the combination 
of tamoxifen (20 mg daily) plus everolimus (10 mg daily) in patients with progressive MBC 
who received prior aromatase inhibitor (AI) therapy. Additionally, patients had to be 
postmenopausal and have hormone-receptor (HR) positive and HER2 (-) disease. Prior AI 
therapy could have been in the adjuvant or metastatic setting. Prior adjuvant tamoxifen and 
prior chemotherapy, administered in the adjuvant or metastatic setting was allowed. Patients 
were stratified based on primary or secondary resistance to AI therapy. Primary resistance was 
defined as relapse during or within 6 months of stopping adjuvant AI therapy or disease 
progression within 6 months of starting AI therapy in the metastatic setting. Secondary 
resistance was defined as relapse occurring 6 months or later after stopping adjuvant AI 
therapy, or prior response of at least 6 months duration to an AI within the metastatic setting. 
No cross-over was planned or allowed. The primary study endpoint was the CBR at 6 months, 
defined as the total number of patients who had a complete response, partial response, or 
stable disease at 6 months. Secondary endpoints included TTP, OS, ORR, toxicity, as well as 
translational studies to evaluate PI3K/mTOR pathway biomarkers (Bachelot et al 2012).
One-hundred and eleven patients were randomized. The median follow-up duration was 22 
months. Over 75% of patients had bone involvement while over 50% had visceral 
involvement. Prior adjuvant AI therapy had been given to 31% of the patients; 58% received 


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an AI in the metastatic setting, and a small number (<10%) received an AI in both the 
adjuvant and metastatic settings. As per planned stratification, half of the patients had primary 
hormone resistance while the other half had secondary hormone resistance (Bachelot et al 
2012).
In the intent-to-treat analysis, CBR in the tamoxifen alone group was 42% (95% CI, 29.1-55.9) 
and 61.1% (95% CI, 46.9-74.1%) in the combination arm, (P=0.045, exploratory analysis). 
Therefore, the requirement of 20% increase in CBR with the combination was met. Median 
TTP was 4.5 months in the tamoxifen arm and 8.6 months in the combination arm (HR=0.53, 
95% CI, 0.35-0.81; P=0.0026). Exploratory analysis demonstrated a higher CBR with the 
combination versus tamoxifen alone across all subgroups. Addition of everolimus had a 
greater benefit in patients with secondary hormone resistance, where the TTP in the TAM + 
RAD group was 17.4 months vs. 5.0 months in the TAM group (HR, 0.38; 95% CI, 0.21-0.71). 
By contrast, the difference between groups in patients with primary hormone resistance was 
not as great (HR, 0.74; 95% CI, 0.42-1.3) (Bachelot et al 2012).
The number of patients who discontinued therapy due to an adverse event was comparable 
between treatment arms (tamoxifen, 7%; combination arm, 5.6%). More patients required a 
dose reduction due to an adverse event in the combination arm versus tamoxifen alone (28% 
versus 0%). Toxicities observed in the combination arm were consistent with those previously 
reported with everolimus. These included fatigue, stomatitis, rash, anorexia, and diarrhea. The 
majority of adverse events were of grade 1 or 2 in severity (Bachelot et al 2012).
The combination of everolimus and tamoxifen contributed to a higher CBR, longer median 
TTP, and longer OS compared to tamoxifen alone, in patients with MBC previously treated 
with an AI. The benefit of the combination appears to favor patients with secondary hormone 
resistance. Additionally, the combination was associated with a manageable toxicity profile 
despite the need for everolimus dose reduction in 28% of patients in the combination arm 
(Bachelot et al 2012).
Following these encouraging results everolimus was evaluated in a pivotal phase III trial. The 
BOLERO-2 trial is a phase III, double-blind, randomized, placebo-controlled study involving 
postmenopausal patients with ER-positive advanced breast cancer. Patients were required to 
have disease refractory to previous letrozole or anastrozole, defined as recurrence during or 
within 12 months of the end of adjuvant treatment or progression during or within one month 
of the end of treatment for advanced disease. Letrozole or anastrozole were not required to be 
the last treatment received prior to enrollment, but recurrence or progression on the last 
systemic therapy had to be documented before randomization. Seven-hundred twenty-four 
patients were randomized to the combination of everolimus (10 mg/day) and exemestane (25 
mg/day) (n=485) or the combination of exemestane (25 mg/day) plus placebo (n=239). 
Randomization, (2:1 in favor of the combination therapy arm), was stratified according to 
presence of visceral metastasis and previous sensitivity to endocrine therapy. (Baselga et al 
2012)
The PFS results after 18 months of median follow-up indicated that the addition of everolimus 
to exemestane prolonged median progression free survival from 3.2 to 7.8 months based on 
local assessment (hazard ratio, 0.45; 95% confidence interval 0.38-0.54; p< 0.0001) and 4.1 to 
11 months based on central radiology review (hazard ratio, 0.38; 95% confidence interval 


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0.31-0.48; p< 0.0001) (Yardley et al 2013). The analysis included 457 PFS events based on 
local radiology review and 282 PFS events based on central radiology review. A significant 
benefit in PFS with consistent magnitude was seen in both the local and central assessment. 
The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-
exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), 
dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis 
(3% vs. 0%) (Piccart et al 2014).
Everolimus has also been evaluated in patients with HER2-overexpressing metastatic breast 
cancer in combination with trastuzumab and vinorelbine. In a phase I trial of daily and weekly 
everolimus in combination with weekly vinorelbine and trastuzumab in heavily pretreated 
patients with HER2-overexpressing MBC with prior resistance to trastuzumab, everolimus 
was well tolerated at doses of 5mg daily and 30mg weekly. A total of 50 patients were 
enrolled. Patients were extensively pretreated, having received a median of 4 prior regimens 
for advanced disease. Thirty-seven patients completed the Core Phase and 35 entered the 
Extension Phase. Of the 13 patients who did not complete the Core Phase, 9 discontinued 
therapy due to progressive disease, three discontinued therapy due to an adverse event, and 1 
patient died. The ORR was 20% (n=6) in the 5 mg daily group versus 15% (n=3) in the 20 or 
30 mg weekly group. The CBR (CR + PR + SD >24 weeks) was 50% (n=15) in the 5 mg 
daily group versus 60% (n=12) in the 20 or 30 mg weekly group. The median PFS for the 
entire patient population was 30.7 weeks (95% CI, 25.9-43) while it was 30.7 weeks (95% CI, 
28-44.9) in the daily dosing arm and 27.1 weeks (95% CI, 25.6-NA) in the weekly dosing arm. 
The dose of everolimus selected for further development was 5mg daily (Jerusalem et al 
2011).
In another phase I of daily and weekly everolimus in combination with weekly paclitaxel and 
trastuzumab in patients with HER2 overexpressing MBC with prior resistance to trastuzumab, 
everolimus was well tolerated at doses of 5mg and 10mg daily and 30mg weekly. The 
combination showed encouraging response in heavily pretreated patients including patients 
refractory to both taxanes and trastuzumab. As of the data cutoff of May 2009, 33 heavily 
pretreated patients were enrolled (5 mg daily n=6; 10 mg daily; n=17, and 30 mg weekly 
n=10). Twenty-nine patients had measurable disease and 27 were evaluable for response. The 
median duration of therapy was 28 weeks in the 5 mg and 10 mg daily cohorts and 33 weeks 
in the 30 mg weekly cohort. The ORR was higher in the 5 mg daily treatment group. The 
median PFS for the entire evaluable patient population was 34 weeks (95% CI, 29.1-40.7); 
while it was 40.7 weeks (95% CI, 30 to NA) for the weekly dosing arm and 33 weeks (95% 
CI, 23.7 to NA) for the daily dosing arm Twenty-nine patients had measurable disease and 27 
were evaluable for response. The median duration of therapy was 28 weeks in the 5 mg and 
10 mg daily cohorts and 33 weeks in the 30 mg weekly cohort (Andre et al 2010).
Results from these two early clinical studies supported the initiation of Phase III trials J2301 
and W2301 to further evaluate the potential of everolimus in combination with trastuzumab 
(Herceptin®) and chemotherapy in HER2-positive metastatic breast cancer patients (Andre et 
al 2010, Jerusalem et al 2011). The PFS analysis and OS analysis for BOLERO-1 (J2301) 
(Hurvitz et al 2015) and for BOLERO-3 (W2301) (Andre et al 2014) have been completed 
and has been reported, details are also included in the IB.


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1.2.1.5
Overview of letrozole
Letrozole is an aromatase inhibitor indicated for the adjuvant treatment of postmenopausal 
women with hormone receptor positive early breast cancer. It is also indicated for the 
extended adjuvant treatment of early breast cancer in postmenopausal women who have 
received 5 years of adjuvant tamoxifen therapy and for neoadjuvant use in Europe. In the first 
line setting, letrozole is indicated for the treatment of postmenopausal women with hormone 
receptor positive, locally advanced or metastatic breast cancer and following anti-estrogen 
therapy for second-line treatment.
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits 
the conversion of androgens to estrogens. Letrozole inhibits the aromatase enzyme by 
competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in 
a reduction of estrogen biosynthesis in all tissues (Femara prescribing information, Novartis 
Pharmaceuticals, 2014).
The recommended dose of letrozole is one 2.5mg tablet administered once a day. Letrozole is 
rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected 
by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is 
excreted renally, representing the major clearance pathway. Letrozole’s terminal elimination 
half-life is about 2 days and steady-state plasma concentration after daily 2.5mg dosing is 
reached in 2-6 weeks. Letrozole is metabolized by CYP3A4 to the carbinol metabolite while 
CYP2A6 formed both this metabolite and its ketone analog. Letrozole strongly inhibits 
CYP2A6 and moderately inhibits CYP2C19 (Femara prescribing information, Novartis 
Pharmaceuticals, 2014).
1.2.1.6
Overview of exemestane
Exemestane is an irreversible steroidal aromatase inactivator that has demonstrated efficacy in 
the treatment of postmenopausal patients with ABC. It is indicated for adjuvant treatment of 
postmenopausal women with estrogen receptor positive 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 in postmenopausal women whose disease has progressed following
tamoxifen therapy (in the US) or following anti-estrogen 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, 2016).
The recommended daily dose of exemestane is 25mg 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 


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days (Demers 1993, Plourde 1995, Buzdar 2003). Exemestane is metabolized by CYP3A4 
and aldeoketoreductases. It does not inhibit any of the major CYP isoenzymes, including 
CYP1A2, 2C9, 2D6, 2E1 and 3A4. Although no formal drug-drug interaction studies have 
been conducted, significant effects on exemestane clearance by CYP isoenzyme inhibitor 
appear unlikely (Aromasin prescribing information, Pfizer-Pharmacia, 2016, Hutson 2005, 
Buzdar 2002).
2
Rationale
2.1
Study rationale and purpose
There is growing evidence to support close interaction between the mTOR pathway and ER 
signaling. mTOR forms two different protein complexes, mTOR-raptor signal transduction 
complexes 1 and 2 (mTORC1 and mTORC2) (Guertin and Sabatini 2007). A substrate of 
mTORC1, p70 ribosomal S6 kinase (S9K1), directly phosphorylates the activation domain 
AF-1 of the ER, responsible for ligand-independent receptor activation (Yamnik et al 2009, 
Yamnik and Holz 2010). Preclinical studies suggest that sensitivity to hormonal therapy may 
be restored by treatment with everolimus or other mTOR inhibitors in breast cancer cells with 
upregulated Akt signaling (Baselga 2009). mTOR inhibitors given in combination with 
aromatase inhibitors (AIs) in preclinical models result in synergistic inhibition of proliferation 
and induction of apoptosis (Boulay et al 2005).
This extensive preclinical work suggests that co-targeting the mTOR pathway and ER 
signaling may improve the effectiveness of endocrine therapy. In addition, endocrine-resistant 
breast cancer cells demonstrate hyperactivation of the PI3K/mTOR pathway, and treatment 
with mTOR inhibitors including rapamycin analogs reverse this resistance (Miller et al 2010).
Results from recent clinical studies support these findings, as previously described in Section 
1.2.1.4. Combining everolimus with letrozole (Baselga et al 2009) in the neoadjuvant setting 
induced higher response rates than with letrozole alone in postmenopausal women with ER-
positive breast cancer. The combination of everolimus with tamoxifen was also associated 
with prolonged PFS and improved overall survival (OS) in a phase II randomized study in 
patients progressing after prior AI treatment compared with tamoxifen alone (Bachelot et al 
2012). An ongoing trial combining everolimus with fulvestrant in postmenopausal women 
with ER positive breast cancer has also shown encouraging activity (Badin et al 2010). In a 
recent pivotal phase III, randomized, double-blind, placebo-controlled trial, BOLERO-2, of 
everolimus plus exemestane versus exemestane plus placebo in ER positive postmenopausal 
women with locally advanced or metastatic disease refractory to letrozole or anastrozole, the 
addition of everolimus to exemestane prolonged median progression free survival 3.2 to 7.8 
months based on local assessment (hazard ratio, 0.45; 95% confidence interval 0.38-0.54; p< 
0.0001) and 4.1 to 11 months based on central radiology review (hazard ratio, 0.38; 95% 
confidence interval 0.31-0.48; p< 0.0001) (Baselga et al 2012, Yardley et al 2013).
Taken together, the above data support the activity of everolimus both in patients progressing 
after initial endocrine treatment and in patients who have not received prior treatment in the 
neoadjuvant setting. However, to date the efficacy of everolimus plus endocrine therapy has 
not been explored for first line therapy of patients with metastatic disease. Preclinical studies 


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have shown that inhibition of the PI3K/mTOR pathway can prevent the emergence of 
hormone-independent cells, suggesting that early intervention with combined endocrine 
therapy and mTOR inhibition may prevent or delay endocrine resistance (Miller et al 2010). It 
is also of interest to investigate whether continued mTOR inhibition with sequential endocrine 
therapy may provide clinical benefit. The proposed trial will assess the efficacy of everolimus 
plus letrozole in the first line treatment of patients with metastatic breast cancer and explore 
the efficacy of continued treatment with everolimus plus exemestane after initial progression.
2.2
Rationale for the study design
This trial is designed to assess the progression free survival of patients treated with 
everolimus in combination with letrozole in the first line setting (primary study endpoint). It is 
also designed to evaluate the efficacy of continued therapy with everolimus in combination 
with a second endocrine agent, exemestane, in patients progressing on first line treatment 
(secondary study endpoint). Allowing patients to continue everolimus in combination with 
exemestane after progression will assess the effectiveness of continued treatment with 
everolimus in this patient population, who have progressed following first line treatment with 
everolimus plus letrozole. The study design will be open-label, single arm and will enroll a 
sufficient number of patients to allow a robust estimate of PFS in the first line setting.
2.2.1
Stomatitis therapeutic intervention
Stomatitis, the inflammation of mucous membranes lining the mouth and throat, has been 
observed in approximately 44-64% of everolimus-treated patients (Afinitor PI). It is also a 
common adverse event associated with radiation and chemotherapy. Specific strategies to 
prevent and/or ameliorate the severity of everolimus-associated mucositis are not well 
documented. Caphosol is an oral mouth rinse indicated as an adjunct to standard oral care in 
the prevention and treatment of stomatitis caused by radiation or high dose chemotherapy. 
Low level laser therapy (LLLT) has also been suggested by the Multinational Association of 
Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) 
to reduce the incidence of oral stomatitis and its associated pain in patients receiving high 
dose chemotherapy or chemo-radiotherapy (Keefe et al 2007). However, mTOR inhibitor-
induced stomatitis is a different clinical entity, manifesting more frequently as discrete 
aphthous-like lesions rather than diffuse inflammation. A recent study evaluated the clinical 
presentation and management of stomatitis in 17 patients treated with an mTOR inhibitor. The 
majority of patients were treated with topical corticosteroids including an oral dexamethasone 
solution which was rinsed and expectorated. Clinical improvement was noted in over 85% of 
topical corticosteroid-treated patients (de Oliveira et al 2011). Additional reports from 
investigators indicate that an oral steroid rinse may help to ameliorate mTOR-induced 
stomatitis (Irene Ghobrial, personal communication, February, 2012 and Ingrid Mayer, 
personal communication, March 2012).
As a secondary endpoint, this trial will assess the effectiveness of treating stomatitis using an 
alcohol-free 0.5mg/5ml dexamethasone mouth rinse in countries where the solution is 
commercially available. At the onset of symptoms, enrolled patients will contact their 
physician. Based on preliminary confirmation of diagnosis, patients will be asked to visit the 
study site within 24 hours. Upon confirmation of the diagnosis of stomatitis the patient will be 


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randomly assigned to use either 0.5mg/5ml dexamethasone mouth rinse swished and 
expectorated 3 times per day or the standard of care normally used to treat stomatitis at the 
patient’s center.
2.3
Rationale for dose and regimen selection
Letrozole has been selected for first line treatment in combination with everolimus and 
exemestane has been selected for second line treatment in combination with everolimus based 
on the following considerations:

The activity of letrozole in the first line setting has been extensively documented 
(Mouridsen et al 2003; Park et al 2010, Baselga et al 2009, Krainich-Strobel et al 2008).

The combination of everolimus and letrozole has been investigated and is generally well 
tolerated (Baselga et al 2009).

Exemestane in the second line setting has been established as an effective treatment in 
combination with everolimus in BOLERO-2 (Baselga 2012, Yardley 2013).
Based on the current literature and product approvals, everolimus, letrozole and exemestane 
will all be given at the standard approved doses for first line and second line treatment in this 
patient population (Baselga et al 2009, Baselga et al 2012).
2.4
Rationale for choice of combination drugs
The activity of letrozole in the first line setting has been extensively documented (Mouridsen 
et al 2003; Park et al 2010, Baselga et al 2009, Krainich-Strobel et al 2008). Letrozole was 
chosen as the combination drug in the first line setting because of its approval in this setting 
and wide-spread use as first line endocrine therapy. Additionally, Baselga and colleagues 
combined everolimus 10mg daily and letrozole 2.5mg daily in the neoadjuvant setting and 
found that the combination induced higher response rates than letrozole alone in 
postmenopausal women with ER-positive breast cancer (Baselga et al 2009). The combination 
was well tolerated.
Exemestane in combination with everolimus has been established as an effective treatment in 
the second line setting. In phase III, randomized, double-blind, placebo-controlled trial, 
BOLERO-2, the combination of everolimus 10mg daily plus exemestane 25mg daily 
prolonged median progression free survival from 3.2 to 7.8 months based on local assessment 
(hazard ratio, 0.45; 95% confidence interval 0.38-0.54; p< 0.0001) and 4.1 to 11 months based 
on central radiology review (hazard ratio, 0.38; 95% confidence interval 0.31-0.48; p< 
0.0001). The combination was generally well tolerated (Yardley et al 2013).
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary:
The primary objective is to estimate progression-free 
survival in patients treated with everolimus + letrozole 
in the first line setting.
PFS
Refer to Section 10.4.
Secondary:
Determine the overall response rate and clinical benefit 
rate of everolimus + letrozole in the first line setting
ORR, CBR
Refer to Section 10.5.1.
Determine the progression free survival, overall 
response rate and clinical benefit rate of everolimus + 
exemestane in second line population
Evaluate the safety of everolimus + letrozole in the first 
line setting
Evaluate the safety of everolimus + exemestane in the 
second line setting
Estimate the overall survival of patients treated with 
everolimus + letrozole in the first line setting
Evaluate a therapeutic intervention to reduce the 
severity and duration of stomatitis
Evaluate clinical benefit as assessed by the
Investigator during the Extension Phase
Evaluate long term safety data
PFS, ORR, CBR
Incidence of Adverse events
Incidence of Adverse events
OS
Oral Stomatitis Daily Questionnaire (OSDQ) 
data
Proportion of patients with clinical benefit as
assessed by the Investigator at scheduled visits
Frequency and severity of AEs/SAEs
Refer to Section 10.5.2 and Section 10.5.3.
Refer to Section 10.5.5.2.
Refer to Section 10.5.5.2.
Refer to Section 10.5.4.
Refer to Section 10.5.5.1.
Refer to Section 10.5.5.3.
Refer to Section 10.5.5.2.


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4
Study design
4.1
Description of study design
This is an open-label, phase II, multicenter, international, single-arm trial for patients with 
ER+, HER2- metastatic or locally advanced breast cancer. Enrolled patients will receive 
everolimus in combination with letrozole in the first line setting until disease progression or 
any other reason for which the patient may be discontinued (refer to Section 7.1.5). PFS in the 
first line setting is the primary study endpoint.
The study will be comprised of 2 phases:

Core Phase: from FPFV to 24 months after LPFV and upon approval of amendment 5; 
safety and efficacy data (including PROs in selected subset) will be collected.

Extension Phase: from the end of the Core Phase (upon approval of amendment 5) until 
LPLV of the Extension Phase for patients that are still deriving benefit at the end of the 
Core Phase. Patients may be transitioned to the Extension Phase and continue to receive 
the drugs up to 3 years or until progression or any other reason for which the patient may 
be discontinued (refer to Section 7.1.5); only safety and clinical benefit as assessed by 
investigator will be collected.
During the Core Phase following disease progression in the first line setting, patients will be 
offered everolimus in combination with exemestane. Patients who discontinue treatment in the 
first line setting due to unacceptable toxicity or due to withdrawal of consent will not be 
offered everolimus plus exemestane. Those patients treated in the second line setting will 
continue treatment until disease progression or any other reason for which the patient may be 
discontinued (refer to Section 7.1.5).
All patients who discontinue study treatment will have a 28 day follow up visit for safety and 
will be followed every 3 months thereafter for overall survival after completing treatment in 
either the first or second line treatment setting. Overall Survival will be followed until 24 
months post LPFV.
At the first onset of symptoms suggestive of stomatitis patients will contact the study site. 
Upon confirmation of stomatitis, patients in countries where the alcohol-free 0.5mg/5ml 
dexamethasone oral solution is commercially available will be randomly assigned to take 
either 0.5mg/5ml dexamethasone mouth rinse or the standard of care used to treat stomatitis at 
the patient’s center. The mouth rinse will be self-administered at a dose of 10ml 3 times per 
day. Patients will be instructed to swish and expectorate the mouth rinse. Patients will also be 
instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until 
the patient recovers. For subsequent episodes of stomatitis patients will be instructed to 
contact the physician. Upon telephone confirmation, they will be instructed to utilize the same 
treatment they were assigned to after the first episode and complete the OSDQ booklet. Note:
only those patients who develop symptoms suggestive of stomatitis and who have the 
diagnosis of stomatitis confirmed by the study site will participate in the investigation of the 
stomatitis intervention. OSDQ will not be administered during the Extension Phase.


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The primary analysis of PFS for first line treatment will be performed 12 months after the last 
patient’s recruitment. The analysis of PFS for second line treatment will be performed 6 
months later (18 months after the last patient’s recruitment) provided that the number of 
patients in second line treatment is adequate for a reliable PFS analysis. Otherwise, this 
analysis will be performed 24 months after the last patient’s recruitment. The overall survival 
analysis will be performed 24 months after the last patient’s recruitment. Assuming an 
enrollment period of 18 months, the expected trial duration is therefore 42 months.
Patients still benefiting from everolimus following the overall survival cutoff and following 
approval of Amendment 5 may continue treatment in the Extension Phase of the study. 
Patients may continue on their existing line treatment (1st or 2nd) in the extension up to 3 years 
or until the following: disease progression as deemed by physician judgement or any other 
reason for which the patient may be discontinued (refer to Section 7.1.5). Patients entering the 
Extension Phase on 1st line treatment and deemed to no longer be clinically benefiting will not 
be offered 2nd line treatment in the context of the study. Rather, these patients can start other 
standard treatments available or approved everolimus combination after exiting the study.
The extension will include required safety evaluations and standard of care, per investigator 
discretion and in consultation with the Sponsor.


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Figure 4-1
Study design


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4.2
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
4.3
Definition of end of study
The planned overall study duration of the Core Phase will from FPFV until 24 months post 
LPFV and approval and implementation of Amendment 5. At the end of the Core Phase, if 
patients are still deriving benefit, patient may be transitioned to the Extension Phase which 
will last a total of 3 years (end of study). The LPLV is when the last patient has discontinued 
treatment for any reason in the Extension Phase and has had the 28 day safety follow up visit. 
The study closure will occur once the LPLV of the Extension Phase of the study has been 
documented.
5
Population
5.1
Patient population
Two hundred postmenopausal women with estrogen receptor positive HER2 negative 
metastatic or locally advanced breast cancer will be enrolled in this study. Patients enrolled in 
this study are not permitted to participate in additional parallel investigational drug or device 
studies.
The investigator or designee must ensure that only patients who meet all the following 
inclusion (Section 5.2) and none of the exclusion (Section 5.3) criteria are offered enrollment 
in the study. Upon enrollment patients will initiate first line treatment with everolimus plus 
letrozole.
All required screening evaluations must be performed to protect the safety of the patients and 
to ensure all inclusion and exclusion criteria are met. The results of all screening evaluations 
must be reviewed by the Principal Investigator or designee prior to enrollment of that patient 
onto the study.
All patients must be thoroughly informed about all aspects of the study including the study 
visit schedule, required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained before any screening evaluations are performed. If 
the patient is unable to read, an impartial witness should be present during the entire informed 
consent discussion.
Prior to patients being offered second line treatment with everolimus plus exemestane in the 
Core Phase, investigators must re-examine specified inclusion criteria 6, 7, 8, 9, 10 and 
exclusion criteria 8, 10, 12, 13, 14 as described in Section 5.2 and Section 5.3 below. Refer to 
Section 7.1.3 for second line treatment procedures.


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5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any screening procedures
1. Adult women (>18 years of age) with metastatic or locally advanced breast cancer not 
amenable to curative treatment by surgery or radiotherapy.
2. Histological or cytological confirmation of estrogen-receptor positive (ER+) human 
epidermal growth factor receptor 2 negative (HER2-) breast cancer.
3. Postmenopausal women. Postmenopausal status is defined either by:
a. Age ≥55 years and one year or more of amenorrhea
b. Age < 55 years and one year or more of amenorrhea, with an estradiol assay 
<20pg/ml
c. Surgical menopause with bilateral oophorectomy
d. Note: Ovarian radiation or treatment with a luteinizing hormone-release hormone 
(LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction 
of ovarian suppression.
4. No prior treatment for metastatic breast cancer
5. Patients must either have at least one lesion that can be accurately measured in at least one 
dimension >20mm with conventional imaging techniques or >10mm with spiral CT or 
MRI OR Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable 
disease as defined above
6. Adequate bone marrow and coagulation function as shown by:
a. Absolute neutrophil count (ANC) ≥1.5x109/L
b. Platelets ≥100x109/L
c. Hemoglobin (Hgb) >9.0g/dL
d. INR ≤2
7. Adequate liver function as shown by:
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5xULN (or ≤5 if hepatic metastases are present)
b. Total serum bilirubin <1.5xULN (<3xULN for patients known to have Gilberts 
Syndrome)
8. Adequate renal function as shown by:
a. Serum creatinine < 1.5xULN
9. Fasting serum cholesterol ≤300 mg/dL or 7.75 mmol/L and fasting triglycerides ≤2.5 x 
ULN.
10. ECOG Performance Status ≤2
11. Written informed consent obtained before any trial related activity and according to local 
guidelines.
12. Willingness to complete a daily stomatitis symptom questionnaire throughout each 
stomatitis event


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5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with only non-measurable lesions other than bone metastasis as define above (e.g., 
pleural effusion, ascites, etc).
2. Patients who have received prior hormonal or any other systemic therapy for metastatic 
breast cancer.
a. Patients may have received prior neoadjuvant or adjuvant endocrine therapy. In the 
case of neoadjuvant or adjuvant NSAI (letrozole/anastrozole) therapy patients must 
have completed therapy at least 1 year prior to study enrollment.
3. Previous treatment with mTOR inhibitors.
4. Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin).
5. Another malignancy within 5 years prior to enrollment with the exception of adequately 
treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-
melanomatous skin cancer
6. Radiotherapy within four weeks prior to randomization except in case of localized 
radiotherapy for analgesic purpose of lytic lesions at risk of fracture which can then be 
completed within two weeks prior to enrollment.
7. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
8. History of brain or other CNS metastases.
9. Patients receiving chronic treatment with systemic immunosuppressive agents
10. Bilateral diffuse lymphangitic carcinomatosis.
11. Patients with a known history of HIV seropositivity. Screening for HIV infection at 
baseline is not required.
12. Active bleeding diathesis.
13. Any severe and/or uncontrolled medical conditions such as:
a. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia.
b. Uncontrolled diabetes as defined by fasting serum glucose >1.5xULN.
c. Acute and chronic, active infectious disorders (except for Hep B and Hep C positive 
patients) and nonmalignant medical illness 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 GI disorders of Grade >1
14. 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 within the last 5 days prior to enrollment (see Section 6.1.3.1)
16. History of non-compliance to medical regimens.


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17. Patients unwilling to or unable to comply with the protocol.
6
Treatment
6.1
Study treatment
Definition of terms
The investigational therapy in the context of this study is everolimus
Study Treatment = Everolimus + Letrozole or Everolimus + Exemestane
Study Drug = Everolimus
Everolimus will be self-administered as a daily dose of 10mg (two 5mg tablets) taken orally 
continuously from study day 1 until progression of disease, unacceptable toxicity or 
withdrawal of consent. Everolimus should be taken at the same time every day. Everolimus 
tablets should be swallowed whole with a glass of water once daily, either consistently with 
food or consistently without food. Tablets should not be chewed or crushed. Letrozole will be 
self-administered as a daily dose of 2.5mg continuously from study day 1 until disease 
progression or any other reason for which the patient may be discontinued (refer to Section 
7.1.5) and should be taken at the same time every day, consistently with or without food. 
Everolimus and letrozole tablets should be taken together.
During the Core Phase of the study following disease progression on everolimus in 
combination with letrozole, patients will be offered everolimus in combination with 
exemestane. Exemestane will be self-administered as a daily dose of 25mg taken orally 
continuously until disease progression or any other reason for which the patient may be 
discontinued (refer to Section 7.1.5) and should be taken at the same time every day. 
Exemestane should be taken after a meal. Everolimus and exemestane tablets should be taken 
together.
During the Core Phase and at the onset of symptoms suggestive of stomatitis patients must 
contact the study site. Upon confirmation of stomatitis at the site, patients in countries where 
the alcohol-free 0.5mg/5ml dexamethasone oral solution is commercially available will be 
randomly assigned to take either 0.5mg/5ml dexamethasone mouth rinse or the standard of 
care used to treat stomatitis at the patient’s center. The mouth rinse will be self-administered 
at a daily dose of 10ml 3 times per day. Patients will be instructed to swish and expectorate 
the mouth rinse. Patients will also be instructed to fill out the Oral Stomatitis Daily 
Questionnaire (OSDQ) at home every day until the patient recovers (see Section 10.5.5.1). 
During the Extension Phase, standard of care at the patient’s site as recommended by the 
investigator to treat stomatitis will be followed and the OSDQ will not be administered when 
the patients are in the Extension Phase.


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6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule (first line setting & Extension Phase)
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Everolimus
Tablet for oral use
10 mg(two 5mg tablets)
Daily (28 day cycles)
Letrozole
Tablet for oral use
2.5mg
Daily (28 day cycles)
Table 6-2
Dose and treatment schedule (second line setting & Extension Phase)
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Everolimus
Tablet for oral use
10 mg(two 5mg tablets)
Daily (28 day cycles)
Exemestane
Tablet for oral use
25mg
Daily (28 day cycles)
Table 6-3
Dose and treatment schedule for oral stomatitis
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
0.5mg/5ml 
dexamethasone
(for patients 
randomized to 
dexamethasone 
treatment)
Oral Solution
10ml
Swish and expectorate 
3 times/day
Standard of Care to 
treat oral stomatitis
See Section 6.2.2.1.
6.1.2
Treatment duration
Core Phase
The study treatment refers to the administration of everolimus in combination with letrozole 
or exemestane to patients. A treatment cycle consists of 4 weeks (or 28 days). The first day of 
the open-label study medication begins at Visit 2 (Cycle 1 day 1). The patient must take the 
first dose of medication at the study center. Patients will receive everolimus 10mg orally daily 
in combination with letrozole until the occurrence of documented disease progression by 
RECIST 1.0 criteria or discontinuation due to unacceptable toxicity (with either study 
treatment) or withdrawal of consent (first line setting). After initial disease progression, 
patients will be offered everolimus in combination with exemestane according to the treating 
physician’s clinical discretion (see Section 7.1.3). Patients will be treated in the second line 
until subsequent disease progression or any other reason for which the patient may be 
discontinued (refer to Section 7.1.5).
Extension Phase
In the Extension Phase, visits will be every 3 months instead of every 28 days hence patients 
will be completing approximately 3 treatment cycles between visits. Patients will continue 
treatment as described in the Core Phase until disease progression or any other reason for 
which the patient may be discontinued (refer to Section 7.1.5).


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6.1.3
Prohibited concomitant therapy
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator. All medications 
taken within 28 days of starting study treatment should be reported on the Concomitant 
Medication eCRF pages.
The following concomitant treatments are not allowed during the study:

Chronic concomitant bisphosphonate therapy for the prevention of bone metastases are not 
permitted during the study. Bisphosphonate therapy for the treatment of osteopenia or 
osteoporosis is permitted during the study. Bisphosphonate or denosumab therapy for the 
management of bone metastases is recommended as standard of care. Please refer to 
prescribing information for details of administration. If bisphosphonate or denosumab 
therapy is initiated after enrollment, the reason for its use must be clearly documented.

Investigational or commercial anticancer agents, such as chemotherapy, immunotherapy, 
targeted therapy, biological response modifiers, or endocrine therapy other than 
exemestane (including steroids) should not be given to patients.

Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (e.g.raloxifene) are 
prohibited.

Prolonged systemic corticosteroid treatment, except for topical applications (e.g. rash), 
inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. 
intraarticular) should not be given. A short duration (<2 weeks) of systemic 
corticosteroids is allowed (e.g. chronic obstructive pulmonary disease, anti-emetic). Please 
note, alcohol-free 0.5mg/5ml dexamethasone oral mouth rinse is allowed for patients 
randomized to receive it at the onset of stomatitis in countries where it is commercially 
available.

Hematopoietic growth factors (e.g. erythropoietins, G-CSF and GM-CSF) are not to be 
administered prophylactically. Use of these should be reserved to cases of severe 
neutropenia and anemia as per the labeling of these agents.
6.1.3.1
Cytochrome P450 and P-glycoprotein (PgP) 
inhibitors/inducers/substrates
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall.
Therefore, the following are recommended:

Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided and may cause increased everolimus 
concentrations.

Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution. If a patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus to half the 
currently used dose (see Table 6-9 for everolimus dose modifications). Additional dose 
reductions may be required to manage toxicities. If the inhibitor is discontinued, consider 
a washout period of at least 2-3 days (average for the most commonly used moderate 


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inhibitors), before the study drug isreturned to the dose used prior to initiation of the 
moderate CYP3A4/PgP inhibitor.

Co-administration with strong inducers of CYP3A4 should be avoided.

If a patient requires co-administration of strong CYP3A4 inducers (i.e., phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort), an increase in the dose 
of everolimus up to twice the currently used daily dose should be considered, using 5mg 
increments or less (see Table 6-9 for everolimus dose modifications). This dose 
adjustment of everolimus is predicted to achieve similar AUC to the range observed 
without inducers. However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a 
washout period of at least 3-5 days (reasonable time for significant enzyme de-induction), 
before the study drug dose is returned to the dose used prior to initiation of the strong 
CYP3A4/PgP inducer.
It is to be noted that:

Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required. Whenever possible, these patients should have a tumor assessment 
of the lesion(s) before they actually receive the radiotherapy. No dose modification of 
study treatment is needed during radiotherapy.

Everolimus may affect the response to vaccinations making it less effective. Live vaccines 
should be avoided while a patient is treated with everolimus.

Lipid-lowering drugs may be given in case of hyperlipidemia.
Otherwise, the use of other concomitant medication/therapy deemed necessary for the care of 
the patient is allowed. The investigator should instruct the patient to notify the study site about 
any new medications she takes after the start of the study drug. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts study treatment and for up to 28 days after 
study drug discontinuation must be listed on the Concomitant medications/Significant 
Nondrug Therapy After Start of Study Drug eCRF. The first regimen of antineoplastic 
medication/treatments received after study treatment discontinuation must also be recorded in 
the antineoplastic treatment eCRF.


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Table 6-4
Clinically relevant drug interactions: inducers and inhibitors of 
isoenzyme CYP3A
Inducers
Strong inducers:
avasimibe, carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin 
(rifampicin), St. John's wort (Hypericum perforatum)
Moderate inducers:
bosentan, efavirenz, etravirine, genistein, lersivirine, lopinavir, modafinil, nafcillin, ritonavir, 
semagacestat, talviraline, thioridazine, tipranavir
Weak inducers:
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, boceprevir, brivacetam, clobazam, 
danshen, dexamethasone, Echinacea, eslicarbazepine, garlic (Allium sativum), gingko (Ginkgo biloba), 
ginseng, glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, 
pleconaril, primidone, quercetin, raltegravir, ritonavir, rufinamide, sorafenib, Stribild (combo of 
elvitegravir, cobicistat, emtricitabine, and tenofovir), sulfinpyrazone,telaprevir, terbinafine, ticagleror, 
ticlopidine, topiramate, troglitazone, vemurafenib, vicriviroc/ritonavir, vinblastine
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, eltegravir/ritonavir, grapefruit 
juice, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, troleandamycin, voriconazole
Moderate inhibitors:
Amprenavir, aprepitant, atazanavir, atazanavir/ritonavir, casopitant, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice (Citrus parasidi fruit juice), imatinib, lomitapide, netupitant, nilotinib, 
Schisandra sphenanthera, tofisopam, verapamil
Weak inhibitors:
almorexant, alprazolam, alprazolam, amiodarone, amlodipine, amlodipine, atorvastatin, azithromycin, 
berberine, bicalutamide, bicalutamide, blueberry juice, cilostazol, cilostazol, cimetidine, clotrimazole, 
clozoxazone, cranberry juice, cyclosporine, delavirdine, everolimus, fluoxetine, fluvoxamine, 
fosaprepritant, ginkgo, goldenseal, isoniazid, isoniazid, ivacaftor, lacipidine, linagliptin, nilotinib, oral 
contraceptives, pazopanib, peppermint oil, propiverine, ranitidine, ranitidine, ranolaxine, ranolazine, 
resveratrol, roxithromycin, Seville orange, simeprevir, sitaxentan, tabimorelin, tacrolimus, 
teriflunomide, ticagrelor, tipranavir/ritonavir, tolvaptan, zileuton


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Table 6-5
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A dual inhibitors
Substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, atorvastatin acid, 
atorvastatin, azithromycin, boceprevir, bosentan, carvedilol, caspofungin, ceritinib, cerivastatin, 
citalopram, colchicine, CP-481,715, cyclosporine, dabigatran, digoxin, docetaxel, domperidone, 
doxepin, doxorubicin, eribulin, everolimus, fentanyl, fexofenadine, fidaxomicin, fluvastatin, 
fosamprenavir, gatifloxacin, idelalisib, iloperidone, indacaterol, indinavir, irbesartan, lacosamide, 
lapatinib, levetiracetam, levofloxacin, linagliptin, linezolid, loperamide, losartan, maraviroc, mirabegron, 
moxifloxacin, naloxegol, nateglinide, nevirapine, nintedanib, lodaterol, paclitaxel, pantoprazole, 
paroxetine, pazopanib, phenytoin, posaconazole, pravastatin, proguanil, quinidine, quinine, ranolazine, 
riociguat, risperidone, ritonavir, rivaroxaban, saquinavir, silodosin, simeprevir, simvastatin, sirolimus, 
sitagliptin, sofosbuvir, sorafenib, tacrolimus,telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, 
topotecan, umeclidinium, valsartan, vardenafil, vincristine, voclosporin, voriconazole
Inducers
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, rifampin, St John’s wort
PgP Inhibitors and PgP/CYP3A Dual Inhibitors
PgP Inhibitors
alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole, lapatinib, lopinavir/ritonavir, 
mirabegron, propafenone, simepravir, valspodar, vandetanib, voclosporin
PgP/CYP3A Dual Inhibitors
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fluvoxamine, ginkgo (Ginkgo biloba), indinavir, indinavir/ritonavir, 
itraconazole, mibefradil, milk thistle (Silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, 
quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir/ritonavir, Schisandra chinensis, St 
John’s wort (Hypericum perforatum), talinolol, telaprevir, telmisartan, ticagrelor, tipranavir/ritonavir, 
tolvaptan, verapamil
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated April-2015 
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.
6.2
Dose modifications and known undesirable effects of study 
drug/treatment
6.2.1
Everolimus
As of 31 March 2016 approximately 35,801 patients with various malignancies (excluding 
patients who received marketed Afinitor®/ Votubia®) have been treated with everolimus in 
either Novartis-sponsored clinical studies, individual patient supply programs or investigator 
sponsored clinical studies.
The most common adverse reactions (incidence ≥10% in at least one pivotal trial) were (by 
decreasing order) stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, 
anemia, dysgeusia, pneumonitis, edema peripheral, hyperglycemia, asthenia, pruritus, weight 
decrease, hypercholesterolemia, epistaxis, cough, and headache, The most common grade 3-4 
adverse reactions (incidence ≥2% in at least one pivotal trial), were stomatitis, anemia, 
hyperglycemia, fatigue, infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, 
neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, 


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hypertension, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) 
increased, pneumonia and diabetes mellitus. For more details about clinically notable adverse 
events, refer to the most recent everolimus investigator brochure. Management of specific 
toxicities is described in Section 6.2.2.
6.2.1.1
Letrozole
The most frequently reported adverse reactions (>20%) were hot flashes, arthralgia, flushing, 
asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, 
bone pain and musculoskeletal pain. Use of letrozole can also cause decreases in bone mineral 
density. Increases in total cholesterol may occur. Letrozole may be taken with or without food. 
Refer to the package insert of the local supply of letrozole for management of toxicities and 
dose adjustments.
6.2.1.2
Exemestane
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, 
hot flushes, arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects 
include headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and 
peripheral and leg edema. Thrombocytopenia and leucopenia have been reported occasionally. 
Reductions in bone mineral density can occur with long-term use of exemestane. 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 management of toxicities and dose adjustments.
6.2.2
Management of specific everolimus-related toxicities
Permitted everolimus (RAD001) dose adjustments are described in Table 6-7, Table 6-8, 
Table 6-9, Table 6-10, and Table 6-11.
6.2.2.1
Management of stomatitis/oral mucositis/mouth ulcers
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately.
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If examination 
reveals mouth ulcers rather than a more general inflammation of the mouth, please classify the 
adverse event as such. As noted in Section 6.1, patients in countries where the alcohol-free 
0.5mg/5ml dexamethasone oral solution is commercially available, randomized to 
dexamethasone will be prescribed a 0.5mg/5ml dexamethasone mouth rinse to swish and 


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expectorate 3 times per day. Treatment of stomatitis/oral mucositis/mouth ulcers for patients 
randomized to standard of care may include the following measures in conjunction with 
institutional standards:
1. For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution.
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 
should be avoided in all patients due to their strong inhibition of everolimus metabolism, 
therefore leading to higher everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir should 
be avoided unless a viral infection is diagnosed.
Additional measures for management of stomatitis consistent with institutional standards 
should be utilized for patients randomized to standard of care.
6.2.2.2
Management of hyperlipidemia and hyperglycemia
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 
hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hyroxy-
3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin, fluvastatin) 
or appropriate triglyceride-lowering medication, in addition to diet.
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, 
markedly 
elevated 
creatinine 
phosphokinase 
(CPK) 
levels 
and 
myoglobinuria, acute renal failure and sometimes death. The risk versus benefit of using this 
therapy should be determined for individual patients based on their risk of cardiovascular 
complications of hyperlipidemia.
Hyperglycemia has been reported in in patients taking everolimus. Monitoring of fasting 
serum glucose is recommended prior to the start of everolimus therapy and periodically 
thereafter. More frequent monitoring is recommended when everolimus is co-administered 
with other drugs that may induce hyperglycemia. Optimal glycemic control should be 
achieved before starting trial therapy.
6.2.2.3
Management of hepatitis reactivation
Monitoring and prophylactic treatment for hepatitis B reactivation


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Table 6-6 provides details of monitoring and prophylactic therapy according to the baseline 
results of viral load and serologic markers testing.
Table 6-6
Action to be taken for positive baseline hepatitis B results
Test
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HBs Ag
+ or -
+
-
-
-
HBsAb
+ or -
+ or -
+
and no prior 
HBV 
vaccination
+ or -
-
or + with prior 
HBV 
vaccination
HBc Ab
+ or -
+ or -
+ or -
+
-
Recommendation
Prophylaxis treatment should 
be started 1-2 weeks prior to 
first dose of study treatment
Monitor HBV-DNA 
approximately every 4-8 
weeks
No prophylaxis
Monitor HBV-DNA 
approximately every 3-4 
weeks
No specific 
action
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study treatment.
For hepatitis B reactivation definition and the management guidelines, see Table 6-7
Guidelines for management of hepatitis B.


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Table 6-7
Guidelines for management of hepatitis B reactivation
HBV reactivation (with or without clinical signs and symptoms)*
For patients with baseline 
results:
Positive HBV-DNA
OR
positive HBs Ag
--------------------------------------
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 6-10 – 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 treatment.
If resolution occurs > 28 days Patients should discontinue study drug
but continue both antiviral therapies at least 4 weeks after last dose 
of study treatment.
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 treatment 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 6-10 – Study drug dose 
reductions) If the patient is already receiving the lowest dose of either 
study treatment 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 treatment.
If resolution occurs > 28 days Patients should discontinue study drug 
but continue antiviral therapy at least 4 weeks after last dose of study 
treatment.
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 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 4.0 Metabolic Laboratory/Other: Viral Re-
activation). Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA was 
recorded.
Monitoring for hepatitis C
The following two categories of patients should be monitored every 4–8 weeks for HCV 
reactivation:

Patients with detectable HCV RNA-PCR test at baseline.

Patients known to have a history of HCV infection, despite a negative viral load test at 
baseline (including those that were treated and are considered ‘cured’)
For definition of hepatitis C reactivation and the management guidelines, see Table 6-8
Guidelines for management of hepatitis C.


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Table 6-8
Guidelines for management of hepatitis C flare
HCV reactivation*
For patients with baseline results:
Detectable HCV-RNA
HCV flare definition:
>2 log10 IU/mL increase in HCV-
RNA
AND
ALT elevation x 5 ULN or 3 x 
baseline level, whichever is 
higher.
Discontinue study treatment
For patients with baseline results:
Knowledge of past hepatitis C 
infection with no detectable HCV-
RNA
HCV flare definition:
New appearance of detectable 
HCV-RNA
AND
ALT elevation>5x ULN or 3x 
baseline level, whichever is 
higher.
Discontinue study treatment
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v 4.0 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 4.0 Metabolic Laboratory/Other: Viral Re-
activation). Date of viral flare is the date on which both the clinical criteria described above were met. 
(e.g., for a patients whose HCV-RNA increased by 2 logs on 01JAN2011 and whose ALT reached >5 
x ULN on 22JAN2011, the date of viral flare is 22JAN2011).
6.2.2.4
Management of diarrhea
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (e.g., 4mg orally followed by 
2mg orally every 2 hours until resolution of diarrhea).
6.2.2.5
Management of 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 
pneumocystis jiroveci pneumonia (PJP) should be ruled out in the differential diagnosis of 
non-infectious pneumonitis. Patients should be advised to report promptly any new or 
worsening respiratory symptoms.


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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 PJP may be considered.
Individuals participating in this trial will be routinely questioned as to the presence of new or 
changed pulmonary symptoms consistent with lung toxicity. Moreover, potential lung 
radiological changes can be detected by chest CT/MRI scans that are performed on all patients 
every 8 weeks for tumor assessments according to the schedule of visits (Table 7-1). In 
addition, PFTs will be conducted, including spirometry, DLCO, and room air O2 saturation at 
rest should be performed. Bronchoscopy with biopsy and/or bronchoalveolar lavage (BAL), if 
clinically indicated to monitor for pneumonitis. If non-infectious pneumonitis develops, the 
guidelines in Table 6-10 should be followed. Dose modification instructions are also provided 
in Table 6-9. Consultation with a pulmonologist is recommended for any case of pneumonitis 
that develops during the study.
6.2.2.6
Management of 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, 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 respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 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. If a diagnosis of invasive systemic 
fungal infection is made, discontinue everolimus and treat with appropriate antifungal therapy.
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.


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Cases of PJP, some with 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 is required.
6.2.2.7
Management of hematologic toxicities
Patients’ blood counts should be monitored regularly during treatment. Please refer to Table 
6-11 for details.
6.2.2.8
Management of skin toxicity
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenphydramine, oral prednisolone (short course) topical corticosteroids or pimecrolimus.
6.2.2.9
Follow up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least weekly until resolution or stabilization 
of the event, whichever comes first. The patient must be discontinued from the study if they 
require a dose delay of ≥ 28 days.
6.2.2.10 Permitted study drug adjustments
For patients who may require dose adjustments because of concomitant medication, please 
refer to Section 6.1.3. For patients who are unable to tolerate the protocol-specified dosing 
schedule, dose adjustments are permitted in order to allow the patient to continue study drug. 
The following guidelines should be followed. These changes must be recorded on the Dosage 
Administration Record eCRF. If treatment is interrupted due to toxicity, study drug should not 
be resumed until recovery to Grade ≤ 1. Study drug can then be reintroduced at the initial dose 
or a lower dose level depending on the toxicity type and Grade (see Table 6-9, Table 6-10, 
Table 6-11).
These changes must be recorded on the Dosage Administration Record eCRF.
Table 6-9
Dose reduction steps for everolimus
Dose reduction*
Starting dose level
Dose level – 1
Dose level - 2
Everolimus
10 mg daily
5 mg daily
5 mg every other day**
*Dose reduction should be based on the worst toxicity demonstrated at the last dose received.
**Dose reduction below 5 mg every other day is not allowed. Treatment must be discontinued.
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary 
dose interruption (with or without dose reduction) or discontinuation of everolimus therapy. If 
dose reduction is required, the suggested dose is approximately 50% lower than the daily dose 


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previously administered. For dose reductions below the lowest available tablet strength, 
alternate day dosing should be considered.
Table 6-10 and Table 6-11 summarize the recommendations for dose interruption, reduction, 
or discontinuation of everolimus in the management of ADRs. General management 
recommendations are also provided as applicable. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment.
Table 6-10
Dosing guidelines for study drug-related non-hematologic toxicities
Adverse drug 
reaction
Severity1
Everolimus dose adjustment2 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 
ADL3
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 
ADL3
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, and consider 
treatment with corticosteroids.


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Adverse drug 
reaction
Severity1
Everolimus dose adjustment2 and management 
recommendations
Stomatitis
Grade 1
Minimal symptoms,
normal diet
No dose adjustment required.
Manage with non-alcoholic or salt water (0.9%) mouthwash 
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).4
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 (e.g., 
benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without topical 
corticosteroids (i.e. triamcinolone oral paste).4
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.
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.


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Adverse drug 
reaction
Severity1
Everolimus dose adjustment2 and management 
recommendations
Metabolic events
(e.g. hyper-
glycemia, dys-
lipidemia)
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.
1 Severity Grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = 
life-threatening symptoms.
2 If dose reduction is required, the suggested dose is approximately 50% lower than the dose 
previously administered.
3 Activities of daily living (ADL)
4 Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in 
management of stomatitis as they may worsen mouth ulcers.


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Table 6-11
Dosing guidelines for study drug-related hematologic toxicities
Adverse event
Severity1
Everolimus Dose Adjustment
Platelet count 
decreased 
(Thrombocytopenia)
Grade 1
(<LLN-75.0x109/L)
No dose adjustment required.
Grade 2
(<75.0-50.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate everolimus at the same dose.
Grade 3
(<50.0-25.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate everolimus at a lower dose.
Grade 4
(<25.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate everolimus at a lower dose.
Neutrophil count 
decreased 
(Neutropenia)
Grade 1
(<LLN-1.5x109/L)
No dose adjustment required.
Grade 2
(<1.5-1.0x109/L)
No dose adjustment required.
Grade 3
(<1.0-0.5x109/L)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.0x109/l).
Re-initiate everolimus at the same dose.
Grade 4
(<0.5x109/L)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.0x109/l).
Re-initiate everolimus at a lower dose.
Febrile neutropenia
Grade 3
(ANC<1.0x109/L 
with single 
temperature >38.3°
C (101°F)
or sustained 
temperature ≥38°C 
(100.4°F) for >1h)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.25x109/l) and no fever.
Re-initiate everolimus at a lower dose.
Grade 4
(Life-threatening 
consequences; 
urgent intervention 
indicated)
Discontinue everolimus.
Any hematologic toxicity requiring study 
drug interruption for >28 days
Discontinue everolimus.
1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03
6.3
Patient numbering, treatment assignment or randomization
6.3.1
Patient numbering
Each patient is identified in the study by a Patient Number that is assigned when the patient is 
first enrolled for screening and is retained as the primary identifier for the patient throughout 
her entire participation in the trial. The Patient No. consists of the Center Number (Center No.) 
(as assigned by Novartis to the investigative site) with a sequential patient number suffixed to 
it, so that each subject is numbered uniquely across the entire database. Upon signing the 
informed consent form, the patient is assigned to the next sequential Patient Number.


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6.3.2
Treatment assignment for oral stomatitis therapy
Upon diagnosis of stomatitis, patients in countries where the alcohol-free 0.5mg/5ml 
dexamethasone oral solution is commercially available, will be randomized in 1:1 ratio to take 
either 0.5mg/5ml dexamethasone mouth rinse or standard of care at the patient’s center. The 
assignment of a patient to a particular cohort will be coordinated by the sponsor. A 
randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management and the Biostatistician. The randomization list will be reviewed by a 
Biostatistics Quality Assurance Group and locked by them after approval.
During the Extension Phase, standard of care at the patient’s site as recommended by the 
investigator to treat stomatitis will be followed.
6.3.3
Treatment blinding
This is an open-label trial, treatment will not be blinded.
6.4
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
Table 6-12
Preparation and dispensing
Study treatments
Dispensing
Preparation
Everolimus (RAD001)
Tablets including instructions for 
administration are dispensed by study 
personnel on an outpatient basis. 
Patients will be provided with adequate 
supply of study treatment for self-
administration at home until at least 
their next scheduled study visit.
Refer to local product information
Letrozole
Oral tablets
Refer to local product information
Exemestane
Oral tablets
Refer to local product information
dexamethasone
Oral solution
Refer to local product information
6.4.1
Study drug packaging and labeling
Everolimus can be provided with locally available commercial material or centrally as needed. 
It will be supplied and labeled accordingly to comply with the legal requirements of local 
Health Authority regulations in each country. Medication labels for the centrally provided 
everolimus (RAD001), under the responsibility of Novartis DSM will comply with the legal 
regulations of each country and be printed in local language. Everolimus (RAD001) will be 
open-label to allow patients to take medication at home. For countries where the study 
medications are supplied by Novartis DSM, the supplies will be sent as open-label bulk 
supply. The storage conditions for study drug will be described on the medication label. 
Commercially available letrozole and exemestane will be supplied to sites or prescribed to 


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patients in accordance with local regulations in participating countries. The storage conditions 
will be described on the medication label.
Table 6-13
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Everolimus (RAD001)
Tablets in blister packs
Labeled as Everolimus (RAD001); 2-
5mg tablets to be taken orally
Letrozole
Refer to local product information
2.5mg tablets to be taken orally. Refer 
to local product information
Exemestane
Refer to local product information
25mg tablet to be taken orally. Refer to 
local product information
dexamethasone (for 
patients randomized to 
dexamethasone 
treatment)
Refer to local product information
0.5mg/5ml Oral solution to be swished 
and expectorated 3 times per day for 
duration of stomatitis. Refer to local 
product information for additional details
6.4.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels.
Table 6-14
Supply and storage of study treatments
Study treatments
Supply
Storage
Everolimus (RAD001)
Locally or centrally supplied by 
Novartis as needed
Refer to study treatment label
Letrozole
Locally supplied by Novartis as 
needed or by prescription in 
applicable countries
Refer to local product information
Exemestane
Locally supplied by Novartis as 
needed or by prescription in 
applicable countries
Refer to local product information
0.5mg/5ml 
dexamethasone
Supplied via prescription in 
countries where it is 
commercially available
Refer to local product information.
6.4.3
Study drug compliance and accountability
6.4.3.1
Study drug compliance
Study drug compliance will be assessed by the investigator and/or study personnel using pill 
counts at each patient visit and information provided by the patient and/or caregiver will be 
captured in the Drug Accountability Form. This information must be captured in the source 
document at each patient visit.


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6.4.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drug in a drug accountability log. Drug accountability will be noted by the field
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study drug and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study drug, packaging, drug labels, and a copy of the completed 
drug accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
6.4.3.3
Handling of other study treatment
Storage conditions for letrozole, exemestane and dexamethasone will be described on the 
medication label.
6.4.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1, Table 7-2 and Table 7-3 lists all of the assessments and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be supported 
in the patient’s source documentation. No CRF will be used as a source document.


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Table 7-1
Visit evaluation schedule (Core Phase: First line treatment)
Category
Reference 
to Section
Screening/
Baseline
Cycles
1 cycle = 28 days*
End of treatment 
(EoT) for first 
line treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
C1
C2
C3
Subsequent 
cycles
Visit Number
1
2
3
4
5,6,7…
777
501
778
Day of cycle
-28 to -1
1
1
1
1
Last dose + ≤15 
days
Last 
dose + 
28 days
Obtain Informed 
Consent
D
7.1.1.1.
X
Eligibility checklist
S
7.1.1.1.
X
Patient history:
Demography
D
7.1.1.4.
X
Inclusion/exclusion 
criteria
S/D
5.2.
5.3.
X
Relevant medical 
history/current 
medical conditions
D
7.1.1.4.
X
Diagnosis and extent 
of cancer
D
7.1.1.4.
X
Prior antineoplastic 
therapy
D
7.1.1.4.
X
Prior/concomitant 
medications
D
7.1.1.4.
X
Continuous during the study up to 28 days after last treatment
Physical examination:
Physical examination
S
7.2.2.1.
X
X
X
X
Day 1 of 
subsequent 
cycles
X


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Category
Reference 
to Section
Screening/
Baseline
Cycles
1 cycle = 28 days*
End of treatment 
(EoT) for first 
line treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
C1
C2
C3
Subsequent 
cycles
Visit Number
1
2
3
4
5,6,7…
777
501
778
Day of cycle
-28 to -1
1
1
1
1
Last dose + ≤15 
days
Last 
dose + 
28 days
ECOG Performance 
status
D
7.2.2.4.
X
X
X
X
Day 1 of 
subsequent 
cycles
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
Day 1 of 
subsequent 
cycles
X
Vital signs
D
7.2.2.2.
X
X
X
X
Day 1 of 
subsequent 
cycles
X
ECG
D
7.2.2.6.1.
X
As clinically indicated
Pulmonary function 
test (PFTs)
D
7.2.2.7.
As clinically indicated
Laboratory 
assessments:
7.2.2.5.
Hematology
D
7.2.2.5.1.
X
X
X
X
Day 1 of 
subsequent 
cycles
X
Chemistry
D
7.2.2.5.2.
X
X
X
X
Day 1 of 
subsequent 
cycles
X
Coagulation
D
7.2.2.5.3.
X
As clinically indicated


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Category
Reference 
to Section
Screening/
Baseline
Cycles
1 cycle = 28 days*
End of treatment 
(EoT) for first 
line treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
C1
C2
C3
Subsequent 
cycles
Visit Number
1
2
3
4
5,6,7…
777
501
778
Day of cycle
-28 to -1
1
1
1
1
Last dose + ≤15 
days
Last 
dose + 
28 days
Hepatitis screening 
and monitoring (if 
applicable)
D
7.2.2.5.4.
7.2.2.5.5.
X
Urinalysis
D
7.2.2.5.6.
X
As clinically indicated
Imaging:
7.2.1.
CT or MRI for chest, 
abdomen, pelvis
D
7.2.1.
X
X
Every 8 
weeks
X
only for patients 
discontinuing for 
reasons other 
than documented 
PD, lost to follow 
up and death
X
CT or MRI for Brain
D
7.1.1.4.
X
As clinically indicated
Bone scan or skeletal 
survey
D
7.2.1.
X
X
Every 8 
weeks
If baseline bone scan 
positive perform X-
ray, CT or MRI
D
7.2.1.
X
X
Every 8 
weeks
X
only for patients 
discontinuing for 
reasons other 
than documented 
PD, lost to follow 
up and death


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Category
Reference 
to Section
Screening/
Baseline
Cycles
1 cycle = 28 days*
End of treatment 
(EoT) for first 
line treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
C1
C2
C3
Subsequent 
cycles
Visit Number
1
2
3
4
5,6,7…
777
501
778
Day of cycle
-28 to -1
1
1
1
1
Last dose + ≤15 
days
Last 
dose + 
28 days
Safety:
7.2.2.
Adverse events
D
7.2.2.
Continuous during the study, 
up to 28 days after the last 
treatment
X
Patient reported 
Outcomes – OSDQ
7.2.6.
Complete OSDQ daily during 
every episode of oral 
stomatitis.
Everolimus 
administration
D
6.1.
Daily dosing
Letrozole 
administration
D
6.1.
Daily dosing for FIRST LINE 
TREATMENT ONLY
Study Evaluation 
Completion
D
7.1.6.1.
X
Survival Follow-up
D
7.1.6.2.
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
5.
X
X


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Category
Reference 
to Section
Screening/
Baseline
Cycles
1 cycle = 28 days*
End of treatment 
(EoT) for first 
line treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
C1
C2
C3
Subsequent 
cycles
Visit Number
1
2
3
4
5,6,7…
777
501
778
Day of cycle
-28 to -1
1
1
1
1
Last dose + ≤15 
days
Last 
dose + 
28 days
Category: ‘S’ indicates assessments that produce data that will remain in source documents only.
‘D’ indicates assessments that produce data that will be entered in the clinical database.
Visit assessment window is defined as +/- 3 days except for on-study imaging assessment: +/- 1 week
*Once the patient starts the Extension Phase those indicated will not be performed as part of the main study phase, refer to Table 7-3 for all that will be performed in the 
Extension Phase.
**Survival Follow-up will only be collected until 24 Months post LPFV (date of OS data cutoff)


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Table 7-2
Visit evaluation schedule (Core Phase: Second-line treatment)
Category
Reference 
to Section
Cycles*
1 cycle = 28 days
End of treatment 
(EoT) for second line 
treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
Completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
Cycle 
101
C102
C103
Subsequent cycles
Visit Number
102
103
104
105, 106, 107…
779
501
778
Day of cycle
Day 1 of each cycle
Last dose + ≤15 days
Last 
dose + 
28 days
Inclusion/exclusion 
criteria re-
examination
S/D
7.1.3.
X
Concomitant 
medications
D
7.1.1.4.
Continuous during the study up to 28 days after last treatment
Physical examination
S
7.2.2.1.
Day 1 of each cycle
X
ECOG Performance 
status
D
7.2.2.4.
Day 1 of each cycle
X
Weight
D
7.2.2.3.
Day 1 of each cycle
X
Vital signs
D
7.2.2.2.
Day 1 of each cycle
X
ECG
D
7.2.2.6.1.
As clinically indicated
Pulmonary function 
test (PFTs)
D
7.2.2.7.
As clinically indicated
Laboratory 
assessments:
7.2.2.5.
Hematology
D
7.2.2.5.1.
Day 1 of each cycle
X
Chemistry
D
7.2.2.5.2.
Day 1 of each cycle
X
Coagulation
D
7.2.2.5.3.
As clinically indicated
Urinalysis
D
7.2.2.5.6.
As clinically indicated


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Category
Reference 
to Section
Cycles*
1 cycle = 28 days
End of treatment 
(EoT) for second line 
treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
Completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
Cycle 
101
C102
C103
Subsequent cycles
Visit Number
102
103
104
105, 106, 107…
779
501
778
Day of cycle
Day 1 of each cycle
Last dose + ≤15 days
Last 
dose + 
28 days
Hepatitis testing
D
7.2.2.5.4.
7.2.2.5.5.
Imaging:
7.2.1.
CT or MRI for Brain
D
7.1.1.4.
As clinically indicated
CT or MRI for chest, 
abdomen, pelvis
D
7.2.1.
X
Every 8 weeks
X
only for patients 
discontinuing for 
reasons other than 
documented PD, lost 
to follow up and death
X
If bone scan positive 
perform X-ray, CT or 
MRI
D
7.2.1.
X
Every 8 weeks
X
only for patients 
discontinuing for 
reasons other than 
documented PD, lost 
to follow up and death
Safety:
7.2.2.
Adverse events
D
7.2.2.
Continuous during the study, up to 28 days after the last treatment
X
Patient reported 
Outcomes – OSDQ
7.2.6.
Complete OSDQ daily during every episode 
of oral stomatitis.
Everolimus 
administration
D
6.1.
Daily dosing
Exemestane 
administration
D
6.1.
Daily dosing after initial progression for 
SECOND-LINE TREAMTENT ONLY


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Category
Reference 
to Section
Cycles*
1 cycle = 28 days
End of treatment 
(EoT) for second line 
treatment
28 Day 
Safety 
Follow 
up*
Study 
Evaluation 
Completion*
Survival 
follow 
up**
Post 
Treatment 
Evaluations
Cycle Number
Cycle 
101
C102
C103
Subsequent cycles
Visit Number
102
103
104
105, 106, 107…
779
501
778
Day of cycle
Day 1 of each cycle
Last dose + ≤15 days
Last 
dose + 
28 days
Study Evaluation 
Completion
D
7.1.6.1.
X
Survival Follow Up
D
7.1.6.2.
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
5.
X
X
Visit assessment window is defined as +/- 3 days except for on-study imaging assessment: +/- 1 week.
*Once the patient starts the Extension Phase those indicated will not be performed as part of the main study phase, refer to Table 7-3 for all that will be performed in the 
Extension Phase.
**Survival Follow-up will only be collected until 24 Months post LPFV (date of OS data cutoff).


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Table 7-3
Visit evaluation schedule (Extension Phase)
Category
Reference to 
Section
Visits
(every 12 weeks ±1 week)
End of 
treatment 
(EoT) for 
extension
28 Day 
Safety 
Follow up
Study 
Evaluation 
Completion
Visit Number
EXT Visit 1
EXT Visit 2, EXT Visit 3,
780
501
778
Day of visit
Day 1 of each visit
Last dose 
+ ≤15 days
Last dose 
+ 28 days
Re-consent
S
7.1.4.
X
Adverse events
D
7.2.2.
X
Continuous during the study, up to 28 days after the last 
treatment
Everolimus administration
D
6.1.
X
Daily dosing
Letrozole administration
D
6.1.
X if current 
treatment prior to 
entry in extension
Daily dosing
Exemestane administration
D
6.1.
X if current 
treatment prior to 
entry in extension
Daily dosing
Confirmation of Clinical Benefit 
from investigator
D
7.1.4.
X
At every visit
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5.
X
Study Evaluation Completion
D
7.1.6.1.
X
Hepatitis monitoring (if applicable)
S
7.2.2.5.4.
7.2.2.5.5.
As clinically indicated


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7.1.1
Screening procedures
7.1.1.1
Screening
Prior to performing any screening procedures, the patient must have signed and dated the 
informed consent document. The investigator is obliged to give the patient thorough 
information about the study and the study related assessments and she should be given ample 
time to consider her participation. If a patient is unable to read, an impartial witness should 
present during the entire informed consent discussion. The original signed informed consent 
should be kept in the patient’s source records and a photocopy of the signed consent should be 
provided to the patient.
For details on the screening assessments please refer to Table 7-1. The investigator or 
designee must ensure that only patients who meet all of eligibility criteria are offered 
enrollment on the study. All data for the Inclusion/Exclusion criteria must be verifiable in the 
patient’s source document.
In case the patient does not fulfill all eligibility criteria, the patient will be a screening failure. 
Re-screening of patients is only allowed once per patient within 28 days of the screening 
period. In the case of re-screening, the original patient number assigned to the patient will be 
used and the patient will be identified with the number throughout her entire participation in 
the study.
Patient eligibility will be checked by the Sponsor once all screening procedures are completed. 
The eligibility checklist form will be sent from the site to the Sponsor either via fax or email 
for evaluation. Upon confirmation of eligibility (Key criteria), the Sponsor will return the 
signed eligibility checklist via fax or email to the site. The investigator site will then be 
allowed to proceed with the enrollment of the patient into the trial, providing that all other 
Inclusion/Exclusion criteria are met.
Screening assessments must be done to confirm eligibility prior to the first dose of study drug. 
Laboratory baseline assessments (including hematology, chemistry, coagulation, and 
urinalysis), physical examination including performance status, ECG, height and weight must 
be performed within 28 days prior to first dose of study treatment. Radiological screening 
assessments performed within 28 days of baseline visit can be used for both study eligibility 
and baseline assessments. Screening evaluations performed ≤7 days before the date of the first 
dose of study treatment for all laboratory assessments and ECOG performance status can be 
used as baseline evaluations (i.e., need not be performed on Cycle 1 Day 1). Patients with 
potassium, sodium and/or calcium levels that are below the LLN at screening must have their 
potassium, sodium and/or calcium replenished through supplementation and the levels must 
be within normal limits prior to the first dose of study drug.
Information from procedures that may have been previously performed as part of the patient’s 
routine disease care (prior to enrolling the trial) is allowed to be used to satisfy inclusion 
criteria as long as the procedures were performed within 28 days of study drug start.


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7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Failure Log. The Demography CRF page must also be completed for all screen 
failures. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a Serious Adverse Event during the Screening Phase 
(see Section 8 for SAE reporting details).
7.1.1.3
Hepatitis screening/baseline
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation 
and associated HBV morbidity and mortality (Loomba et al 2008).
7.1.1.3.1 Screening for hepatitis B
Prior to starting trial therapy, the following three categories of patients should be tested for 
hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc 
Ab:
1. All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal and Greece.
(http://nc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849 )
2. Patients with any of the following risk factors:

known or suspected past hepatitis B infection,

blood transfusion(s) prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact with hepatitis B infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,

mother known to have hepatitis B

history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain.
3. Additional patients at the discretion of the investigator
The management guidelines, in Section 6.2.2.3, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B.
7.1.1.3.2 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,


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
current or prior IV drug users,

current or prior dialysis,

household contact of hepatitis C infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,
At the discretion of the investigator, additional patients may also be tested for hepatitis C.
The management guidelines, in Section 6.2.2.3, are provided according to the results of the 
baseline assessment of hepatitis C viral load.
7.1.1.4
Patient demographics and other baseline characteristics
The following patient demographic and baseline characteristics will be collected on the eCRF:

General demography including age, gender, race, ethnic origin

Medical history/current medical conditions (including prior and concomitant medications 
and prior antineoplastic therapies)

History and current disease status (including staging, diagnosis information, hormonal 
receptor and HER2 status, previous anticancer treatments and sites of disease). The 
following information must be collected for all previous anticancer therapies: start date, 
end date, setting (neoadjuvant vs. adjuvant vs. therapeutic), best response, reason for 
treatment discontinuation.

Physical/neurological examination, weight and height

Vital signs including sitting blood pressure, pulse and temperature

ECOG performance status

ECG

Safety laboratory assessments: chemistry, hematology, urinalysis coagulation

HBV testing: prior to enrollment, the categories of patients listed in Section 7.1.1.3 should 
be tested for hepatitis B serologic markers and viral load: HBV-DNA HBsAg, HBcAb, 
and HBsAb. HBVDNA monitoring should be done depending on results from serologic 
markers and viral load as listed in Table 6-6.

HCV testing: patients with hepatitis C risk factors and additional patients at the discretion 
of the investigator should be testing for HCV RNA-PCR test at baseline. For a list of 
hepatitis C risk factors, refer to Section 7.1.1.3. Follow-up testing will be performed, as 
per Section 6.2.2.3, only if the patient has a history or is positive at baseline or both.

Bone scan or skeletal survey

Radiological tumor assessment (CT or MRI for chest, abdomen, pelvis, brain and bone 
scan or skeletal survey); positive areas on bone scans must be assessed by X-ray, CT scan 
with bone windows or MRI
7.1.2
Treatment period
Patients will start study treatment at treatment 1 day 1 (cycle 1 day 1) and continue to be 
treated per protocol until documentation of disease progression or any other reason for which 


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the patient may be discontinued (refer to Section 7.1.5). However, study treatment may 
prematurely be discontinued for other reasons as well.
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and/or information provided by the patient or caregiver. This information should be 
captured in the source document at each visit for all study drugs (everolimus, letrozole and 
exemestane).
To accurately record the administration of study treatments, the following information must 
be recorded on the DAR page of the eCRF throughout the study:

Actual total dose administered

Regimen

Start/End date of drug administration

Dose change/delay and reason for such
7.1.3
Second line treatment
Following disease progression in the first line setting, patients will be offered everolimus in 
combination with exemestane during the Core Phase, during the Extension Phase these 
patients will be discontinued from the study. Patients who discontinued first line treatment 
due to reasons other than disease progression are not eligible for second line treatment.
Informed consent will not be repeated for patients moving into the second line treatment 
period. However, specified inclusion / exclusion criteria must be re-examined (see Section 5.1) 
and collected on the eCRF.
At the determination of documented disease progression (e.g., image scan that determined the 
disease progression) in the first line treatment, the patient must begin second line treatment 
within 28 days.
A complete schedule of evaluations required for the second line treatment period are provided 
in Table 7-2.
The procedures for patients receiving second line treatment will proceed as follows:

Re-examination of specified inclusion/exclusion criteria, see Section 5.1.

ECOG Status

Current concomitant medications

Safety laboratory assessments: chemistry, hematology, urinalysis, coagulation

HBV and HCV testing and monitoring should be continued only for those patients 
identified during enrollment on first line treatment. Testing should be performed as per 
Section 6.2.2.3.

Tumor evaluations will follow the same schedule used in the first line treatment period. If 
the end of treatment tumor evaluations from the first line treatment period that lead to 
documentation of disease progression is <28 days prior to starting the second line 
treatment medication, then the end of treatment tumor evaluations from the first line will 
serve as Cycle 101 day 1 tumor evaluations for second line treatment period


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
All continuing concomitant medications from the first line treatment period will be 
followed into the second line treatment period and will be recorded on the Concomitant 
Medications eCRF

Treatment with everolimus and exemestane in the second line period continues until 
documented disease progression or any other reason for which the patient may be 
discontinued (refer to Section 7.1.5)

When patients discontinue the second line treatment for any reason, an end of treatment 
visit following discontinuation of the second line medication will be performed. The 28 
day follow up visit will also be performed to check on continuing AEs/SAEs or any new 
AEs/SAEs that may have occurred

The first dose of open-label second line study medication begins at Cycle 101 day 1
7.1.4
Extension Phase
Following the overall survival cut-off (24 months post LPFV) and approval of Amendment 5, 
patients continuing to derive benefit from everolimus will be transitioned to an Extension 
Phase until disease progression or any other reason for which the patient may be discontinued 
(refer to Section 7.1.5).
Patients will be re-consented prior to starting the Extension Phase.
Patients must return to the study center on a quarterly basis (12 weeks ± 1 week) for resupply 
of medication at which time drug dispensing information and adverse event information will 
be collected.
A complete schedule of evaluations required for the Extension Phase is provided in Table 7-3.
The procedures for patients entering the Extension Phase will proceed as follows:

Safety laboratory assessments: chemistry, hematology, urinalysis, coagulation will be 
done as clinically indicated

HBV and HCV testing and monitoring should be continued only for those patients 
identified during enrollment on first line treatment. Testing should be performed as per 
Section 6.2.2.3.

Treatment with everolimus and letrozole (1st line) or everolimus and exemestane (2nd line) 
until lack of clinical benefit as assessed by Investigator at the site or any other reason for 
which the patient may be discontinued (refer to Section 7.1.5) Patients entering the 
Extension Phase on 1st line treatment and deemed to no longer be clinically benefiting will 
not be offered 2nd line treatment in the context of this study)

At every quarterly visit, the investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment.
Although formal assessment of efficacy is not required during the Extension Phase, 
confirmation of continued treatment benefit as per standard of care is mandatory.

When patients discontinue the first or second line treatment for any reason, an end of 
treatment visit following discontinuation of the medication will be performed. The 28 day 
follow up visit will also be performed to check on continuing AEs/SAEs or any new 
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7.1.5
End of treatment visit including study completion and premature 
withdrawal
At the time patients discontinue study treatment (in the first line treatment or, if applicable, 
second line treatment and Extension Phase), a visit should be scheduled as soon as possible 
(within 2 weeks), at which time all of the assessments listed for the End of Treatment (EOT) 
visit will be performed. An End of Treatment eCRF page should be completed separately for 
both first and second line treatment for the core study phase, and an End of Treatment eCRF 
for the Extension Phase should be completed for those subjects ending treatment while in the 
Extension Phase. The EOT eCRF will provide the date and reason for stopping the study 
treatment.
If patients refuse to return for an end of treatment visit or are unable to do so, every effort 
should be made to contact them or a knowledgeable informant by telephone to determine the 
primary reason for premature withdrawal from the study and record this information on the 
End of Treatment eCRF page.
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur:

Pregnancy

Discovery of patient ineligibility

Protocol violation or errors in treatment compliance [study treatment, other prescribed or 
non-prescribed medications]

Missed/unscheduled/off-schedule/incomplete/incorrect assessments

Adverse events (including abnormal laboratory value, abnormal test procedure result)

Unacceptable toxicity

Subject withdrew consent

Lost to follow up

Administrative problems

Death

New cancer therapy

Disease progression

Treatment duration completed as per protocol

Discontinuation of everolimus development by Novartis
At a minimum, all patients who discontinue study treatment for any reason, including those 
who refuse to return for a final visit, will be contacted for safety evaluations during the 28 
days following the last dose of study treatment. If patients begin second line treatment < 28 
days after completion of first line treatment, safety evaluations should continue until second 
line treatment begins.
All patients who discontinue treatment due to disease progression should be scheduled for a 
visit as soon as possible (within 2 weeks), at which time all of the assessments listed for the 
End of Treatment visit will be performed. After the 28-day safety follow-up visit, the patient 


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will begin the survival follow up period. At the start of new antineoplastic therapy, the patient 
will complete the Study Evaluation Completion eCRF.
If a patient discontinues treatment for reasons other than progression of disease according to 
RECIST 1.0 (see Appendix 2) tumor imaging evaluations should be performed at the End of 
Treatment visit (along with EOT assessments) unless the last tumor imaging evaluation was 
performed ≤ 4 weeks earlier. This does not apply to the Extension Phase, once the patient 
enters the extension, tumor imaging is no longer required per the study schedule.
All information on the start of a new antineoplastic therapy should be obtained and must be 
recorded in the Antineoplastic Therapies Since Discontinuation of Study Drug eCRF. If 
patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine the patient’s disease 
status or any start of new antineoplastic therapy. The Study Evaluation Completion eCRF 
page should be completed upon the patient’s completion of the study.
7.1.6
Follow up period
All patients must have safety evaluations for 28 days after the last dose of study treatment.
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. The investigator must determine the primary reason for a patient’s premature withdrawal 
from the study and record this information on the End of Treatment or Study Evaluation 
Completion eCRF as applicable.
7.1.6.1
Study evaluation completion
The study evaluation completion eCRF will be completed once all study evaluations are 
completed and patients are only being followed for survival (if applicable).
7.1.6.2
Survival follow up
All patients who discontinued study treatment, have started a new antineoplastic therapy, 
and/or are no longer followed radiologically will be contacted (via telephone) for survival 
information every 12 weeks from the patient’s last visit (which can be the safety follow up 
visit), until death, lost to follow up or withdrawal of consent. The investigator or his designee 
will collect this survival information and any additional antineoplastic therapies for all 
patients until the final survival analysis.
Patients who withdraw consent from participation in study should be asked to consent for 
survival follow up. If applicable, information regarding the death should be captured in the 
eCRF.
Patients completing the Extension Phase will not be followed for survival.


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7.2
Assessment types
7.2.1
Efficacy assessments
Core Phase
Patients should have either at least one lesion that can be measured as per RECIST 1.0 criteria 
OR have bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease 
as defined above.
For patients with measurable disease at baseline (as per RECIST 1.0 criteria), efficacy 
(overall tumor response and progression) will be evaluated every 8 weeks (+/- 1 week) during 
the Core Phase according to the RECIST 1.0 criteria. If an initial observation of response is 
made, a confirmation scan (or photography for measurable skin lesions) should be obtained at 
least 4 weeks after the initial observation. All patients being discontinued from the study for 
disease progression must have their progression documented using the criteria specified in 
Appendix 2. All patients who discontinue study treatment for any reason (i.e., an adverse 
event, administrative reasons etc) other than disease progression or consent withdrawal will 
continue to have tumor assessments per the schedule during the Core Phase until disease 
progression or until new anti-cancer therapy is initiated.
All primary and secondary endpoints based on radiological (and photographical when 
applicable) assessments of tumor burden will be derived using the local (treating centers) 
radiologist’s / investigator’s assessment.
A bone scan or a skeletal survey should be performed at baseline for all patients within 28 
days of enrollment. Any abnormalities (i.e., hotspots) identified on the bone scan must be 
confirmed by X-ray, CT scan with bone windows or MRI. Bone lesions identified at baseline 
should follow the same assessment schedule as for measurable lesions. Additional bone scans 
or skeletal surveys should be performed if clinically indicated. Abnormalities found on 
subsequent bone scans must also be confirmed by X-ray, CT scan or MRI.
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.
If possible, each center should have a designated radiologist responsible for the interpretation 
of CT or MRI scans and the evaluation according to RECIST 1.0 criteria (see Appendix 2 for 
details). The same radiologist/physician should perform the evaluation for the entire duration 
of the study. All radiology evaluations will be performed initially by the local radiologist.


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Table 7-4
Imaging collection plan during Core Phase
Procedure
Screening/Baseline
During Treatment/Follow-up
CT or MRI
(Chest, Abdomen, Pelvis)
Mandated
Mandated, every 8 weeks
(+/- 1 week)
CT or MRI
(brain)
Mandated
As clinically indicated
Bone scan or Skeletal survey (X-
ray, CT or MRI)
Mandated
Mandated, every 8 weeks if 
applicable (Section 7.2.1)
(+/- 1 week)
Extension Phase
During the Extension Phase there will be no efficacy assessments other than physician’s 
determination of whether or not the patient is continuing to derive clinical benefit from the 
study treatment.
7.2.2
Safety and tolerability assessments
Core Phase
Safety assessments will consist of monitoring and recording all adverse events (AEs) 
including serious adverse events (SAEs), the regular monitoring of hematology, serum 
chemistry, routine monitoring of vital signs (heart rate, blood pressure and body temperature), 
weight, ECOG performance status, CT scans and physical conditions. For details on AE 
collection and reporting, refer to Section 8.
Extension Phase
Safety assessments in the Extension Phase will consist of monitoring and recording all AEs) 
including SAEs, refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination will be conducted at screening and day 1 (+/- 3 days) of 
every cycle and as clinically indicated during the Extension Phase. It will include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams 
will be performed.
Significant findings that were present prior to the signing of informed consent for the Core 
Phase of the study must be included in the Relevant Medical History/Current Medical 
Conditions page on the patient’s eCRF. The Relevant Medical History/Current Medical 
Conditions collected at the beginning of the study will serve as baseline for transition to the 
Extension Phase. Significant new findings that begin or worsen after informed consent must 
be recorded on the Adverse Event page of the patient’s eCRF. This is applicable for the 
duration of patient participation including the Extension Phase.


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7.2.2.2
Vital signs
Vital signs will be assessed at screening and day 1 (+/- 3 days) of every cycle and as clinically 
indicated during the Extension Phase. Vital signs will include blood pressure, pulse 
measurements and body temperature. After the patient has been sitting for five minutes, with 
back supported and both feet placed on the floor, systolic and diastolic blood pressure will be 
measured three times using an automated validated device, e.g. OMRON, with an 
appropriately sized cuff. The repeat sitting measurements will be made at 1 - 2 minute 
intervals and the mean of the three measurements will be used. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. Vital signs that may be assessed during the Extension 
Phase will not be collected in the eCRF.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured and as clinically indicated during the Extension 
Phase. (Note: eCRFs are designed to collect the data in the units they are measured in; e.g., 
height in cm or in and weight in kg or lb). Height and Weight that may be assessed during the 
Extension Phase will not be collected in the eCRF.
7.2.2.4
Performance status
ECOG Performance Status will be assessed and recorded at screening or on Treatment Day 1 
(prior to administration of the study drug unless PS in screening was done less than 7 days 
before Day 1), and every cycle thereafter until progression and as clinically indicated during 
the Extension Phase. ECOG performance status that may be assessed during the Extension 
Phase will not be collected in the eCRF.
Assessment of ECOG Performance Status will be performed on the scheduled day, even if 
study medication is being held. The ECOG performance status Scale Index (Oken 1982) 
allows patients to be classified as to their functional impairment, the definition of scores in 
relation to PS is given below:
Table 7-5
ECOG Performance Status Scale
Score
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confirmed to bed or chair.
5
Death


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7.2.2.5
Laboratory evaluations
Table 7-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC 
Morphology with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, 
Calcium, Chloride, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, 
Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Sodium, Potassium, Glucose, 
Phosphorous
Urinalysis
Standard Dipstick:Bilirubin, Blood, Glucose, Ketones, Leukocytes, pH, Protein, 
Specific Gravity
Coagulation
Prothrombin time (PT) or International normalized ratio [INR]), Partial 
thromboplastin time (PTT)
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
The standard clinical laboratory analyses described below are to be performed by the local 
laboratory according to the Visit Schedule. All attempts should be made to obtain scheduled 
laboratory evaluations ≤48 hours of the specified time periods, whether or not study treatment 
is administered. More frequent examinations may be performed at the investigator’s discretion 
if medically indicated; results should be recorded in the eCRFs. Laboratory evaluation that 
may be performed during the Extension Phase will not be collected in the eCRF.
7.2.2.5.1 Hematology
Hemoglobin, hematocrit, platelet count, red blood cells (RBC) count, white blood cell (WBC) 
count with differential including lymphocytes, monocytes, neutrophils, eosinophils, basophils, 
neutrophils will be measured. Hematologic test will be performed at screening, treatment day 
1 and day 1 (+/- 3 days) of all subsequent cycles. In the event of Grade 2, Grade 3 or Grade 4 
hematological toxicities that require study drug dose modifications or interruptions, 
hematological test must be repeated weekly until recovery to the baseline value or Grade 1. 
Any particular clinical finding seen before ICF signature must be documented in the Relevant 
Medical History eCRF. Findings compatible with adverse events after ICF signature must be 
documented in the Adverse Event eCRF.
7.2.2.5.2 Clinical chemistry
Blood urea nitrogen or urea, total bilirubin, direct bilirubin, indirect bilirubin, AST, ALT, 
alkaline phosphatase, sodium, albumin, creatinine, creatine kinase, potassium, bicarbonate, 
chloride, calcium, phosphorous, total protein, triglycerides, total cholesterol, LDL, HDL, 
glucose and uric acid will be measured. Serum chemistries must be performed at screening, 
treatment day 1 and day 1 (+/- 3 days) of all subsequent cycles. In the event of Grade 2, Grade 
3, or Grade 4 non-hematological toxicities that require study drug dose modifications or 
interruptions, biochemistry tests must be repeated until recovery to the baseline value or 
Grade 1. Any particular clinical finding seen before taking ICF signature must be documented 


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in the Relevant Medical History eCRF. Findings compatible with adverse events after ICF 
signature must be documented in the Adverse Event eCRF.
7.2.2.5.3 Coagulation
The prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin 
time (PTT) will be performed at screening and as clinically indicated.
7.2.2.5.4 HBV testing
Prior to enrollment, the categories of patients listed in Section 7.1.1.3 should be tested for 
hepatitis B serologic markers and viral load (local results are acceptable for screening only):

HBV-DNA, HBsAg, HBc Ab, and HBs Ab.

During the treatment period, HBV DNA monitoring should be done depending on results 
from serologic markers and viral load as listed in Table 6-6.

The final monitoring visit for HBV will be at the 28-day safety follow-up.
7.2.2.5.5 HCV testing
Patients with hepatitis C risk factors and at the discretion of the investigator should be tested 
for HCV RNA prior to enrollment (local results are acceptable for screening only). For a list 
of hepatitis C risk factors, refer to Section 7.1.1.3.
Follow-up testing will be performed, as per the visit schedule (see Section 6.2.2.3), only if the 
patient has a history of Hepatitis C. The final monitoring visit for HCV will be at the 28-day 
safety follow-up.
7.2.2.5.6 Urinalysis
A urinalysis will be performed at screening and as clinically indicated. Urinalysis standard 
dipstick test (protein, glucose, blood, ketones,leucocytes, bilirubin, pH and specific gravity) to 
be supplemented with laboratory quantification of any potential laboratory abnormalities. Any 
particular clinical findings seen before ICF signature must be documented in the Relevant 
Medical History eCRF. Findings compatible with adverse events after ICF signature must be 
documented in the Adverse Event eCRF.
7.2.2.5.7 Pregnancy and assessments of fertility
Women enrolled in this trial will be postmenopausal as defined in the inclusion criteria. 
Pregnancy testing will not be performed.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed at screening and if clinically indicated, during the 
study. Tracings must be dated and signed by the investigator (or his/her designee) and filed 
with the subjects’ source documentation. Results from 12-lead ECG should be captured on the 
ECG Evaluation eCRF. Significant findings must be recorded as Relevant Medical History (if 
present before ICF signature). ECG may be repeated at the discretion of the investigator at 


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any time during the study and as clinically indicated, any clinically relevant findings should 
be added to the Adverse Event eCRF. ECG that may be assessed during the Extension Phase 
will not be collected in the eCRF.
7.2.2.7
Pulmonary function tests
Pulmonary function tests (DLCO and room air O2 saturation at rest) will be performed as 
medically necessary if there is evidence of non-infectious pneumonitis. Refer to Table 6-9 for 
management of non-infectious pneumonitis.


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Other assessments
7.2.6
Patient reported outcomes
Patient reported outcome (PRO) and impact of oral stomatitis burden on patient’s daily living 
will be evaluated using the Oral Stomatitis Daily Questionnaire (OSDQ). The PRO will be not 
be administered during the Extension Phase. Completion of the PRO questionnaire will be 
dependent on the availability of OSDQ in the local language. The OSDQ is a patient self-
administered 6-item questionnaire with a 24-hour recall period. Sample of the questionnaires 
can be found in the Appendix 1.
The OSDQ is an oral stomatitis-specific exploratory questionnaire developed for the purpose 
of this study. It is based on prior work by Stiff et al (2006) who developed and validated the 
Oral Mucositis Daily Questionnaire (OMDQ) to assess impact of oral mucositis on pain and 
daily functioning in patients undergoing autologous hematopoietic stem cell transplantation 
(HSCT). Although the OMDQ is available in the public domain (personal communication 
with the author, March 2012), it does not readily meet the need of this study as it contains 
diarrhea items more sensitive in measuring the symptoms intrinsic to the HSCT setting.
At the first episode of stomatitis, an OSDQ booklet will be handed out to patients at the study 
site upon confirmation of an oral stomatitis diagnosis. The booklet will contain 28 copies of 
the OSDQ, marked from Day 1 to Day 28, to be filled out by the patient up to 28 consecutive 
days, as long as the episode continues. During first episode of oral stomatitis, Day 1 OSDQ 
should be filled out on site by the patient. The patient should be given sufficient space and 


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time to complete the questionnaire. The site personnel should check the OSDQ for 
completeness and ask the patient to complete any missing responses but should not guide 
them in any way in their responses. Patient’s refusal to complete all or any part of the Day 1 
OSDQ should be documented in the study data capture system and should not be captured as a 
protocol deviation.
Booklets should be returned to site by patient at next scheduled visit and site should remind 
the patient to bring booklet with her. Site personnel will then give the patient a new OSDQ 
booklet. For patients who withdraw from study because of an oral stomatitis adverse event, 
effort should be made by site to collect the OSDQ on day of exit visit and to collect the 
OSDQ booklet back from the patient. OSDQ should be completed in the language most 
familiar to the patient. The original OSDQ booklet will be kept with the patient’s file as the 
source document. For subsequent episodes of stomatitis patients will be instructed to contact 
the physician. Upon telephone confirmation, they will be instructed to utilize the same 
treatment they were assigned to after the first episode and fill in the OSDQ booklet as above.
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. Please refer to Section 6.1 for the protocol specific 
definition of study treatment.
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 medication(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 Relevant Medical History/Current 
Medical Conditions of the patient’s CRF. Adverse event monitoring should be continued for 
at least 28 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. Adverse 
events will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through End of 
Treatment eCRF, Study Evaluation Completion eCRF and/or Survival information.


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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 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates or Ongoing at End of Study)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
or
Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken 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.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.0 criteria for solid tumors), should not be reported as a 
serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
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 


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sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 28 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 28 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. 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.


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable Sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Chief Medical Office and Patient Safety (CMO&PS) department.
The telephone and telefax number of the contact persons in the local department of CMO&PS, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis CMO&PS department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that 
this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Pregnancies
Postmenopausal women will be enrolled in this trial, there will be no pregnancy testing for 
patients enrolled in this study. Women of child bearing potential are not permitted to enroll.
8.4
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.
8.5
Data Monitoring Committee
A Data Monitoring Committee will not be used for this trial.


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8.6
Steering Committee
The steering committee will be established comprising investigators participating in the trial 
and Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 


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assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff, including data from the Oral Stomatitis Daily Questionnaires, for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The data analysis will be performed by Novartis and/or a designated CRO. It is planned that 
the data from all centers participating in the trial will be combined, so that an adequate 
number of patients are available for analysis. Any data analyses performed independently by 
any investigator should be submitted to Novartis before publication or presentation.


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10.1
Analysis sets
10.1.1
Full Analysis Set
The primary efficacy population is defined as the Full Analysis Set (FAS), which consists of 
all patients to whom the first line study treatment has been assigned. All primary efficacy 
analyses will be evaluated based on data from this population.
For second line efficacy analyses a subset of the FAS will be used and referred to as Full 
Analysis Set 2nd line (FAS-2L), which consists of all patients in the FAS who received at least 
one dose of 2nd line study medication.
10.1.2
Safety Set
The Safety Population includes all patients who received at least one dose of study medication 
and had at least one post-baseline safety assessment.
The safety analysis for the second line will be performed on the subset of patients receiving at 
least one dose of second line medication. This subset will be referred to as Safety Population 
2nd line (Safety 2L). Note: the statement that a patient had no adverse events (on the adverse 
event eCRF), constitutes a safety assessment.
10.2
Patient demographics/other baseline characteristics
Baseline demographics and disease characteristics data will be listed and summarized for both 
first line and second line using the FAS and FAS-2L, as appropriate for the study and the 
Extension Phase. Qualitative data, such as gender, race, etc, will be presented by contingency 
type tables. Descriptive summary statistics (e.g. frequency, mean, median, range and standard 
deviation) will be used to present numeric data.
10.3
Treatments (study drug, concomitant therapies, compliance)
10.3.1
Study medication
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
separately for each study treatment both in first line (everolimus and letrozole) and second 
line treatment (everolimus and exemestane), as appropriate for the core and the Extension 
Phase. The number of patients with dose changes/interruptions will be presented, along with 
reasons for the dose change.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized by Anatomical Therapeutic Chemical Classification 
System (ATC) term and preferred term by means of frequency counts and percentages. These 
summaries will include medications starting on or after the start of study treatment or 
medications starting prior to the start of study treatment and continuing after the start of study 
treatment. Concomitant medications will not be collected during the Extension Phase.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed.


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The safety population will be used for all above mentioned concomitant medication tables and 
listings.
10.4
Primary objective
The primary objective is to estimate the progression-free survival in patients treated with 
everolimus + letrozole in the first line setting.
10.4.1
Variable
The primary efficacy endpoint in this study is PFS, defined as the time from the date of 
enrollment to the date of first documented progression or death due to any cause. If a patient 
has not had an event, PFS will be censored at the date of the last adequate tumor assessment. 
See RECIST, Appendix 2. The primary efficacy endpoint will be assessed as per local 
radiological assessment.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy endpoint, PFS, will be analyzed based on the data from FAS. The 
median PFS as well as the 25th and 75 quartile will be estimated using the Kaplan-Meier 
method and presented along with 95% confidence intervals.
10.4.3
Handling of missing values/censoring/discontinuations
In this study the primary analysis of PFS for first line treatment will be performed 12 months 
after the last patient’s recruitment. The analysis of PFS for second line treatment will be 
performed 6 months later (18 months after the last patient’s recruitment) provided that the 
number of patients in second line treatment is adequate for a reliable PFS analysis. Otherwise, 
this analysis will be performed 24 months after the last patient’s recruitment. For the analyses, 
PFS will be censored on the date of last adequate tumor assessment, if no PFS event is 
observed before the cut-off date or before the date a new anti-neoplastic therapy or another 
investigational treatment for cancer is started, whichever occurs earlier. If a PFS event is 
observed after two or more missing or non-adequate tumor assessments, then the date of 
progression will be censored at the latest occurring evaluable tumor assessment. If a PFS 
event is observed after a single missing or non-evaluable tumor assessment, the actual date of 
event will be used.
10.5
Secondary objectives
The secondary objective in this study is to determine the overall response rate and clinical 
benefit rate of everolimus + letrozole in the first line setting. Additionally, the median 
progression free survival and clinical benefit rate of everolimus + exemestane in 2nd line 
population will be evaluated. Additional secondary objectives are to evaluate the safety of 
everolimus + letrozole in the first line settingand to evaluate the safety of everolimus + 
exemestane in the second line setting. For the Extension Phase, the proportion of patients with 
clinical benefit will be reported and long term safety as assessed by the occurrence of 
AEs/SAEs will be evaluated.


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The overall survival of patients treated with everolimus + letrozole in the first line setting will 
also be evaluated.
10.5.1
Overall response rate and clinical benefit rate in first line
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) according to RECIST version 1.0 (see 
Appendix 2). Clinical benefit rate (CBR) is defined as the proportion of patients with best 
overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer 
according to RECIST. ORR and CBR will be calculated based on the FAS, using local 
radiologist’s/investigator’s tumor assessment.
Patients with only non-measurable disease at baseline will be included in the numerator for 
ORR if they achieve a complete response and in the numerator for CBR if they achieve a 
complete response or stable disease lasting 24 weeks or longer. Proportions of subjects with 
ORR and CBR will be presented along with exact 95% confidence intervals (Clopper and 
Pearson 1934). The above analyses will also be repeated based on the data from subset of 
patients with only measurable disease at baseline.
10.5.2
Progression free survival in second line
Progression-free survival in the second line (PFS-2L) is defined as the time interval between 
start of 2nd line treatment and documented disease progression or death due to any cause 
reported during or after second-line treatment. The median PFS in the second line will be 
estimated using the Kaplan-Meier method and presented along with 95% confidence intervals.
10.5.3
Overall response rate and clinical benefit rate in second line
The analysis described in Section 10.5.1 will be repeated on FAS-2L population to estimate 
the ORR and CBR of the second line study treatment.
10.5.4
Overall survival (OS)
The overall survival (OS) following first line treatment with Everolimus + Letrozole is 
defined as the time from the date enrollment to date of death due to any cause. The OS 
analysis will be performed 24 months after the last patient’s recruitment. If a death has not 
been observed by the date of analysis cutoff, then OS will be censored at the date of last 
contact. The analysis for OS will be based on the data from FAS. The median OS as well as 
the 25th and 75th quartile will be estimated using the Kaplan-Meier method and presented 
along with 95% confidence intervals.
10.5.5
Other secondary objective
10.5.5.1 Therapeutic intervention for stomatitis
The secondary objective, to evaluate a therapeutic intervention to reduce the severity and 
duration of stomatitis, will be performed using the PRO questionnaire OSDQ data from 
patients in FAS who had an incidence of stomatitis while on study and were enrolled in 
countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution is commercially 
available. The analysis for this objective will be based on PRO data for the first incidence of 


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stomatitis AE. The mean, standard deviation and 95% confidence interval of each severity 
items in the questionnaire will be calculated at each day for the two therapeutic interventions 
for stomatitis groups and presented graphically. The duration of the first stomatitis incidence 
will be calculated using the dates reported in the PRO, the median duration with 95% 
confidence interval of the first stomatitis AE will be estimated using Kaplan-Meier method 
for the two therapeutic interventions for stomatitis groups. As supportive analysis, the median 
duration will also be estimated using the duration calculated from start dates and end dates 
reported in AE CRFs.
As an exploratory analysis, sensitivity analysis for duration and severity may be performed on 
PRO data from multiple occurrences on the same patient. In this analysis appropriate methods 
will be used to account for within patient correlation.
The PRO will be not be administered during the Extension Phase.
10.5.5.2 Safety
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs) will be considered as appropriate. All safety data collected will 
be listed. For all safety analyses, the safety population will be used. The safety summary 
tables will include only assessments collected no later than 28 days after study drug 
discontinuation.
10.5.5.2.1
Adverse events (AE)
All adverse events recorded during study the core study phase and cumulatively reporting 
core and Extension Phase will be summarized. The incidence of treatment emergent adverse 
events will be summarized by system organ class, severity (based on CTCAE grades), type of 
adverse event, relation to the study drug by treatment group. Deaths reportable as SAEs and 
non-fatal serious adverse events will be listed by patient and tabulated by type of adverse 
event and treatment group. Adverse events will be summarized by presenting the number and 
percentage of patients having any adverse event in each body system and having each 
individual adverse event. Any other information collected (e.g., severity or relatedness to 
study medication) will be listed as appropriate. In addition, adverse events of related nature 
may be analyzed by categories regrouping the relevant preferred terms, as appropriate.
10.5.5.2.2
Laboratory abnormalities
All laboratory values collected during the core study phase will be converted into SI units and 
the severity grade calculated using appropriate common toxicity criteria (CTCAE). A listing 
of laboratory values will be provided by laboratory parameter, patient, and treatment group. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by parameter and treatment group.
Laboratory data will be classified into CTC grades according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0. A severity grade of 0 will be 
assigned when the value is within normal limits. In the unlikely case when a laboratory 


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normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory value will still 
be taken as within normal limits and assigned a CTC grade of zero. Besides listings, the 
following summaries will be produced for the laboratory data (by laboratory parameter and 
treatment):

Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed post 
baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades. For 
laboratory parameters where CTC grades are not defined, shift tables to the worst post 
baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges.
10.5.5.2.3
Other safety data
Data from other tests (e.g. vital signs) collected during the Core Phase will be listed, notable 
values will be flagged, and any other information collected will be listed as appropriate. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration.
10.5.5.3 Extension Phase
The secondary objective related to the Extension Phase of the study is to evaluate clinical 
benefit as assessed by the Investigator. Proportion of patients with clinical benefit as assessed 
by the Investigator will be summarized at scheduled visits.
10.7
Interim analysis
No formal interim analysis is planned.


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10.8
Sample size calculation
The sample size is calculated based on an estimate of median PFS with reasonable accuracy 
(width of 95% confidence interval) for first line treatment with everolimus in combination 
with anastrozole or letrozole. The progression-free survival (PFS) for the population of 
patients treated with anastrozole or letrozole alone as first line therapy is approximately 9 
months (Mouridsen et al 2003, Bonneterre et al 2001). Combining everolimus, the median 
PFS is expected to increase to 11 – 14 months. Considering a recruitment period of 18 months
(1.5 years) and one year of follow up after the last patient is enrolled the expected 95% CIs 
for median PFS for 200 patients with 10% lost to follow-up, are provided in the table below 
for median PFSs of 11, 12, 13 and 14 months.
Median PFS
Expected 95% CI
95% CI width
11 months
9.32, 12.98
3.66
12 months
10.13, 14.22
4.09
13 months
10.93, 15.46
4.53
14 months
11.73, 16.71
4.98
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s 
originalInformed Consent for the Core Phase was actually obtained will be captured in their 
CRFs; the date for any subsequent reconsent will be stored in the source document


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Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.2.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The 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 


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


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site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.
13
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Yue W, Fan P, Wang J, et al (2007). Mechanisms of acquired resistance to endocrine therapy 
in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol; 106:102-110.
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cells.Neuroendocrinology; 85(1):54-60.


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14
Appendices
14.1
Appendix 1: Oral Stomatitis Daily Questionnaire (OSDQ)
Oral Stomatitis Daily Questionnaire
The following questions ask about the effect of your mouth and throat soreness on your ability 
to perform regular daily activities. By mouth and throat soreness we mean any inflammation 
of the mouth and throat, with redness, irritation, and/or swelling or mouth ulcers. Think about 
the current episode of mouth and throat soreness only. This questionnaire includes 6 questions. 
Please reserve some time (5 minutes) for answering the questions. Answer every question by 
selecting the answer as indicated. If you are unsure about how to answer a question, please 
give the best answer you can. Try to respond to questionnaire each day at same of the day.
Table 14-1
Oral Stomatitis Daily Questionnaire
1. What is the date today?
DD – MM – YYYY
1b. When did you experience the first symptoms 
of mouth and throat soreness?
(only ask this question on Day 1 of the 
questionnaire)
DD – MM – YYYY
2. How would you rate your OVERALL HEALTH during the PAST 24 HOURS?
Worst possible
Half-way 
between
Perfect health
worst possible and perfect health
0 1 2 3 4 5 6 7 8 9 10
CIRCLE A NUMBER
3. During the PAST 24 HOURS, how much MOUTH AND THROAT SORENESS did you have?
CIRCLE A NUMBER
4. During the PAST 24 HOURS, how much did MOUTH AND THROAT SORENESS limit you in each 
of the following activities?
CIRCLE A NUMBER for each question


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1. What is the date today?
DD – MM – YYYY
5. During the PAST 24 HOURS, how severe was the PAIN in your MOUTH?
No pain at all
Unbearable pain
__________________________________________
0 1 2 3 4 5 6 7 8 9 10
CIRCLE A NUMBER
6. During the PAST 24 HOURS, how much did your MOUTH AND THROAT SORENESS affect your 
ability to do your regular daily activities?
By regular activities, we mean the usual activities you do, such as employment (working for pay), work 
around the house, shopping, childcare, exercising, studying, etc. Think about times you were limited in 
the amount or kind of activities you could do and times you accomplished less than you would like. If 
MOUTH AND THROAT SORENESS affected your activities only a little, choose a low number. 
Choose a high number if MOUTH AND THROAT SORENESS affected your activities a great deal.
Consider only how much during the PAST 24 HOURS, MOUTH AND THROAT SORENESS affected 
your ability to do your regular daily activities.
Had no effect on my daily activities Completely prevented me from doing my daily activities
__________________________________________
0 1 2 3 4 5 6 7 8 9 10
CIRCLE A NUMBER


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14.2
Appendix 2: Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST version 1.0)
Harmonization of efficacy analysis of solid tumor studies
Authors (Version 2):
Authors (Version 1):
Document type:
TA Specific Guideline
Document status:
Final
Version 2: 18-Jan-2007
Version 1: 13-Dec-2002


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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
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Report Analysis Preparation
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


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14.2.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000).
The efficacy assessments described in Section 14.2.2 and the definition of best response 
(Section 14.2.9) are based on the RECIST criteria but also give more detailed instructions and 
rules for determination of best response. Section 14.2.10 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions, as the RECIST criteria 
do not define these variables in detail. Section 14.2.19 of this guideline describes data 
handling and programming rules. This section may be used in the analysis plan(s) to provide 
further details needed for programming.
14.2.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16).
It is assumed that all information which is considered for assessment of the tumor is captured 
in the RECIST eCRF, i.e. not merged from several sources.
14.2.3
Eligibility
Using RECIST criteria implies that only patients with measurable disease at baseline should 
be included in the study:

Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.
If patients without measurable disease are allowed to be included in the study (when the 
primary endpoint is not the objective tumor response), please adapt the sentence accordingly.

Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter 20 mm using conventional techniques or 10 mm with spiral CT 
scan (with minimum lesion size no less than double the slice thickness).

Non-measurable lesions - all other lesions, including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by 
imaging techniques, and cystic lesions.
If any of lesion should be handled differently, this must be clearly stated and justified in the 
protocol, e.g. tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable, and the conditions under which such lesions should be considered 
must be defined in the protocol when appropriate.


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14.2.4
Methods of tumor measurement
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation, 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.
If different window for baseline assessments is allowed in the protocol this must be justified 
in the protocol.

The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

CT and MRI: CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT and MRI 
should be performed with cuts of 7.5 mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 5 mm contiguous reconstruction algorithm. This applies to 
tumors of the chest, abdomen and pelvis. To calculate the sum of all target lesions, their 
size must be entered throughout the study. Actual measurement of each lesion should be 
entered in the eCRF regardless of the size of the measurement. A size of 0 mm should 
only be entered if the lesion completely disappeared. If a very small lesion cannot be 
reliably measured because of its size, it is recommended to enter the minimum lesion size 
(e.g. 5 mm for spiral CT). 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.
If head and neck tumors and those of extremities are evaluated in the study, please specify the 
methods in detail in the protocol.

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.

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. 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.


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If tumor markers are used in the study for the response assessment, the criteria must be clearly 
stated in the protocol and the presence of abnormality in tumor markers be entered in the 
eCRF page for RECIST evaluations (see also Section 14.2.6).

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).
When pathological response is being used, the protocol must clearly state details on how 
pathological responses are documented.

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.
If the protocol is considering specific symptoms as objective signs of clinical progression, e.g. 
bone pain or GI bleeding, then the criteria for clear worsening of these non-measurable 
‘lesions’ indicative of PD should be clearly specified in the protocol. In that case, the protocol 
should clearly specify that additional criteria are used to complement RECIST criteria.
14.2.5
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, 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).
A sum of the longest diameter for all target lesions will be calculated and reported as the 
baseline sum of the longest diameter. The baseline sum of the longest diameter will be 
used as reference by which to characterize the objective tumor response.

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.
If the protocol is considering specific symptoms for assessment of the tumor, e.g. bone pain or 
GI bleeding, then these symptoms are to be entered as non-target lesions with either presence 
or absence or as a new lesion (based on protocol specified criteria). In that case, the protocol 
should clearly specify that additional criteria are used to complement RECIST criteria.


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For cancers which are known to metastasize in bone, the protocol should specify if and how 
bone lesions should be handled, e.g. if they are not identified only at baseline and end of study 
by scintigram but also followed throughout the study by bone X-ray or CT scan.
If no measurable lesions are identified at baseline, the patient is not evaluable for RECIST. 
Therefore, the Guideline leaves the decision to the study teams to determine how to handle 
time to event endpoints, e.g. in the metastatic setting non-target lesions could be followed for 
PFS/ TTP.
14.2.6
Evaluation of target and non-target lesions
To assess tumor response, the sum of the longest diameter 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 14-2) and non-target lesions (Table 14-3) identified at 
baseline. These evaluations are then used to calculate the overall lesion response considering 
both the target and non-target lesions together (Table 14-4) as well as the presence or absence 
of new lesions.
The response for non-target lesions is CR only if all non-target lesions which were evaluated 
at baseline are now all absent. If any of the non-target lesions is still present, the response can 
only be ‘Incomplete response/Stable disease’ 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).
If tumor markers are used as non-target lesions to evaluate response, please specify criteria for 
CR, SD and PD in the protocol, e.g. CR=’Normalization of tumor marker level’, 
PD=’Elevation of tumor markers to certain level’, SD=’Not qualifying for CR or PD’. These 
criteria are indication and study specific. In that case, the protocol should clearly specify that 
additional criteria are used to complement RECIST criteria.
Table 14-2
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all target lesions
Partial Response (PR):
At least a 30% decrease in the sum of the longest diameter of all target 
lesions, taking as reference the baseline sum of the longest diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of the longest diameter of all 
measured target lesions, taking as reference the smallest sum of longest 
diameter of all target lesions recorded at or after baseline.
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.


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Table 14-3
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Incomplete Response/ 
Stable Disease (SD):
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).

The appearance of a new lesion is always associated with Progressive Disease (PD) and 
has to be recorded as a new lesion in the appropriate module of the CRF.

If a 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 has not been possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
two 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 re-appearance 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 14-2 above 
(i.e., a PD will be determined if there is at least 20% increase in the sum of the longest 
diameter of all measured target lesions, taking as reference the smallest sum of 
longest diameter of all target lesions recorded at or after baseline). Proper 
documentation should be available to support this decision.

For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion, which disappeared previously, is considered a PD.
14.2.7
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 14-4.


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Table 14-4
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Incomplete response/SD3
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 14.2.6.
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.
14.2.8
Efficacy definitions
14.2.9
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.
To be assigned a status of 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.
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.

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR).

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).


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The protocol should state if randomization or start of treatment is used as start date (baseline). 
This is then used in all definitions.
If a different minimum follow-up period is required to classify for overall response= ’stable 
disease’, this must be specified in the protocol.

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).
If PD in a different follow-up period is considered overall response=’progressive disease’, this 
must be specified in the protocol.
The protocol should state if discontinuation due to ‘Disease progression’ or death due to study 
indication is considered PD even if this was not accompanied by documentation of PD based 
on tumor measurements. This depends on Phase of the study and the primary endpoint (e.g. 
Phase III studies in which progression-free survival is primary endpoint should consider only 
documented PD, whereas Phase I and II studies may consider all clinical deteriorations PD). 
The following sentence therefore is only applicable if this is specified in the protocol:

Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower status 
other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD.
Once confirmed overall lesion responses of PR must stay the same or improve over time until 
progression sets in, with the exception of a UNK status. However, if a patient has a 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.
Example: The sum of lesion diameters is 20 cm at baseline and then 14 cm - 15 cm - 14 cm -
16 cm - 16 cm 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 14 cm 
confirms the PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (20 cm to 16 cm) at the following 
assessments.
If the patient progressed but continues study medication, 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 
best overall response rate.


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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.
Specify which determination of best overall response will be considered primary (and delete 
the other terms in the text). If a central blinded review is used (e.g. in an open-label study in 
which response is the primary endpoint), the best overall response evaluated by the central 
blinded review will always be considered the primary response.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. Time duration for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee 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 unknown 
assessment at that time point and no PD before, are also considered PD.
14.2.10
Time to event variables
The protocol should state which of the following variables is used in that study.
14.2.11
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.
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 


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patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.2.12
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 contacted, 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 contact.
14.2.13
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.
14.2.14
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.
14.2.15
Duration of response
If the following variables are analyzed, it should be stated that this analysis might introduce a 
bias as it includes only responders. There have been reports where a treatment with a 
significantly higher response rate had a significantly shorter duration of response. The 
analysis of duration of responses should only be used as a descriptive analysis. If they are 
used as inferential comparison between treatments, clear justification must be given in the 
protocol. It should also be stated in the protocol if duration of response is to be calculated in 
addition for unconfirmed response.


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Duration of overall response (CR or PR) applies only to patients whose best overall 
response was CR or PR. 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. Justification must be given in the protocol 
when these endpoints are used for any comparison between treatments.
Duration of overall complete response (CR) applies only to patients whose best overall 
response was CR. 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) applies only to patients whose best overall response 
was SD, PR or CR. The start and end date as well as censoring is defined the same as that for 
time to progression.
14.2.16
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). This analysis will include all 
patients/responders. Patients who did not achieve a confirmed PR or CR will be censored at 
last adequate tumor assessment date when they did not progress (including deaths not due to 
underlying disease) or at maximum follow-up (i.e. FPFV to LPLV used for the analysis) when 
they had an event for progression-free survival.
Time to overall complete response (CR) is the time between date of randomization/start of 
treatment until first documented CR. This analysis will include all patients/responders. 
Patients who did not achieve a confirmed CR will be censored at last adequate tumor 
assessment date when they did not progress (including deaths not due to underlying disease) 
or at maximum follow-up (i.e. FPFV to LPLV used for the analysis) when they had an event 
for progression-free survival.
Indicate whether this analysis should include only the responder (in which case please delete 
‘patients/’ and the sentence on patients who did not respond) or should estimate the time to 
response for the whole study population (in which case please delete ‘/responders’). If both 
methods should be used, please state that in the protocol.
14.2.17
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
State in the protocol if date of randomization or date of start of treatment is to be used for all 
definitions. For randomized studies specify exactly where the randomization date comes from, 


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e.g. from IVRS, or if start of treatment is used as randomization date. For non-randomized 
studies please specify which treatment start date is taken if more than one treatment is to be 
given.
For all “time to event” variables, other than the duration of responses, the randomization/ date 
of treatment start will be used as the start date.
For the calculation of duration of responses the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page, or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.
If applicable, if patients who discontinued due to ‘Disease progression’ are considered to be 
PD solely based on clinical deterioration, then add the following in the protocol:
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of 
disease, the date of discontinuation is used as date of progression.

Date of last adequate tumor assessment is the date the last tumor assessment with 
overall lesion response of CR, PR or SD which was made before an event or a censoring 
reason occurred. In this case the last tumor evaluation date at that assessment is used. If no 
post-baseline assessments are available (before an event or a censoring reason occurred) 
the date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.2.18).
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 corresponds 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 contact date from that survival follow-up page is used. If no 
survival follow-up is available, the date of discontinuation is used as last contact date.
In comparative studies with long follow-up period and therefore extended visit schedule, it 
may be useful to collect the survival status at a pre-specified cut-off within a limited 
timeframe for all patients with no documented death. In this case, this requires a contact to be 


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made with the patient or with any reliable source of information on the patient’s status, but 
not requiring a specific visit to be scheduled

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
If this is applicable for the study, it should be specified in the protocol if new cancer therapy 
is considered an event or endpoints are censored.
14.2.18
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well is 
addressing 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 analysis 
plan 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 14.2.17, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics-April 
2005) as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression)1
(1) = default unless specified differently 
in the protocol or analysis plan
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment
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
Censored
Censored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP)
1 = Definitions can be found in Section 14.2.17.
2 = After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.2.17.


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The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments:
The primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead 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.
14.2.19
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).


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14.2.20
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).
14.2.21
Treatment and study completion CRFs
If study drug is discontinued, the treatment completion page is to be completed with a visit 
date reflecting the date the discontinuation decision was made, and with the ‘Last known date 
subject took study drug’ and one of the following reasons:

Adverse event(s)

Abnormal laboratory value(s)

Abnormal test procedure results(s)

Protocol violation

Subject withdrew consent

Lost to follow-up

Administrative problems

Death

Disease progression

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
For reasons other than progression (and death) it should be checked if this was not in fact 
progression (especially reasons Adverse Events, Abnormal laboratory value (s), Abnormal 
test procedure result and subject withdrew consent). Also it should be checked if patient 
withdrew consent because of safety issues, in which case reasons Adverse Events, Abnormal 
laboratory value (s), Abnormal test procedure result should be used.
All patients who discontinued study drug for reasons other than documented progression, 
death or lost to follow-up will be followed for progression thereafter (patients who withdrew 
consent might not be followed with regular tumor assessments at the study site, but should 
ideally be followed until progression outside the study site). Ideally, all patients who 
discontinued study drug for progression without documented progression will still be 
followed with regular tumor assessments (e.g. in case of central radiology review). During 
that evaluation period, usually only tumor measurements (and/or response status) and survival 
data are collected. In some protocols, the subsequent anti-cancer therapies may also be 
recorded.
At the end of the study evaluation period, the study evaluation completion page is filled out 
with the following options:

Subject withdrew consent

Lost to follow-up


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
Administrative problems (when follow-up for progression has met protocol required 
events, e.g. follow-up stopped at certain number of events or certain time)

Death

New cancer therapy (optional, to be used when follow-up for progression is stopped in this 
case)

Disease progression
Thereafter, patients will be followed for survival using the survival follow-up pages. If 
information on death becomes available for patients who were lost to follow-up or withdrew 
consent, this may also be entered in the database. The reason for death must be documented 
(and will be coded using MedDRA); it must be also stated if death was due to ‘Study 
indication’ or ‘Other’ reason.
In comparative studies with long follow-up period and therefore extended visit schedule, it 
may be useful to collect the survival status at a pre-specified cut-off within a limited 
timeframe for all patients with no documented death. In this case, this requires a contact to be 
made with the patient or with any reliable source of information on the patient’s status, but 
not requiring a specific visit to be scheduled
Until the specified cut-off point has been reached, the goal is to collect tumor assessments 
until disease progression for all patients regardless of whether the patients are still receiving 
study drug. If patients are not followed for progression, e.g. in a Phase I or II study mainly 
evaluating safety, the evaluation is completed when study drug is completed (in this case only 
the first completion page is used).
14.2.22
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’ 
opinion does not match the programmed calculated response based on RECIST criteria. This 
may be queried for clarification. However, the investigator response assessment will never be 
overruled.
If Novartis elect to invalidate an evaluation of overall lesion response 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.


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14.2.23
Programming rules
The following should be used for programming of efficacy results:
14.2.24
Calculation of ‘time to event’ variables
Time to event = enddate - startdate + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as enddate (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.25
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 14.2.17). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.2.26
Incomplete dates for last contact 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.
14.2.27
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)’.
14.2.28
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.29
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 (treatment / study evaluation / survival)

Lost to follow-up (during treatment* / study evaluation* / survival)
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:


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
Ongoing without event (treatment / study evaluation)

Lost to follow-up (during treatment / study evaluation)

Withdrew consent (during treatment* / study evaluation)

Study evaluation stopped (when follow-up for progression is stopped after certain number 
of events or at certain time, i.e. reason=’Administrative problems’ on study evaluation 
completion page, or when patients are not followed for progression after treatment 
completion)

Death due to reason other than underlying cancer (only used for TTP)

New cancer therapy added (optional; only if the protocol specified that PFS/TTP will be 
censored at that date)
*Note = this category is to be used if no further information is available (as information on 
death may be available in patients who were originally lost to follow-up, and information on 
progression may be received in patients who withdrew consent to continue study drug).
14.2.30
References (available upon request)
FDA Guidelines (2005). Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April.
Therasse P, Arbuck S, Eisenhauer E, et al (2000). New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.

SAP_001.pdf: 


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Template Document History – Changes compared to previous version
Date
Version 
number
Summary of changes
21-JUN-
2018
1.0
N/A - First version


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................18
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................18
2.5.4
Supportive analyses...............................................................................18
2.6
Analysis of secondary efficacy objective(s)..........................................................19
2.6.1
Secondary endpoints .............................................................................19
2.6.2
Statistical hypothesis, model, and method of analysis..........................19
2.6.3
Handling of missing values/censoring/discontinuations.......................19
2.7
Safety analyses.......................................................................................................20
2.7.1
Adverse events (AEs)............................................................................20
2.7.2
Deaths....................................................................................................21
2.7.3
Laboratory data .....................................................................................21
2.7.4
Other safety data ...................................................................................21
2.8
Pharmacokinetic endpoints....................................................................................21
2.9
PD and PK/PD analyses.........................................................................................21
2.10
Patient-reported outcomes .....................................................................................21
21
21


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2.13
Interim analysis......................................................................................................21
3
Sample size calculation .....................................................................................................22
4
Change to protocol specified analyses ..............................................................................22
5
Appendix ...........................................................................................................................23
5.1
Imputation rules.....................................................................................................23
5.1.1
Study drug.............................................................................................23
5.1.2
AEdate imputation ................................................................................23
5.2
Other imputations ..................................................................................................24
5.3
AEs coding/grading ...............................................................................................24
5.4
Laboratory parameters derivations ........................................................................25
5.5
Statistical models...................................................................................................25
5.5.1
Primary analysis....................................................................................25
5.5.2
Key secondary analysis.........................................................................25
6
Reference...........................................................................................................................25


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List of Abbreviations
AE 
Adverse Event
ATC
Anatomical Therapeutic Chemical (ATC) Classification System
AUC 
Area Under the Curve
 
BMI
Body Mass Index
BOR
Best Overall Response
BP
Blood Pressure
CBR 
Clinical Benefit Rate
CIs
Confidence Intervals
CR
Complete Response
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or paper
CRO 
Contract Research Organization
CSR 
Clinical Study Report
CT
Computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
 
CYP3A4 
Cytochrome P450 3A4
DI
Dose Intensity
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ER 
Estrogen Receptor
FAS-2L
Second line Efficacy Analyses a Subset of the FAS
FAS 
Full Analysis Set
HER-2 
Human Epidermal Growth Factor Receptor 2
IHC 
Immunohistochemistry
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging 
mTOR 
Mammalian Target Of Rapamycin
o.d.
omnia die/once a day
ORR 
Overall Response Rate
OS 
Overall Survival
OSDQ 
Oral Stomatitis Daily Questionnaire
PD
Progressive Disease
PFS 
Progression Free Survival
PgP 
P-glycoprotein
 
PR
Partial Response 
PS
Performance Status
PT_TXT
Preferred Term
Q1
the 25th Percentile
Q3
the 75th Percentile


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RDI
Relative Dose Intensity
RAP 
Report Analysis Preparation
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
SD
Standard Deviation 
SOC_TXT
Body System/Primary System Organ Class
UNK 
Unknown 
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes the detailed statistical methodology and analyses
for the Extension Phase of the Clinical Study Report (CSR) of study CRAD001Y24135, an 
open-label, phase II, single-arm study of everolimus in combination with letrozole in the 
treatment of postmenopausal women with estrogen receptor positive HER2 negative metastatic 
or locally advanced breast cancer.
The content of this SAP is based on protocol CRAD001Y24135 Amended Protocol Version 5. 
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to database lock of the study data.
1.1
Study design
This is an open-label, phase II, multicenter, international, single-arm trial for patients with ER+, 
HER2- metastatic or locally advanced unresectable breast cancer. Enrolled patients will receive 
everolimus in combination with letrozole in the first line setting until disease progression or any 
other reason for which the patient may be discontinued.  
The study counts 2 phases:

Core Phase: from FPFV to 24 months after LPFV and upon approval of amendment 5; 
safety and efficacy data (including PROs in selected subset) will be collected.

Extension Phase: from the end of the Core Phase (upon approval of amendment 5) to 
LPLV of the Extension Phase for patients that are still deriving benefit at the end of the 
Core Phase. Patients may be transitioned to the Extension Phase and continue to receive 
the drugs up to 3 years or until disease progression or for any other reason the patient 
may be discontinued. Only safety and clinical benefit as assessed by investigator will 
be collected.
During the Core Phase following disease progression in the first line setting, patients will be 
offered everolimus in combination with exemestane. Patients who discontinue treatment in the 
first line setting due to unacceptable toxicity or due to withdrawal of consent will not be offered 
everolimus plus exemestane. Those patients treated in the second line setting will continue 
treatment until disease progression or any other reason for which the patient may be 
discontinued .
All patients who discontinue study treatment will have a 28 day follow up visit for safety and 
will be followed every 3 months thereafter for overall survival after completing treatment in 
either the first or second line treatment setting. 
Patients still benefiting from everolimus following the overall survival cutoff and following 
approval of Amendment 5 may continue treatment in the Extension Phase of the study. Patients 
may continue on their existing line treatment (1st or 2nd) in the extension up to 3 years or until 
the following: disease progression as deemed by physician judgement or any other reason for 
which the patient may be discontinued. Patients entering the Extension Phase on 1st line 


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treatment and deemed to no longer be clinically benefiting will not be offered 2nd line treatment 
in the context of the study. Rather, these patients can start other standard treatments available 
or approved everolimus combination after exiting the study.
The extension will include required safety evaluations and standard of care, per investigator 
discretion and in consultation with the Sponsor.
The study design including Core and Extension Phases is  illustrated  in Figure 1.
The core phase has been reported previously (Primary analysis CSR: 31-Aug-2016; Overall 
Survival CSR: 23-Oct-2017), this is the SAP of the Extension phase of the study. 


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Figure 1 
Study design
1.2
Study objectives and endpoints
The objectives and related endpoints are described in Table 1 below:


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Table 1 
Objectives and related endpoints
Objective
Endpoint
Phase 
Primary:
The primary objective is to estimate progression-free
survival in patients treated with everolimus + letrozole
in the first line setting.
PFS 
Core 
Secondary:
Determine the overall response rate and clinical benefit
rate of everolimus + letrozole in the first line setting
ORR, CBR
Core 
Determine the progression free survival, overall
response rate and clinical benefit rate of everolimus +
exemestane in second line population
PFS, ORR, CBR
Core
Evaluate the safety of everolimus + letrozole in the first
line setting
Incidence of Adverse events
Core
Evaluate the safety of everolimus + exemestane in the
second line setting
Incidence of Adverse events
Core
Estimate the overall survival of patients treated with
everolimus + letrozole in the first line setting
OS
Core
Evaluate a therapeutic intervention to reduce the
severity and duration of stomatitis
Oral Stomatitis Daily Questionnaire 
(OSDQ) data
Core
Evaluate clinical benefit as assessed by the 
Investigator during the Extension Phase
Proportion of patients with clinical 
benefit 
as 
assessed 
by 
the
Investigator at scheduled visits
Extension
Evaluate long term safety data
Frequency and severity of AEs/SAEs
Extension 
2
Statistical methods
2.1
Data analysis general information
The final analysis for the Extension Phase will be performed by 
and reviewed by Novartis. SAS version 9.4 or later will be used to perform all data analyses
and to generate tables and listings.


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Data included in the analysis
During the Extension Phase, there will be no efficacy assessments other than the physician’s 
determination of whether or not the patient is continuing to clinically benefit from the study 
treatment. Safety assessments will consist of monitoring and recording all adverse (AEs), 
including serious adverse events (SAE). All statistical analyses will be performed using all data
collected in the database up to the data cut-off date. All data with an assessment date or event
start date (e.g. vital sign assessment date or start date of an adverse event) prior to or on the
cut-off date will be included in the analysis. Any data collected beyond the cut-off date will
not be included in the analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these cases, the end date will not be imputed and 
therefore will not appear in the listings.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by first- and second-line therapy; a missing category will be included as applicable. Percentages 
will be calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by first-
and second-line therapy.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to everolimus only. Whereas, study treatment will refer to 
everolimus + letrozole and everolimus + exemestane. 
The term investigational treatment may also be referred to as study treatment which is used 
throughout this document.


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Date of first administration of investigational drug
The date of first administration of investigational drug is derived as the first date when a nonzero 
dose of investigational drug was administered and recorded on the dose administration DAR 
eCRF in the first line setting and second line setting respectively.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug was administered and recorded on the DAR eCRF in the first line 
setting and the second line setting respectively.
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the Dosage Administration
(e)CRF. (Example: if 1st dose of Everolimus (RAD001) is administered on 05-Jan-2015, and 1st
dose of combination partner (Letrozole) is administered on 03-Jan-2015, then the date of first 
administration of study treatment is on 03-Jan-2015).
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per Dose Administration (e)CRF. 
(Example: if the last Everolimus (RAD001)  dose is administered on 15-Apr-2014, and the last 
dose of a combination partner (Letrozole) is administered on 17-Apr-2014, then the date of last 
administration of study treatment is on 17-Apr-2014).
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference date for all assessments (safety, efficacy, pk, QoL/PRO, etc.) is the start of 
study treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods 
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 28 days after 
date of last actual administration of any study treatment (including start and stop date)
3. post-treatment period: starting at day 29 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Windows for multiple assessments 
Not applicable.
Last contact date 
Not applicable.
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) consists of all patients to whom the first line study treatment has 
been assigned. All primary efficacy analyses will be evaluated based on data from this 
population. 
For second line efficacy analyses a subset of the FAS will be used and referred to as Full 


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Analysis Set 2nd line (FAS-2L), which consists of all patients in the FAS who received at least 
one dose of 2nd line study medication. 
Safety
The Safety set consists of all patients who received at least one dose of first line study 
medication and had at least one post-baseline safety assessment. 
The safety analysis for the second line will be performed on the subset of Safety set patients 
receiving at least one dose of second line medication. This subset will be referred to as Safety 
set 2nd line (Safety-2L). 
Patients will be analyzed according to the study treatment actually received.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in
Table 2. 
Table 2
Subject classification based on protocol deviations and non-PD criteria
Analysis sets
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS /FAS 2L
No written inform consent
Not applicable
Safety set/ Safety set 2L 
No written inform consent
No dose of study medication 
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.
2.2.1
Subgroup of interest
For the extension  phase no subgroup analyses will be performed. For the detail of the subgroup 
analysis on safety and efficacy on the core phase data please refer to SAP amendment 2 (RAP 
Module 3 Am. 2, 4-MAR-2016) section 2.9.1 and section 2.9.2 respectively.  
2.3
Patient disposition, demographics and other baseline 
characteristics


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The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings. Summaries will be reported by first (FAS) and second-line (FAS 2L) therapy.  
Basic demographic and background data
Baseline demographics and disease characteristics data will be listed and summarized for both 
the first line and the second line using the FAS and FAS-2L.
All demographic and background disease characteristics data will be listed in detail. Qualitative 
data (i.e., gender, race, ECOG performance status, etc.) will be summarized by means of 
contingency tables by the first line and the second line setting and quantitative data (i.e., age, 
body weight, etc.) will be summarized by appropriate descriptive statistics (frequency, mean, 
standard deviation, median, minimum, and maximum) by the first line and the second line.
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. According to the data 
collected on the eCRF, this analysis will include the following: primary site of cancer, details 
of tumor histology/cytology, histological grade, time since initial diagnosis, date of first 
recurrence/metastasis, date of most recent recurrence/metastasis, current disease status, number 
and type of metastatic sites in the current extent of disease, presence/absence of target and non-
target lesions, number and type of organs involved.
The numbers and percentages of patients in categories defined by the following variables 
‘presence/absence of target and non-target lesions’, ‘number of organs involved’ and ‘organ 
types involved’ will be based on the data collected on the radiology RECIST eCRFs, in 
particular, on the individual target and non-target lesion codes. 
Time since initial diagnosis, time since first recurrence/metastasis, as well as time between first 
diagnosis and first recurrence/metastasis will be summarized in months.
Medical history
Reported for Core Phase.  Not applicable for the Extension Phase.
2.3.1
Patient disposition
The number (%) of patients in the FAS who are still on treatment, who discontinued the study 
phases and the reason for discontinuation will be presented:.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment – first line of treatment’ page);

Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment of first line of treatment’ page)

Reasons for study treatment discontinuation (based on ‘End of Treatment of first line of 
treatment’ page).

Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment – second line of treatment’ page);


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
Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment of second line of treatment’ page)

Reasons for study treatment discontinuation (based on ‘End of Treatment of second line of 
treatment’ page).

Number (%) of patients who completed  from the post-treatment evaluations (based on 
‘Study Evaluation Completion’ page); 

Number (%) of patients who discontinued from the post-treatment evaluations (based on 
‘Study Evaluation Completion’ page); 

Reasons for discontinuation from the post-treatment evaluations phase (based on ‘Study 
Evaluation Completion’ page).
Protocol deviations
All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized by
the first line and the second line.
2.4
Treatments 
(study 
treatment, 
rescue 
medication, 
concomitant therapies, compliance)
2.4.1
Study treatment / compliance
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized separately for each study treatment both in first line 
(everolimus and letrozole) and second line treatment (everolimus and exemestane). In addition, 
the duration of exposure to study treatment will be categorized into time intervals; frequency 
counts and percentages will be presented for the number of patients in each interval. 
The safety and safety-2L sets will be used for all summaries and listings of study treatment in 
the first line setting and the second line setting, respectively.
Duration of exposure to study treatment
The following algorithm will be used to calculate the duration of study treatment exposure for 
patients who took at least one dose of any of the components of the study treatment:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first 
administration of study treatment) + 1.
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason).
Duration of exposure to each component of the study treatment will also be calculated.


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The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug or any combination partner (see Section 2.1.1).
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries (<2 months, 2-<4 months, 4-<6 months etc.) and continuous summaries 
(i.e. mean, standard deviation etc.) using appropriate units of time.
Duration of exposure to investigational drug and combination partner
Duration of exposure to investigational drug (days) = (last date of exposure to investigational 
drug) – (date of first administration of investigational drug) + 1.
Duration of exposure to combination partner (days) = (last date of exposure to combination 
partner) – (date of first administration of combination partner) + 1.
Summary of duration of exposure to investigational drug or combination partner in appropriate 
time units will include categorical summaries (<2 months, 2-<4 months, 4-<6 months etc.) and 
continuous summaries (i.e. mean, standard deviation etc.) using appropriate units of time.
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components 
(Everolimus or Letrozole for first line therapy, Everolimus or Exemestane for second line 
therapy). 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.
For patients who did not take any drug the cumulative dose is by definition equal to zero.
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the subject is assumed to have taken a non-zero dose during dosing periods. 
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:


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DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of 
time).
For patients who do not receive any drug, the DI will be set to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to patients 
as per protocol in the same dose unit and unit of time as that of the Dose Intensity. 
Relative dose intensity (RDI), expressed in %, is defined as follows:
RDI = [DI (dosing unit / unit of time) / PDI (dosing unit / unit of time)]*100.
DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of the study treatment exposure, not the duration of each of the components.
2.4.2
Prior, concomitant and post therapies
Not applicable.
2.5
Analysis of the primary objective
The primary objective is to estimate the progression-free survival in patients treated with 
everolimus + letrozole in the first line setting.
2.5.1
Primary endpoint
The primary efficacy endpoint in this study is PFS, defined as the time from the date of 
enrollment to the date of first documented progression or death due to any cause. If a patient 
has not had an event, PFS will be censored at the date of the last adequate tumor assessment. 
The primary efficacy endpoint will be assessed as per local radiological assessment.
Please refer to section 2.6.1 of the SAP for the Core Phase (RAP Module 3 Am. 2, 4-MAR-
2016).
2.5.2
Statistical hypothesis, model, and method of analysis
Please refer to section 2.6.1 of the SAP for the Core Phase (RAP Module 3 Am. 2, 4-MAR-
2016).
2.5.3
Handling of missing values/censoring/discontinuations
Please refer to section 2.6.1 of the SAP for the Core Phase (RAP Module 3 Am. 2, 4-MAR-
2016).
2.5.4
Supportive analyses
Not applicable.


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2.6
Analysis of secondary efficacy objective(s)
Table 1 listed all secondary objectives and secondary efficacy endpoints. This SAP will only 
discuss of the secondary efficacy objectives related to the Extension Phase, which are described 
as follows:

Evaluate clinical benefit as assessed by the investigator during the Extension Phase
All other secondary objectives and secondary endpoints have been detailed in Section 2.6.2 of 
the SAP for the Core Phase (RAP Module 3 Am. 2, 4-MAR-2016).
2.6.1
Secondary endpoints
Proportion of patients with clinical benefit 
Proportion of patients with clinical benefit as assessed by the Investigator will be summarized 
at scheduled visits for the first line treatment on FAS population and the second line treatment 
on the FAS-2L population.
2.6.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.6.3
Handling of missing values/censoring/discontinuations
Not applicable.


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2.7
Safety analyses
All safety analyses will be based on the safety set 1st and 2nd Line (Section 2.2). 
2.7.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational arm.
The following adverse event summaries will be produced by first line or second line therapy; 
overview of adverse events and deaths (number and % of subjects who died, with any AE, any 
SAE, any AE leading to treatment discontinuation), AEs by SOC and PT, summarized by 
relationship (all AEs and AEs related to study treatment), seriousness (SAEs and non-SAEs), 
leading to treatment discontinuation.. 
First-line treatment-emergent adverse events are defined by all AEs reported with a start date 
within the first-line safety time window defined in Section 2.1.1. This will capture both new 
events as well as events which worsened since baseline during the first-line treatment period 
because any change in the severity or seriousness of an ongoing AE is recorded as a new AE in 
the case report form.
Second-line treatment-emergent adverse events are defined by all AEs reported with a start date 
within the second-line safety time window defined in Section 2.1.1. This will capture both new 
events as well as events which worsened since baseline during the second-line treatment period 
because any change in the severity or seriousness of an ongoing AE is recorded as a new AE in 
the case report form.
2.7.1.1
Adverse events of special interest / grouping of AEs
Not applicable. 




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3
Sample size calculation
The sample size is calculated for the core phase and based on an estimate of median PFS with 
reasonable accuracy (width of 95% confidence interval) for first line treatment with everolimus 
in combination with anastrozole or letrozole. The progression-free survival (PFS) for the 
population of patients treated with anastrozole or letrozole alone as first line therapy is 
approximately 9 months (Mouridsen et al, 2003, Bonneterre et al, 2001). Combining everolimus, 
the median PFS is expected to increase to 11 – 14 months. Considering a recruitment period of 
18 months (1.5 years) and one year of follow up after the last patient is enrolled the expected 
95% CIs for median PFS for 200 patients with 10% lost to follow-up, are provided in the table 
below for median PFSs of 11, 12, 13 and 14 months. 
Median PFS 
Expected 95% CI 
95% CI width 
11 months 
9.32, 12.98 
3.66 
12 months 
10.13, 14.22 
4.09 
13 months 
10.93, 15.46 
4.53 
14 months 
11.73, 16.71 
4.98 
4
Change to protocol specified analyses
No changes were made from protocol version 5 and the current SAP.


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5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
If the dose end date is completely or partially missing and the EOT page is available:
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AEdate imputation
Table 5-1
Imputation of start dates (AE) 
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY


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Missing 
Element
Rule
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE) 
Missing 
Element
Rule
(*=last treatment date plus <30> days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed by 
the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of last 
day of the month or end date of the on-treatment period*
Any AEs with partial/missing dates will be displayed as such in the data listings.
Any AEs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than the 
end date provided. 
5.2
Other imputations
Incomplete date of initial diagnosis of cancer 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.3
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The latest available MedDRA version at the time of the analyses would be used. 
The MedDRA version used would be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (CTCAEv4.0). 


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The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.4
Laboratory parameters derivations
Not applicable.
5.5
Statistical models
5.5.1
Primary analysis
Not applicable.
5.5.2
Key secondary analysis
Not applicable.
6
Reference
1. Allison PD (2000). Survival analysis using the SAS system. Cary, NC, SAS Institute Inc.
2. Armitage P, McPherson CK, Rowe BC (1969): Repeated significance tests on accumulating 
data. J .R. Statist. Soc. A, 132, 232-244.
3. Brookmeyer, R. and Crowley, J. (1982): A Confidence Interval for the Median Survival 
Time, Biometrics 38, 29 - 41.
4. Clopper, C., Pearson, S (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 26: 404-413.
5. Collet D (1994): Modeling survival data in medical research. London, Chapman & Hall
6. Dimitrienko A., Molenberghs G., Chuang-Stein Ch., Offen W. (2005). Analysis of clinical 
trials using SAS. SAS Institute Inc., SAS press.
7. Fleming TR, Rothmann MD, Lu HL (2009). Issues in Using Progression-Free Survival 
When Evaluating Oncology Products. Journal of Clinical Oncology 27, 2874-2880.  
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.
8. FDA Guidelines (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs 
9. Biologics, April. Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to 
Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer


Clinical Development
RAD001/Everolimus
CRAD001Y24135 / NCT01698918
An open-label, phase II, single-arm study of everolimus in 
combination with letrozole in the treatment of 
postmenopausal women with estrogen receptor positive 
HER2 negative metastatic or locally advanced breast 
cancer
RAP Module 3 – Detailed Statistical Methodology 
Amendment 2
Author(s):
, Trial Statistician
, CRO Statistician
Document type:
RAP Documentation
Document status
Final version number 1.0
Release date:
4 Mar 2016
Number of pages
46
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 1
22-Jan-2016
Various edits were deemed necessary following discussion raised at 
Dry Run meeting. All changes are detailed below. 
Section 2.2
Data Included in the analysis
Analysis of PFS second line timelines updated to match protocol 
Amendment 4
The following sentence was modified: The analysis of PFS for second 
line treatment will be performed 6 months later (18 months after the 
last patient’s recruitment) provided that the number of patients in 
second line treatment is adequate for a reliable PFS analysis. 
Otherwise, this analysis will be performed 24 months after the last 
patient’s recruitment.
The analysis of the secondary objective, to evaluate a therapeutic 
intervention to reduce the severity and duration of stomatitis will be 
performed at the time of the primary analysis of 1st line PFS (12 
months after the last patient’s recruitment). In this analysis, the PRO 
questionnaire OSDQ data from patients who were randomized to 
receive either 0.5mg/5ml solution dexamethasone mouth rinse or 
standard of care up to the cutoff date for 1st line PFS analysis will be 
used.
Section 2.3 Definitions of analysis populations
The stomatitis analysis set (SAS) was removed as it was not used in 
the analysis.
Section 2.4 Major Protocol Deviations 
The following PD was rephrase to be aligned with VAP M3. Previous 
wording:

Use of other anticancer agents before documented PD 
assessed by the investigator
Current wording :

Administration of other antineoplastic medication/therapies 
other than the study drug during the study treatment
Section 2.6.1 Primary Efficacy 
The following statement was introduced to clarify the date of 
enrollment:
Date of enrollment is defined as the first day of study treatment.
Section 2.6.2.7.1 therapeutic intervention for stomatitis  :
Following Dry Run 1, some revisions and clarifications of this analysis 
were deemed necessary.
Categorical summaries replaced by shift tables :
-shift tables will be presented to compare baseline value to the value 
at the end of the first episode of stomatitis.
The definition of first incidence of stomatitis was clarified:
-The analysis for this objective will be based on OSDQ data for the 
first incidence of stomatitis which will be identified using the answer 


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provided to question 1b of the OSDQ: “When did you experience the 
first symptoms of mouth and throat soreness”. More information on 
the definition of the first incidence of stomatitis based on OSDQ data 
is provided in Section 3.1.5 of Appendix 16.1.9.”
Censoring rules for duration of the first stomatitis incidence were 
updated to take into account the upper end of the relevant time 
window:
-the patient discontinues from the study treatment with no resolution 
of the AE (up to the upper end of the relevant time window defined in 
Section 3.1.1.8 of Appendix 16.1.9)
-In the absence of an end date of the stomatitis event, the censoring 
date applied will be the earliest from the following dates: upper end of 
the relevant time window defined in Section 3.1.1.8 of Appendix 
16.1.9, analysis cut-off, new anticancer therapy start, death and last 
contact date.
For duration of stomatitis based on AE CRF, the AE grouping 
Stomatitis/related events will be used:
-As supportive analysis, the median duration will also be estimated 
using the duration calculated from start dates and end dates reported 
on the AE CRFs for the AE grouping stomatitis/related events (see 
Section 2.7.1.5). The same censoring rules as described above will 
be applied.
Addition of the following sentence :
-Definition of first and end dates of the first occurrence of stomatitis 
based on OSDQ and on AE CRFs is given in Section 3.1.5 of 
Appendix 16.1.9.
Removal of the following sentences :
-Furthermore, subgroup summaries by “Steroid” vs. “Non-steroid” use 
will be produced.
Section 2.7.1.4 AE summaries  :
Death reporting updated to match the new BDM guidance on the 
reporting of deaths. Addition of the two following summaries :
-All deaths during the study, by primary system organ class and 
preferred term (this summary will include deaths occurring during the 
study regardless of the treatment line and study phase)
-On-treatment deaths by preferred term
Section 2.7.1.6
Time to first onset of specific AEs
Censoring rules were updated to take into account the upper end of 
the relevant time window: 
-The patient discontinues from the study drug with no event (up to the 
upper end of the relevant time window defined in Section 3.1.1.8 of 
Appendix 16.1.9)
Section 2.9.2 Efficacy 
The definition of “visceral metastasis” has been clarified. 
Previous version:

presence of visceral metastasis (yes vs. no). Visceral refers to 
lung, liver, brain, pleural and peritoneal involvement


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Version
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Current version:

presence of visceral metastasis (yes vs. no). Visceral refers 
brain, pleura, pleural effusion, lung, liver, peritoneum and 
ascites. 
Appendix 16.1.9 :
Creation of the following new sections and subsections to clarify the 
definition of the fist occurrence of stomatitis as well as its start and 
end dates:
3.1.5  Definition of the first occurrence of stomatitis 
3.1.5.1 Based on OSDQ
3.1.5.2 Based on AE CRFs
Amendment 2
4-Mar-2016
Throughout the document, the terminology ‘AE grouping 
stomatitis/related event’ or ‘stomatitis/related event’ has been 
replaced with ‘AESI grouping stomatitis’ and ‘stomatitis, respectively, 
as a result of the new CRS process. Stomatitis is considered as an 
AESI.
Section 2.6.2.7.1 Therapeutic intervention for stomatitis
Added ‘last questionnaire date before’ in paragraph:
In the absence of an end date of the stomatitis event, the censoring 
date applied will be the last questionnaire date before the earliest 
from the following dates: upper end of the relevant time window 
defined in Section 3.1.1.8 of Appendix 16.1.9, analysis cut-off, new 
anticancer therapy start, death and last contact date.
Text added:
In the absence of an end date of the stomatitis event, the censoring 
date applied will be the earliest from the following dates: upper end of 
the relevant time window defined in Section 3.1.1.8 of Appendix 
16.1.9, analysis cut-off, new anticancer therapy start, death and last 
contact date.
Text removed:
The same censoring rules as described above will be applied.
Section 2.7.1.4 AE Summaries
The terms ‘clinically notable adverse events’ was changed to 
‘Adverse events of special interest (AESI)’.
Section 2.7.1.5 title changed to: Adverse events of special 
interest
Text added:
An adverse event of special interest is a grouping of adverse events 
that are of scientific and medical concern specific to RAD001. These 
groupings are defined using MedDRA terms, SMQs (standardized 
MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis 
MedDRA queries, NMQ) may also be used. A NMQ is a customized 


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group of search terms which defines a medical concept for which 
there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms 
and/or an existing SMQ, narrow or broad. 
For each specified AESI, number and percentage of subjects with at 
least one event of the AESI occurring during on-treatment period will 
be summarized.
Summaries of these AESIs will be provided by treatment arm, 
(specifying 
grade, 
SAE, 
relationship, 
leading 
to 
treatment 
discontinuation, leading to dose adjustment/interruption, etc.). If 
sufficient number of events occurred, analysis of time to first 
occurrence will be applied. 
A listing of all grouping levels down to the MedDRA preferred terms 
used to define each AESI will be generated.
Text deleted:
Specific groupings of clinically notable adverse events will be 
considered and the number of patients with at least one event in each 
grouping will be reported. Such groups consist of adverse events for 
which there is a specific clinical interest in connection with RAD001 
treatment (i.e. where RAD001 may influence a common mechanism 
of action responsible for triggering them) or adverse events which are 
similar in nature (although not identical). 
The groups are defined at the RAD001 project level and the latest 
groupings definition up-to-date at time of the analysis will be used.
All notable adverse event groupings are defined through the use of 
Preferred Terms (PT), High Level Terms (HLT) or System Organ 
Classes (SOC) or through a combination of these three components. 
MAP Module 3 Post-text Supplement 2 v14.0 contains all the 
grouping terms to be used to map reported adverse events to the 
clinically notable adverse events groupings. 
This file may be updated (i.e., it is a living document) based on 
review of accumulating trial data. The latest version of this document 
available prior to database lock will be used. Note that certain 
adverse events may be reported within multiple groupings.
Section 2.7.1.6 title was changed to: Time to first onset of 
specific AESI
Text inserted:
For the AE groupings stomatitis and non-infectious pneumonitis the 
following analysis of time to first occurrence will be considered.
Section 2.9.1 Safety
The terms ‘clinically notable adverse events’ was changed to 
‘Adverse events of special interest (AESI)’.


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Table of contents
List of tables ...............................................................................................................................7
List of Abbreviations..................................................................................................................8
1
Introduction .......................................................................................................................10
1.1
Document content..................................................................................................10
1.2
References..............................................................................................................10
2
CSR Section 9.7 – Statistical methods planned in the protocol and determination of 
sample size.........................................................................................................................10
2.1
CSR Section 9.7.1 – Statistical and analytical plans .............................................10
2.2
Data Included in the analysis.................................................................................10
2.3
Definitions of analysis populations .......................................................................11
2.4
Major Protocol Deviations.....................................................................................12
2.5
Subjects and treatments .........................................................................................12
2.5.1
Patient disposition.................................................................................12
2.5.2
Protocol deviation summaries...............................................................13
2.5.3
Groupings for analysis ..........................................................................13
2.5.4
Background and demographic characteristics.......................................13
All data collected at baseline, including source of subject referral, child 
bearing potential 
 informed consent, will 
be listed for the FAS population. ..........................................................15
2.5.5
Study treatment .....................................................................................15
2.5.6
Concomitant therapy.............................................................................16
2.6
Efficacy evaluation ................................................................................................17
2.6.1
Primary Efficacy ...................................................................................18
2.6.2
Secondary Efficacy ...............................................................................19
2.6.3
Waterfall graphs....................................................................................22
2.6.4
ECOG performance status.....................................................................22
2.7
Safety evaluation ...................................................................................................24
2.7.1
Adverse events data...............................................................................24
2.7.2
Laboratory data .....................................................................................27
2.7.3
Vital signs..............................................................................................27
2.7.4
Other safety data ...................................................................................28
28
28
2.9
Subgroup analyses .................................................................................................30


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2.9.1
Safety.....................................................................................................30
2.9.2
Efficacy .................................................................................................30
2.10
Interim analyses .....................................................................................................31
2.11
CSR Section 9.7.2 – Sample size calculation........................................................31
3
CSR Appendix 16.1.9 – Documentation of statistical methods ........................................32
3.1
Definitions and general methodology....................................................................32
3.1.1
Definitions.............................................................................................32
3.1.2
Concomitant medications with specific impact on the analysis............34
3.1.3
Implementation of RECIST ..................................................................36
3.1.4
Time interval for ECOG performance status ........................................41
3.1.5
Definition of the first occurrence of stomatitis .....................................41
3.2
Details of the statistical analysis............................................................................42
3.2.1
Baseline comparability..........................................................................42
3.2.2
Time-to-event analyses .........................................................................43
3.2.3
Exact confidence intervals for response rate.........................................44
44
4
References .........................................................................................................................46
List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Table 2-1
Sources for overall lesion response.......................................................17
Table 2-2
ECOG Performance Status Scale..........................................................22
29
Table 3-1 
Last contact date data sources...............................................................33
Table 3-2
Inclusion/exclusion of assessments used in waterfall graph.................39


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List of Abbreviations
AE 
Adverse Event
ATC
Anatomical Therapeutic Chemical (ATC) Classification System
AUC 
Area Under the Curve
 
BMI
Body Mass Index
BOR
Best Overall Response
BP
Blood Pressure
CBR 
Clinical Benefit Rate
CIs
Confidence Intervals
CR
Complete Response
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or paper
CRO 
Contract Research Organization
CSR 
Clinical Study Report
CT
Computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
 
CYP3A4 
Cytochrome P450 3A4
DI
Dose Intensity
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ER 
Estrogen Receptor
FAS-2L
Second line Efficacy Analyses a Subset of the FAS
FAS 
Full Analysis Set
HER-2 
Human Epidermal Growth Factor Receptor 2
IHC 
Immunohistochemistry
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging 
mTOR 
Mammalian Target Of Rapamycin
o.d.
omnia die/once a day
ORR 
Overall Response Rate
OS 
Overall Survival
OSDQ 
Oral Stomatitis Daily Questionnaire
PD
Progressive Disease
PFS 
Progression Free Survival
PgP 
P-glycoprotein
 
PR
Partial Response 
PS
Performance Status
PT_TXT
Preferred Term
Q1
the 25th Percentile
Q3
the 75th Percentile


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RDI
Relative Dose Intensity
RAP 
Report Analysis Preparation
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
SD
Standard Deviation 
SOC_TXT
Body System/Primary System Organ Class
UNK 
Unknown 
WHO
World Health Organization


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1
Introduction
1.1
Document content
This document has been developed according to Sponsor Protocol No. CRAD001Y24135 
(Amended protocol version V02) and the corresponding case report forms (CRF).
This document provides the detailed statistical methodology of the Report Analysis Plan 
(RAP) of Study CRAD001Y24135: “An open-label, phase II, single-arm study of everolimus 
in combination with letrozole in the treatment of postmenopausal women with estrogen 
receptor positive metastatic breast cancer.” It is structured as

A draft of CSR Section 9.7 (Statistical methods planned in the protocol and determination 
of sample size)

A draft of Appendix 16.1.9 (Documentation of statistical methods) of the CSR
The data analysis will be performed by 
 and reviewed by 
Novartis. The table/figure/listing shells of the statistical analysis plan can be found in Module 
7. 
1.2
References
Please refer to the following documents:

CSR template (Full Clinical Study Report)

The Master Analysis Plan for the project

Guidelines for content of Statistical Appendices of the Clinical Study Report
2
CSR Section 9.7 – Statistical methods planned in the protocol and 
determination of sample size
2.1
CSR Section 9.7.1 – Statistical and analytical plans
The planned analysis is described in section 10 of the protocol (Appendix 16.1.1 of the CSR). 
Important information is given in the following sections and details are provided, as 
applicable, in Appendix 16.1.9 of the CSR.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented unless specified in a 
different way.
It is planned that the data from all centers that participate in this protocol will be used.
2.2
Data Included in the analysis
An analysis cut-off date will be determined separately for the final efficacy and safety 
analyses in the first line setting and in the second line setting.


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In this study the primary analysis of PFS for first line treatment will be performed 12 months 
after the last patient’s recruitment. The analysis of PFS for second line treatment will be 
performed 6 months later (18 months after the last patient’s recruitment) provided that the 
number of patients in second line treatment is adequate for a reliable PFS analysis. Otherwise, 
this analysis will be performed 24 months after the last patient’s recruitment. The OS analysis 
will be performed 24 months after the last patient’s recruitment.
The analysis of the secondary objective, to evaluate a therapeutic intervention to reduce the 
severity and duration of stomatitis will be performed at the time of the primary analysis of 1st
line PFS (12 months after the last patient’s recruitment). In this analysis, the PRO 
questionnaire OSDQ data from patients who were randomized to receive either 0.5mg/5ml 
solution dexamethasone mouth rinse or standard of care up to the cutoff date for 1st line PFS
analysis will be used. 
Only data with an assessment date or event start date (e.g. vital sign assessment date or start 
date of an adverse event) prior to or on the cut-off date will be included in all the analyses, 
including the final primary analysis. (Example: If the cut-off date is 15JUN2013 then an AE 
starting on 13JUN2013 will be reported, whereas an AE with start date on 17JUN2013 will 
not be reported.)
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the cut-off 
date will not be imputed and therefore will not appear in the listings.
If it is required to impute an end date to be able to perform a specific analysis (e.g. for a dose 
administration record with missing end date or end date after the cut-off date) the cut-off date 
needs to be imputed as an end date to allow for calculation of treatment exposure duration and 
dose intensity, the imputed date will be displayed and flagged in the listings.
Data included in efficacy analyses
Efficacy analyses will include all data observed in patients from FAS and FAS -2L population 
regardless whether it was observed on-treatment or after the study treatment discontinuation 
till the analysis cut-off date. In particular, the “28 days” rule applied to all safety analyses will 
NOT be used for efficacy analyses.
For patients who took other anti-neoplastic drugs their efficacy data (other than overall 
survival) will be censored so that the tumor assessments made after the administration of the 
other anti-neoplastic drugs are not included in the primary and secondary efficacy analyses. 
Further details on censoring can be found in Section 2.6.1 and Appendix 16.1.9.
2.3
Definitions of analysis populations
The Full Analysis Set (FAS-population) consists of all patients to whom the first line study 
treatment has been assigned. All primary efficacy analyses will be evaluated based on data 
from this population. 


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For second line efficacy analyses a subset of the FAS will be used and referred to as Full 
Analysis Set 2nd line (FAS-2L), which consists of all patients in the FAS who received at 
least one dose of 2nd line study medication. 
The Safety set consists of all patients who received at least one dose of first line study 
medication and had at least one post-baseline safety assessment. 
The safety analysis for the second line will be performed on the subset of Safety set patients 
receiving at least one dose of second line medication. This subset will be referred to as Safety 
set 2nd line (Safety-2L). 
The statement that a patient had no adverse events (AEs; on the adverse event eCRF), 
constitutes a safety assessment. Occurrence of a death constitutes a valid safety assessment as 
well. Patients who have received at least one dose of study drug but who have no post-
treatment safety data of any kind will be excluded from the Safety Set and will be listed
The Stomatitis Analysis Set 1st line (SAS-1L) consists of patients in the FAS who filled in 
the OSDQ and who developed their first stomatitis event (based on OSDQ) in the first line. 
Similarly, the Stomatitis Analysis Set 2nd line (SAS-2L) includes all patients in the FAS-2L
who filled in the OSDQ and who developed their first stomatitis event (based on OSDQ) in 
the second line. The first date reported in the OSDQ will be used to map the first stomatitis 
event either to first or second line treatment. 
The Stomatitis Randomized Set consists of all patients in the FAS who were randomized to 
receive dexamethasone or standard of care to treat oral stomatitis.
2.4
Major Protocol Deviations 
The following protocol deviations are considered for major deviations:

Written informed consent not obtained

ECOG performance status >2

Not histologically or cytologically confirmed ER+ HER2- breast cancer

No metastatic or locally advanced breast cancer

Prior treatment for metastatic breast cancer

Previous treatment with mTOR inhibitors

Administration of other antineoplastic medication/therapies other than the study drug 
during the study treatment
Major protocol deviations will be summarized and tabulated. Other protocol deviations will 
also be identified, summarized and listed.
2.5
Subjects and treatments 
2.5.1
Patient disposition
FAS and FAS-2L will be used for the patient disposition summaries. Based on the three eCRF 
pages ‘End of Treatment – first line of treatment’, ‘End of Treatment – second line of 


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treatment’ and ‘Study Evaluation Completion’ there will be one combined summary for each 
treatment-line by showing:
1. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of Treatment – first line of treatment’ page);
2. Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment of first line of treatment’ page)
3. Reasons for study treatment discontinuation (based on ‘End of Treatment of first line 
of treatment’ page).
4. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of Treatment – second line of treatment’ page);
5. Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment of second line of treatment’ page)
6. Reasons for study treatment discontinuation (based on ‘End of Treatment of second 
line of treatment’ page).
7. Number (%) of patients who completed  from the post-treatment evaluations (based on 
‘Study Evaluation Completion’ page); 
8. Number (%) of patients who discontinued from the post-treatment evaluations (based 
on ‘Study Evaluation Completion’ page); 
9. Reasons for discontinuation from the post-treatment evaluations phase (based on 
‘Study Evaluation Completion’ page).
2.5.2
Protocol deviation summaries
The number and percentage of patients in the FAS and FAS-2L with any protocol deviation 
will be tabulated by the deviation category (as specified in the VAP documents). All protocol 
deviations will be listed.
2.5.3
Groupings for analysis
The number and percentage of patients in each analysis population (definitions are provided 
in Section 2.3) will be summarized. The distribution of patients in selected analysis 
populations will also be summarized by country.
2.5.4
Background and demographic characteristics
Baseline demographics and disease characteristics data will be listed and summarized for both 
the first line and the second line using the FAS and FAS-2L.
2.5.4.1
Basic demographic and background data
All demographic and background disease characteristics data will be listed in detail. 
Qualitative data (i.e., gender, race, ECOG performance status, etc.) will be summarized by 
means of contingency tables by the first line and the second line setting and quantitative data 
(i.e., age, body weight, etc.) will be summarized by appropriate descriptive statistics 
(frequency, mean, standard deviation, median, minimum, and maximum) by the first line and 
the second line.


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Baseline demographics and disease characteristics will also be summarized by treatment 
group for patients in the Stomatitis Randomized Set.
2.5.4.2
Diagnosis and extent of cancer
Summary statistics will be tabulated for diagnosis and extent of cancer. According to the data 
collected on the eCRF, this analysis will include the following: primary site of cancer, details 
of tumor histology/cytology, histological grade, time since initial diagnosis, date of first 
recurrence/metastasis, date of most recent recurrence/metastasis, current disease status, 
number and type of metastatic sites in the current extent of disease, presence/absence of target 
and non-target lesions, number and type of organs involved.
The numbers and percentages of patients in categories defined by the following variables 
‘presence/absence of target and non-target lesions’, ‘number of organs involved’ and ‘organ 
types involved’ will be based on the data collected on the radiology RECIST eCRFs, in 
particular, on the individual target and non-target lesion codes. 
Time since initial diagnosis, time since first recurrence/metastasis, as well as time between 
first diagnosis and first recurrence/metastasis will be summarized in months.
2.5.4.3
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
will be summarized and listed. Separate summaries will be presented for ongoing and 
historical medical conditions. The summaries will be presented by primary system organ class 
and preferred term. (Medical history/current medical conditions are coded using the Medical 
dictionary for regulatory activities MedDRA terminology.
In addition, descriptive summaries of ongoing adverse events at second-line baseline by CTC 
maximum grade will be presented for the FAS-2L population.
2.5.4.4
Prior anti-neoplastic therapy
Prior anti-neoplastic therapy will be listed in three separate listings: (i) medications, (ii) 
radiotherapy, and (iii) surgery for the FAS.
The number and percentage of patients recording any prior anti-neoplastic medications, prior 
anti-neoplastic radiotherapy and prior anti-neoplastic surgery will be summarized.
The summary of prior anti-neoplastic medication will include the total number of regimens 
used, setting at last treatment, and the best response at last treatment.
All prior antineoplastic medications will also be tabulated by ATC code and preferred term.


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2.5.4.5
Other
All data collected at baseline, including source of subject referral, child bearing potential 
 
 informed consent, will be listed for the FAS population.
2.5.5
Study treatment
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized separately for each study treatment both in first line 
(everolimus and letrozole) and second line treatment (everolimus and exemestane). In 
addition, the duration of exposure to study treatment will be categorized into time intervals; 
frequency counts and percentages will be presented for the number of patients in each interval. 
The number of patients with dose reductions/interruptions will be presented, along with 
reasons for the dose changes. 
The safety and safety-2L sets will be used for all summaries and listings of study treatment in 
the first line setting and the second line setting, respectively.
2.5.5.1
Duration of study treatment exposure
The following algorithm will be used to calculate the duration of study treatment exposure for 
patients who took at least one dose of any of the components of the study treatment:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first 
administration of study treatment) + 1.
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason).
Duration of exposure to each component of the study treatment will also be calculated.
2.5.5.2
Cumulative dose
Cumulative dose is defined as the total dose given during the study treatment exposure and 
will be summarized for each of the study treatment components separately. For patients who 
do not receive any drug the cumulative dose will be set to zero.
2.5.5.3
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:
DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of 
time).
For patients who do not receive any drug, the DI will be set to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol in the same dose unit and unit of time as that of the Dose Intensity. 
Relative dose intensity (RDI), expressed in %, is defined as follows:
RDI = [DI (dosing unit / unit of time) / PDI (dosing unit / unit of time)]*100.


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DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of the study treatment exposure, not the duration of each of the components. 
2.5.5.4
Dose reductions or interruptions
The number of patients, who have dose reductions or interruptions, and the reasons for such 
reductions/interruptions, will be summarized separately for each of the study treatment 
components, by treatment line.
Interruption: An interruption is defined as a 0 mg / 0 tablets dose given on one or more days.
Reduction: A reduction is defined as a decrease in dose from the protocol planned dose or a 
decrease from the previous non-zero dose, even if this decrease has been directly preceded by 
an interruption. For example, in the sequence 10mg – 0mg – 5mg, the 5mg dose will be 
counted as a reduction. A decrease in frequency of administration which results in a lower 
cumulative dose is also counted as a reduction, e.g. in the sequence 10mg – 5mg – 5mg, two 
reductions will be counted.
If a patient moves from a higher than protocol planned dose down to the planned dose then 
this is not be counted as a reduction, however if they move directly from a higher than 
planned dose down to a lower than protocol planned dose or the planned dose on a less 
frequent regimen, then this is counted as a reduction.
If one of the study treatment component is permanently discontinued (before any protocol 
planned discontinuation date) while the other is ongoing it is counted as a reduction.
The number of dose reductions and interruptions per patient will be tabulated both separately 
and combined. The reasons for reductions/interruptions will also be summarized. Dose 
escalations should not be counted in these summaries.
Missing data : If dose is recorded but regimen is missing or entered as ‘none’, it is assumed 
that the study drug was taken as per-protocol.
2.5.6
Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, preceding or coinciding with 
the study assessment period. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. Details regarding WHO Drug 
Reference List version will be included in the footnote in the corresponding tables and listings. 
In addition to categorizing medication data by preferred term, drugs will be classified 
according to their ATC classification in order to present and compare how they are being 
utilized.
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug(s) will be listed and summarized by ATC class and preferred term by means of 
frequency counts and percentages both in first line (everolimus and letrozole) and second line 
treatment (everolimus and exemestane). These summaries will include medications starting on 


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or after the start of study treatment or medications starting prior to the start of study treatment 
and continuing after the start of study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed.
Concomitant therapy will be descriptively analyzed by treatment period in the safety and 
safety-2L sets. Frequency distribution tables and listings will be prepared.
Concomitant medications which start during the first-line and are continuing in the second-
line will be reported in both first-line and second-line tables.
Concomitant medications that have the potential to impact some specific analyses (e.g. 
efficacy analyses) will be identified prior to database lock. Separate summaries of these 
concomitant medications will be produced and the corresponding analysis populations will be 
used (e.g. FAS and FAS-2L). Strong and moderate inhibitors, inducers, or substrates of the 
isoenzyme CYP3A will be identified as described in Appendix 16.1.9. The strong ones will be 
tabulated by ATC code. Both strong and moderate ones will be listed. Further on treatment 
anti-neoplastic therapies will be listed based on their identification (by the method given in 
Appendix 16.1.9) by the protocol deviation process.
Antineoplastic therapies administered since discontinuation of study drug will be listed and 
summarized by ATC class, preferred term and treatment period by means of frequency counts 
and percentages using the FAS and FAS-2L. Antineoplastic therapies administered after first-
line treatment period in patients who did not start second-line study drug and in patients who 
received second-line treatment will be summarized separately.
2.6
Efficacy evaluation
The efficacy endpoints based on the tumor assessments will be derived according to the 
RECIST 1.0 guideline version 2 (see [Protocol Appendix 2] for details). The tumor endpoints 
derivation is based on the sequence of overall lesion responses at each assessment/time point. 
However, the overall lesion response at a given assessment/time point may be provided from 
different sources as illustrated in Table 2-1.
Table 2-1
Sources for overall lesion response
Source 1
Local (treating center) radiologist/investigator reported overall lesion 
response
Source 2
Calculated overall lesion response based on raw (i.e. individual lesion)
measurements obtained from local (treating center) radiologist/Investigator
The primary efficacy analysis will be based on local (treating center) radiologist/Investigator
tumor assessment data and will use Source 1 in Table 2-1 as a basis for endpoint derivation. In 
particular, the final local (treating center) radiologist/Investigator visit response for each 
assessment/time point collected on the RECIST 1.0 overall response category collection CRF 
page will be used to derive the primary efficacy endpoints. The assessment time point dates 
will be derived using the dates of the individual lesion measurements. 
The overall response at each assessment will also be re-calculated using raw lesion 
measurements obtained from local (treating center) radiologist/investigator (Source 2, Table 


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2-1) and  will be listed against Source 1, Table 2-1. Discrepancies between the calculated and 
the local radiologist/investigator reported overall responses will be identified and listed.
2.6.1
Primary Efficacy
Progression-free survival (PFS) derived from local radiological assessment will be used as the 
primary efficacy variable. The PFS is defined as the time from the date of enrollment to the 
date of the first documented disease progression or death due to any cause. Date of enrollment 
is defined as the first day of study treatment. If a patient has not progressed or died at the 
analysis cut-off date or when she receives any further anti-neoplastic therapy (including per 
protocol second-line treatment), PFS would be censored at the time of the last tumor 
assessment before the cut-off date or the anti-neoplastic therapy date. Further anti-neoplastic 
therapies taken during study treatment will be identified as protocol deviations (see Appendix 
16.1.9), recognized from the data collected on ‘Antineoplastic therapies since discontinuation 
of study drug’ eCRF, and from the data on ‘Dosage Administration Record’. Definitions and 
further details on PFS can be found in [Protocol Appendix 2].
Discontinuation due to disease progression (collected on the “End of treatment” and “Study 
Evaluation Completion” page) without supporting objective evidence (as defined in Section 
3.1.3.2 of Appendix 16.1.9) satisfying progression criteria per RECIST 1.0 will not be 
considered a progressive disease. 
Primary analysis
The primary analysis of PFS will be based on the data from investigator/local radiology 
review (Source 1 in Table 2-1). The analysis will be performed on the FAS and will use the 
default censoring and event date options from section 14.2.18 of [Protocol Appendix 2], i.e. A 
(1), B (1), C1 (1), C2 (1), D (1), E (1), and F (1). In particular, the PFS will be censored at the 
last adequate tumor assessment if one of the following occurs: absence of event before cut-off 
date for final primary analysis; the event occurred after a new anticancer therapy is given 
(including per protocol second-line treatment); the event occurred after two or more missing 
tumor assessments (see Section 3.1.3.5 of Appendix 16.1.9). See also Section 3.1.3.6 of 
Appendix 16.1.9 describing the special case of missing baseline tumor assessment. 
Discontinuation of study treatment (for any reason) will not be considered as a reason for 
censoring. 
Kaplan-Meier estimates
The Kaplan-Meier estimate of the PFS survival distribution function will be computed. The 
results will be plotted graphically (Kaplan-Meier curves). The plots will display the number of 
patients at risk at equidistant time points. 
The Median PFS will be provided along with the 95% confidence intervals. Additionally, the 
25% and 75% percentiles will also be provided. The survival probabilities at 6, 10, 14 and 18 
months, and the associate 95% confidence intervals will be summarized.


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Sensitivity analyses of the primary endpoint PFS
The following sensitivity PFS analyses will be performed to address the impact of 
missing/unknown tumor assessments:
1. PFS using local radiology assessments (Source 1 in Table 2-1) on the FAS and using 
the following options from Table 14-5 of the [Protocol Appendix 2]: A(1), B(1), C1(1), 
C2(3), D(1), E(1), and F(1), i.e. taking the event whenever it occurs even after two or 
more missing tumor assessments (see Appendix 16.1.9). In the summary table, this 
approach will be referred as “Actual event PFS analysis”.
2. PFS using local radiology assessments (Source 1 in Table 2-1) on the FAS and using 
the following options from Table 14-5 of the [Protocol Appendix 2]: A(1), B(1), C1(2), 
C2(2), D(1), E(1), and F(1), i.e. backdating of events occurring after missing tumor 
assessments. In the summary tables, this approach will be referred as “Backdating PFS 
analysis”. 
PFS censoring reasons
The number of patients with a PFS event and number of patients censored for the PFS 
analysis will be summarized for PFS based on local radiology assessments for the FAS. In 
addition, a summary of reasons for PFS censoring will be provided. The following categories 
will be used as appropriate:

Ongoing without event 

Adequate assessment no longer available (when follow-up for progression is stopped 
at a certain time or interrupted for a certain time period before cut-off or any other 
censoring reason)

New cancer therapy added 

Event documented after two or more missing tumor assessments based on the distance 
D2 defined in Section 3.1.3.5 of Appendix 16.1.9
The distance D2 will also to be used to determine other PFS censoring reasons defined in 
Section 3.1.3.5 of Appendix 16.1.9.
For patients censored at the date of enrollment due to missing baseline tumor, the censoring 
reason will be “Adequate assessment no longer available”.
2.6.2
Secondary Efficacy
The secondary efficacy objectives in this study are to determine the overall response rate 
(ORR) and clinical benefit rate (CBR) of everolimus + letrozole in the first line setting; 
determine the progression free survival, ORR and CBR of everolimus + exemestane in the 
second line setting; estimate the overall survival of patients treated with everolimus + 
letrozole in the first line setting; evaluate a therapeutic intervention to reduce the severity and 
duration of stomatitis. 
2.6.2.1
Overall response rate (ORR) in first line
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.0 (see [Protocol 
Appendix 2]). ORR will be calculated based on the FAS, using local (treating center) 


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radiologist’s/investigator’s review of the tumor assessment data. However patients with only 
non-measurable disease at baseline will be included in the numerator if they achieve a 
complete response. Proportions of subjects with ORR will be presented along with exact 95% 
confidence intervals (Clopper and Pearson 1934). 
The above analyses will also be repeated based on the data from subset of patients with only 
measurable disease at baseline. 
2.6.2.2
Progression Free Survival in Second line 
Progression-free survival in the second line (PFS-2L) is defined as the time interval between 
start of 2nd line treatment and documented disease progression or death due to any cause 
reported during or after second-line treatment. The median PFS in the second line will be 
estimated using the Kaplan-Meier method and presented along with 95% confidence intervals 
for the FAS-2L. The same censoring rules as for the PFS in the first line will be applied (see 
Section 2.6.1).
2.6.2.3
Overall response rate in second line 
The analysis described in Section 2.6.2.1 will be repeated on FAS-2L population to estimate 
the ORR of the second line study treatment. 
2.6.2.4
Overall survival (OS)
The overall survival (OS) following first line treatment with everolimus + letrozole is defined 
as the time from the date of enrollment to date of death due to any cause. The final OS 
analysis will be performed 24 months after the last patient’s recruitment. If a death has not 
been observed by the date of analysis cut-off, then OS will be censored at the date of last 
contact (see Section 3.1.1.9 of Appendix 16.1.9). 
The analysis of OS will be based on the data from the FAS population regardless of whether 
they were observed during the first line setting, during the second line setting, or during 
survival follow-up. The median OS as well as the 25th and 75th quartile will be estimated using 
the Kaplan-Meier method and presented along with 95% confidence intervals. In addition, 
Kaplan-Meier survival estimates with 95% confidence intervals will be summarized at 12, 18, 
24 and 30 months.
2.6.2.5
Clinical benefit rate (CBR) in first line
CBR is defined as the proportion of patients with either a best overall response of CR, PR or 
SD lasting for 24 weeks or longer. A patient will be considered to have a SD for 24 weeks or 
longer if a SD response is recorded at 24 weeks or later. Taking into account the allowed visit 
window for tumor assessments, the SD response has to be recorded at 23 weeks or later to be 
included in the CBR calculation. CBR will be calculated on the FAS based on the local 
(treating center) radiologist’s/Investigator’s tumor assessment. Patients with only non-
measurable disease at baseline will be included in the numerator if they achieve a complete 
response or stable disease lasting 24 weeks or longer. Proportions of subjects with CBR will 
be presented along with exact 95% confidence intervals (Clopper and Pearson 1934).


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2.6.2.6
Clinical benefit rate (CBR) in second line
The analysis described in Section 2.6.2.5 will be repeated on FAS-2L population to estimate 
the CBR of the second-line study treatment.
2.6.2.7
Other secondary objective 
2.6.2.7.1
Therapeutic intervention for stomatitis 
The secondary objective, to evaluate a therapeutic intervention to reduce the severity and 
duration of stomatitis, will be performed using the patient reported outcome (PRO) Oral 
Stomatitis Daily Questionnaire (OSDQ) data from patients in the Stomatitis Randomized Set. 
The analysis for this objective will be based on OSDQ data for the first incidence of stomatitis
which will be identified using the answer provided to question 1b of the OSDQ: “When did 
you experience the first symptoms of mouth and throat soreness”. More information on the 
definition of the first incidence of stomatitis based on OSDQ data is provided in Section 3.1.5 
of Appendix 16.1.9.
The number of patients filling OSDQ and the number of patients missing OSDQ assessments 
as well as the reasons for missing OSQD assessments will be summarized by each treatment 
group for scheduled assessment time points.
Descriptive statistics (N, mean, SD, median, minimum, maximum) will be used to summarize 
the individual severity items of the OSDQ data at each scheduled assessment time point. 
Additionally, change from Day 1 at the time of each assessment will be summarized. Patients 
with an evaluable Day 1 score and at least one evaluable score after Day 1 during the 
treatment period will be included in the change from Day 1 analyses. A repeated 
measurements analysis model that includes terms for Day 1 score, time of visit, treatment 
group and time of visit by treatment group interaction will be used to compare the two 
treatment groups with respect to actual and change from Day 1 OSDQ severity scores 
longitudinally over time. To account for correlated repeated measures within patients a first-
order autoregressive variance-covariance matrix will be used. Longitudinal plots at selected 
timepoints displaying the model adjusted, least square means and 95% confidence intervals 
will be produced.
For selected severity items, shift tables will be presented to compare Day 1 value to the value 
at the end of the first episode of stomatitis.
The time to first occurrence of stomatitis will be calculated using the dates reported in the 
OSDQ and is defined as time from first study treatment administration in the first line to start 
date of the AE, i.e. time in days is calculated as (start date of first occurrence of stomatitis) –
(date of first administration of study treatment in the first line) +1. The duration of the first 
stomatitis incidence will also be calculated using the dates reported in the OSDQ. Duration of 
the first stomatitis incidence is defined as time from start date of the AE to end date of the AE, 
i.e. time in days is calculated as (end date of first occurrence of stomatitis) – start date of first 
occurrence of stomatitis) +1. 
A patient will be censored for duration of the first stomatitis incidence if:

the patient dies before resolution of the AE


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
the patient receives a new anticancer therapy (excluding protocol specified second line
with no event or before the event has occurred 

the patient discontinues from the study treatment with no resolution of the AE (up to the 
upper end of the relevant time window defined in Section 3.1.1.8 of Appendix 16.1.9)

the AE is still on-going at the cut-off with no event
In the absence of an end date of the stomatitis event, the censoring date applied will be the last 
questionnaire date before the earliest from the following dates: upper end of the relevant time 
window defined in Section 3.1.1.8 of Appendix 16.1.9, analysis cut-off, new anticancer 
therapy start, death and last contact date.
Ascending Kaplan-Meier curves will be constructed. The median duration of the first 
stomatitis AE with 95% confidence interval will be estimated using Kaplan-Meier method for 
the two therapeutic interventions for stomatitis groups. Additionally, 25% and 75% 
percentiles will be also provided.
As supportive analysis, the median duration will also be estimated using the duration 
calculated from start dates and end dates reported on the AE CRFs for the AESI grouping 
stomatitis (see Section 2.7.1.5). In the absence of an end date of the stomatitis event, the 
censoring date applied will be the earliest from the following dates: upper end of the relevant 
time window defined in Section 3.1.1.8 of Appendix 16.1.9, analysis cut-off, new anticancer 
therapy start, death and last contact date.
Definition of first and end dates of the first occurrence of stomatitis based on OSDQ and on 
AE CRFs is given in Section 3.1.5 of Appendix 16.1.9.
These analyses will be repeated by treatment line for the SAS-1L and SAS-2L respectively.
2.6.3
Waterfall graphs
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from the treatment-line specific baseline in the sum of the longest 
diameter of all target lesions for each patient. The proportions of patients with various degrees 
of tumor shrinkage or growth which can be read directly from the graph can then re present a 
useful efficacy metric. Only patients with measurable disease at baseline and valid post 
baseline assessments will be included in the waterfall graphs. Construction of waterfall graphs 
is detailed in Appendix 16.1.9.
2.6.4
ECOG performance status
ECOG Performance Status (PS) scale will be used to assess physical health of patients, 
ranging from 0 (most active) to 5 (Dead):
Table 2-2
ECOG Performance Status Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 


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Score
Description
and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
ECOG Performance Status will be assessed and recorded at screening/baseline, on Treatment 
Day 1 (prior to administration of the study drug, unless PS in screening was done less than 7 
days before Day 1), and Day 1 of every cycle thereafter until progression.
Time based intervals will be used to group the ECOG PS data over time for each treatment 
line. Definition of the time intervals is provided in Appendix 16.1.9. Descriptive statistics (N, 
mean, SD, median, minimum and maximum) will be used to summarize the ECOG PS data at 
each scheduled assessment time point. Additionally, change from baseline at the time of each 
assessment will be summarized. Patients with an evaluable baseline score and at least one 
evaluable post baseline score during the treatment period will be included in the change from 
baseline analyses. 
An analysis of the time to definitive deterioration of the ECOG PS by one category of the 
score from baseline (see section 3.1.4 Time interval for ECOG performance status in 
Appendix 16.1.9) will be performed in FAS set for the whole treatment period, i.e., not 
separately for the first-line and second-line settings. A deterioration is considered definitive if 
no improvements in the ECOG PS status is observed at a subsequent time of measurement 
during the treatment period following the time point where the deterioration is observed 
(Example 1: if the score is 1 at baseline and then 1 , 2 , 1 , 2 , 3 at study days 28 , 57 , 83 , 
115 , 150, respectively, then the time to definitive worsening is 115 days, Example 2: if the 
score is 1 at baseline and then 1 , 1 , 2 at study days 28 , 57 , 83, respectively, with no 
assessment of the ECOG performance status after day 83 then the time to definitive worsening 
is 83 days).
Death is considered as worsening of ECOG PS if it occurs close to the last available 
assessment, where “close” is defined as being within twice the planned period between two 
assessments. This avoids overestimating the time to definitive worsening in patients dying 
after an irregular assessment scheme. Patients who die after more than twice the planned 
period between two assessments since the last assessment are censored at the date of their last 
available questionnaire. For example, if the last assessment is at week 4 and the patient dies 
on week 10, the definitive deterioration date will be week 10. On the other hand, if the last 
assessment is at week 4 and the patient dies on week 16, which is after more than twice the 
planned period between two assessments (8 weeks) since the last assessment (week 4), then 
the patient is censored for definitive deterioration and the censoring date will be week 4.
Patients receiving any further anti-neoplastic therapy (excluding per protocol second-line 
treatment) prior to definitive worsening will be censored at their date of last available 
assessment prior to start of therapy. Patients that have not worsened at the data cut-off point 
will be censored at the date of last available assessment prior to data cut-off. Kaplan-Meier 
method will be used to estimate the survival distribution function of time to definitive 
worsening. The median time to definitive worsening along with a 95% confidence interval 


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will be presented.
2.7
Safety evaluation
The assessment of safety will be based mainly on the frequency of adverse events (AEs) and 
on the number of laboratory values that fall outside of pre-determined ranges. Other safety 
data (e.g. electrocardiogram, vital signs, and special tests) will be considered as appropriate.
All safety outputs will use the defined Safety sets (Section 2.3). The analyses will be 
performed per treatment line in the Safety and Safety-2L sets except for time to first onset of 
specific AEs which will be calculated for the whole treatment period.
The safety summary tables will only include “treatment-emergent” events/assessments 
occurring in the windows defined in Section 3.1.1.8 of Appendix 16.1.9, however, safety 
events/assessments outside of these windows will be listed and flagged.
2.7.1
Adverse events data
2.7.1.1
Coding of AEs
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. Details regarding MedDRA version will be included in the footnote in the 
corresponding tables and listings. 
2.7.1.2
Grading of AEs
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) 
version 
4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf).
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE v4.0 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a Grade 2 is not necessarily twice as bad as a Grade 1).
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the 
severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) 
will not be used in this project; rather, this information will be collected on the “End of 
Treatment”, “Study Completion Evaluation” or “Survival Information” eCRF pages. 
2.7.1.3
General rules for AE Reporting
First-line treatment-emergent adverse events are defined by all AEs reported with a start date 
within the first-line safety time window defined in Section 3.1.1.8 of Appendix 16.1.9. This 
will capture both new events as well as events which worsened since baseline during the first-
line treatment period because any change in the severity or seriousness of an ongoing AE is 
recorded as a new AE in the case report form.
Second-line treatment-emergent adverse events are defined by all AEs reported with a start 
date within the second-line safety time window defined in Section 3.1.1.8 of Appendix 16.1.9. 


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This will capture both new events as well as events which worsened since baseline during the 
second-line treatment period because any change in the severity or seriousness of an ongoing 
AE is recorded as a new AE in the case report form.
In the following sections, the term AE refers to treatment-emergent adverse events.
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary system organ class 
(SOC_TXT), and for each preferred term (PT_TXT) using MedDRA coding. A subject with 
multiple occurrences of an AE will be counted only once in the AE category.
Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum CTC grade (AEVGRD1C). A patient with multiple CTC grades for an AE will be 
summarized under the maximum CTC grade recorded for the event. In the summaries 
presented by grade, all AEs will be pooled regardless of whether they are CTC gradable or not, 
i.e. regardless of whether the question “CTC AE” (variable CTIAEV1C) on the Adverse 
Events eCRF is answered ‘Yes’ or ‘No’.
The frequency of CTC grade 3 and 4 AEs will be summarized separately.
Any information collected (e.g. CTC grades, relatedness to study drug, action taken etc.) will 
be listed as appropriate.
2.7.1.4
AE summaries
Unless otherwise specified, the following adverse event summaries will be produced by 
treatment line, on the Safety set for the first-line treatment (or Safety-2L set for the second-
line treatment):

Adverse events, regardless of study drug relationship by primary system organ class 
and preferred term

Adverse events with suspected relationship to study drug by primary system organ 
class, preferred term

Adverse events, regardless of study drug relationship by primary system organ class, 
preferred term and maximum CTC grade

All deaths during the study, by primary system organ class and preferred term (this 
summary will include deaths occurring during the study regardless of the treatment 
line and study phase)

On-treatment deaths by preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Serious adverse events with suspected study drug relationship, by primary system 
organ class and preferred term

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term

Adverse events requiring dose adjustment or study-drug interruption, regardless of 
study drug relationship, by primary system organ class and preferred term


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
Adverse events requiring additional therapy, regardless of study drug relationship, by 
primary system organ class and preferred term

Adverse events of special interest (AESI) (Section 2.7.1.5) regardless of study drug 
relationship, by grouping and preferred term

Adverse events of special interest (AESI) (Section 2.7.1.5) regardless of study drug 
relationship, by grouping, preferred term and maximum CTC grade

Time to first occurrence of the adverse events of special interest (AESI): stomatitis

Time to first occurrence of the adverse events of special interest (AESI): non-
infectious pneumonitis
2.7.1.5
Adverse events of special interest
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to RAD001. These groupings are defined using MedDRA terms, 
SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may 
also be used. A NMQ is a customized group of search terms which defines a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 
need. It may include a combination of single terms and/or an existing SMQ, narrow or broad. 
For each specified AESI, number and percentage of subjects with at least one event of the 
AESI occurring during on-treatment period will be summarized.
Summaries of these AESIs will be provided , (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, etc.). 
2.7.1.6
Time to first onset of specific AESI
For the AE groupings stomatitis and non-infectious pneumonitis the following analysis of 
time to first occurrence will be considered if sufficient number of events occurred.
All the adverse events of interest occurring within the windows defined in Section 3.1.1.8 of 
Appendix 16.1.9 (whole sequence of treatment) will be taken into account.
The time to the first occurrence of an AE is defined as the time from the start of study 
treatment to the date of the first occurrence of an adverse event, and it is calculated in days as:
(Start date of first occurrence of AE) - (date of first dose of study drug) + 1.
A patient will be censored for the time to first occurrence if:

the patient dies with no event

the patient receives a new anticancer therapy (excluding second-line treatment) with no 
event or before the event has occurred

the patient discontinues from the study drug with no event (up to the upper end of the 
relevant time window defined in Section 3.1.1.8 of Appendix 16.1.9)

the patient is still on-going at the cut-off date with no event
The censoring date applied will be the earliest among the following dates:


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
upper end of the relevant time window defined in Section 3.1.1.8 of Appendix 16.1.9,

analysis cut-off date,

new anti-cancer therapy start date (excluding second-line treatment),

death date or, in patients with no death data, last contact date (Section 3.1.1.9 of Appendix 
16.1.9).
Kaplan-Meier curves for time to first onset of the AE will be estimated. Estimates of the 
median and 25th and 75th percentiles will be presented with 95% confidence intervals.
2.7.2
Laboratory data
Data from both central and local laboratories will be combined when analyzing laboratory 
data and will be assigned to the first or second line treatment period using the windows 
defined in Section 3.1.1.8 of Appendix 16.1.9. Baseline assessments in each treatment line 
period are defined in Section 3.1.1.7 of Appendix 16.1.9. All laboratory assessments will be 
listed and those collected outside of the windows defined in Appendix 16.1.9 will be flagged.
Laboratory data will be classified programmatically into CTC grades according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0. A severity grade of 0 will 
be assigned when the value is within normal limits. (In the case when a local laboratory 
normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory value will still 
be taken as within normal limits and assigned a CTC grade of zero.) 
The following summaries will be produced for the laboratory data by laboratory parameter
and for each treatment line, on the Safety (respectively Safety-2L) set for the first-line 
(respectively second-line treatment) with reference to the appropriate baseline:

Number and percentage of patients with worst post-baseline CTC grade (regardless of 
the baseline status). Each patient will be counted only for the worst grade observed 
post baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value 
will be produced for hematology and biochemistry laboratory parameters with CTC 
grades.

For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges.
The following listings will be produced for the laboratory data:

Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative 
to the laboratory reference ranges. 

Listing of all laboratory data with values flagged to show the corresponding CTC 
grades and the classifications relative to the laboratory reference ranges.
2.7.3
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height (cm) (only collected in screening/baseline), 


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weight (kg), body temperature (°C), sitting blood pressure systolic, diastolic (mmHg) and 
sitting pulse (bpm).
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline

Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline.

Body temperature: ≥ 39.1°C

Weight: Increase from baseline of ≥ 10%

Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm
Clinically notable below normal values

Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline

Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline

Body temperature: ≤ 35°C

Weight: decrease from baseline of ≥ 10%

Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm
Vital signs shift table based on notable values will be produced for each vital sign parameter
for each treatment line, on the Safety (respectively Safety-2L) set for the first-line 
(respectively second-line treatment) with reference to the appropriate baseline.
In addition, the following two listings will be produced by treatment group:

Patients with clinically notable vital sign abnormalities.

All vital sign assessments will be listed by patient and vital sign parameter.
In both listings, the clinically notable values will be flagged and assessments outside of the 
windows defined in Section 3.1.1.8 of Appendix 16.1.9 will be flagged.
2.7.4
Other safety data
Data from other tests (e.g. electrocardiogram, pulmonary function tests) will be listed, notable 
values will be flagged, and any other information collected will be listed as appropriate.
All assessments collected later than 28 days after the last treatment/exposure date (see 
Appendix 16.1.9) will be flagged in the listings.


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2.9
Subgroup analyses
2.9.1
Safety
Selected first-line safety analyses will be repeated on the Safety set in the following 
subgroups:

age (< 65 years and ≥ 65 years)

race (Asian vs. non-Asian)
Selected safety analyses include:

Adverse events, regardless of study drug relationship by primary system organ class
and preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ
class and preferred term

Adverse events of special interest (AESI) regardless of study drug relationship, by
grouping and preferred term
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that are limited to a subgroup of patients, or safety issues that are more commonly observed in 
a subgroup of patients.
2.9.2
Efficacy
The primary PFS analysis in the first line will be repeated in the following subgroups for the 
FAS:

age (< 65 years and ≥ 65 years)

race (Asian vs. non-Asian)bone only lesions at baseline (yes vs. no)


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
presence of visceral metastasis (yes vs. no). 

Visceral refers brain, pleura, pleural effusion, lung, liver, peritoneum and ascites. 
2.10
Interim analyses
No interim analysis is planned.
2.11
CSR Section 9.7.2 – Sample size calculation
The sample size is calculated based on an estimate of median PFS with reasonable accuracy 
(width of 95% confidence interval) for first line treatment with everolimus in combination 
with anastrozole or letrozole. The progression-free survival (PFS) for the population of 
patients treated with anastrozole or letrozole alone as first line therapy is approximately 9 
months (Mouridsen et al, 2003, Bonneterre et al, 2001). Combining everolimus, the median 
PFS is expected to increase to 11 – 14 months. Considering a recruitment period of 18 months 
(1.5 years) and one year of follow up after the last patient is enrolled the expected 95% CIs 
for median PFS for 200 patients with 10% lost to follow-up, are provided in the table below 
for median PFSs of 11, 12, 13 and 14 months. 
Median PFS 
Expected 95% CI 
95% CI width 
11 months 
9.32, 12.98 
3.66 
12 months 
10.13, 14.22 
4.09 
13 months 
10.93, 15.46 
4.53 
14 months 
11.73, 16.71 
4.98 


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3
CSR Appendix 16.1.9 – Documentation of statistical methods
The statistical methods used to perform the analyses presented in the clinical study report will 
be described in Section 9.7. Section 16.1.9 will provide further details of the statistical 
methods not already provided in Section 9.7.
3.1
Definitions and general methodology
3.1.1
Definitions
3.1.1.1
Study drug and study treatment
Study drug is defined as everolimus.
Study treatment is defined as everolimus + letrozole and everolimus + exemestane 
3.1.1.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug was administered and recorded on the dose administration DAR eCRF in the 
first line setting and second line setting respectively. 
3.1.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug was administered and recorded on the DAR eCRF in the first line setting and the 
second line setting respectively.
3.1.1.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered and recorded on the dose 
administration record (DAR) eCRF in the first line setting and the second line setting 
respectively. 
The dates of first administration of study treatment are calculated separately for each 
treatment line and, for simplicity, are referred to as DFirstTrt1L and DFirstTrt2L, respectively.
3.1.1.5
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR eCRF 
in the first line setting and the second line setting respectively.
The dates of last administration of study drug are calculated separately for each treatment line 
and, for simplicity, are referred to as DLastTrt1L and DLastTrt2L, respectively.
3.1.1.6
Study day
The study day for all assessments (i.e. safety and non-safety assessments) will be calculated 
as the difference between the date of the assessment and the start of study treatment of the 


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first line setting and the second line setting respectively (plus 1 if assessment occurred on or 
after start of study treatment). Note that the study day for OSDQ assessments will also be 
based on this rule. Note: if an adverse event starts before the start of study treatment the study 
day displayed on the listing will be negative.
3.1.1.7
Baseline
Baseline value is the result of an investigation describing the “true” uninfluenced state of the 
subject. 
For all evaluations (i.e. safety and non-safety), the last available assessment before or at date 
of start of study treatment of first line setting and second line setting respectively  is taken as 
‘baseline’ assessment. 
If patients have no value as defined above, the baseline results will be missing.
3.1.1.8
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. On-treatment assessment/event is defined as any assessment/event 
obtained in the time interval:

First-line treatment: 
o
For patients who subsequently begin second-line study treatment: From the 
date of first administration of the first-line study treatment until the minimum 
between the date of last administration of the first-line study treatment plus 28 
days and the date of first administration of second-line study treatment minus 
one day, that is, DFirstTrt1L until min (DLastTrt1L+28 days, DFirstTrt2L-1).
o
For patients who do not receive second-line study treatment: From the date of 
first administration of the first-line study treatment until the date of last 
administration of the study treatment in first-line treatment plus 28 days, that is, 
DFirstTrt1L until DLastTrt1L+28 days.

Second-line treatment: From the date of first administration of second-line study 
treatment until the date of last administration of the study treatment in second-line 
treatment plus 28 days, that is, DFirstTrt2L until DLastTrt2L+28.

Whole sequence of treatment: From the date of first administration of the first-line 
study treatment until the date of last administration of study treatment (first-line study 
treatment for patients not entering second-line and second-line study treatment 
otherwise) + 28 days.
3.1.1.9
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the sources presented in Table 3-1 below.
Table 3-1 
Last contact date data sources
Source data
Condition
Last contact date/last date patient was known to be 
alive from survival follow-up page 
Patient status is reported to be alive.


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Source data
Condition
Do not use if patient status is reported unknown.
Start/End dates from further antineoplastic therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
Tumor (RECIST) assessment date
Evaluation is marked as ‘done’.
Vital signs date
At least one non-missing parameter value.
Performance status date
Non-missing performance status.
Start/End dates of AE 
Non-missing verbatim term.
The last contact date on or before the data cut-off date should be used; the cut-off date should 
not be used as the censoring date (even in presence of post cut-off data) unless the patient was 
seen or contacted on the cut-off date.   
Imputed dates (e.g., analysis cut-off date programmatically imputed to replace the missing 
end date of a dose administration record) will not be used to derive the last contact date. 
Partially imputed dates (i.e., only day or day and month imputed) are allowed to be used for 
last contact date only if coming from Survival Follow-up page.
The last contact date will be used for censoring of patients in the analysis of overall survival.
3.1.1.10
Month
For the analysis of time related endpoints, a month is defined as being equal to:
365.25 / 12 = 30.4375 days
For all time related efficacy endpoints, time will be calculated in days, but analyzed and 
reported in months.
3.1.2
Concomitant medications with specific impact on the analysis
3.1.2.1
Inhibitors of CYP3A4 and/or PgP
The following rules are consistent with Internal Clinical Pharmacology Drug-drug interaction 
(DDI) memo, which was updated Dec 2, 2009. The memo 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."
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided.


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Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution. If patient requires co-administration of moderate 
CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus to half the currently used 
dose. Additional dose reductions to every other day may be required to manage toxicities. If 
the inhibitor is discontinued the everolimus dose should be returned to the dose used prior to 
initiation of the moderate CYP3A4/PgP inhibitor.
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant 
use should be avoided.
Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. 
John’s wort), an increase in the dose of everolimus up to twice the currently used daily dose 
should be considered, using 2.5mg - 5mg increments. Enzyme induction usually occurs within 
7-10 days; therefore everolimus dose should be increased by one increment 7 days after the 
start of the inducer therapy. If no safety concerns are seen within the next 7 days, the dose can 
be increased again one additional increment up to a maximum of twice the daily dose used 
prior to initiation of the strong CYP3A4 inducer.
This dose adjustment of everolimus is intended to achieve similar AUC to the range observed 
without inducers. However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers. If the strong inducer is discontinued the everolimus dose 
should be returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer.
The following will be tabulated and summarized:

Clinically relevant drug interactions: substrates, inducers, and inhibitors of isoenzyme 
CYP3A (table  

List of clinically relevant drug interactions mediated by PgP substrates

List of clinically relevant drug interactions mediated by PgP inhibitors

List of clinically relevant drug interactions mediated by PgP inducers
Despite the fact that some of these drugs should be avoided completely and some used with 
caution, there will be patients who took these drugs during the study and therefore these 
concomitant medications need to be identified and classified (review to be performed by a 
Clinical Pharmacologist) and then tabulated and/or listed in the Clinical Study Report as 
appropriate. 
3.1.2.2
Further anti-neoplastic therapy 
Administration of anti-neoplastic drugs (apart from study treatment) and other investigational 
drugs is not allowed during study treatment. Patients who take such anti-neoplastic drugs after 
enrollment but before end of treatment may be identified as protocol deviations. In addition, 
their efficacy data (other than overall survival) will be censored so that the tumor assessments 
made after the intake of anti-neoplastic drugs are not included in efficacy analyses. For details 
on the censoring rules see the [Protocol Appendix 2]. 
Clinical review of individual study data will be performed in order to identify those anti -
neoplastic medications which are considered disallowed. At the project level a list of ATC 
classes and medications is maintained which includes:


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
those ATC classes/medications which have been identified as being disallowed at the 
project level

additional ATC classes/medications which are disallowed for specific indications

those ATC classes/medications which need to be subjected to clinical review at the 
study level. 
3.1.3
Implementation of RECIST
Response and progression evaluation will be performed according to the RECIST 1.0 
guideline version 2 (as described in detail in [Protocol Appendix 2]) whenever it applies. The 
text below gives more detailed instructions and rules to provide further details needed for 
programming.
3.1.3.1
Overall lesions response for patients with only bone lesions at baseline
For patients with only bone lesions at baseline, the RECIST 1.0 will be extended to include 
the evaluation of overall lesion response, which will be based solely on non-target lesion 
responses or an occurrence of a new lesion. Bone lesions will be entered as non-target lesions. 
Specifically, in absence of new lesions, the overall lesion response at each assessment will be 
one of the following: complete response, stable disease, unknown, or progressive disease 
based on non-target lesion responses. Stable disease would include all assessments not 
qualifying for complete response, progressive disease or unknown. In presence of any new 
lesion, the overall lesion response will be progressive disease.
3.1.3.2
Disease progression
For patients with measurable disease at baseline, disease progression will only be assigned if 
it is documented as per RECIST 1.0 by an objective assessment method (e.g. CT scan, MRI, 
X-rays, photos for skin lesions, etc.). 
Patients with bone only lesions, lytic or mixed (lytic+sclerotic) will be allowed to enter the 
study and the following will be considered disease progression among these patients:

The appearance of one or more new lesions in bone

The appearance of one or more new lesions outside of bone

Unequivocal progression of existing bone lesions
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression, unless one of the above-mentioned 
criteria is fulfilled.
In particular, to be considered as an event, disease progression should be demonstrated with 
objective evidence.
3.1.3.3
Best overall response
The best overall response (BOR) will be derived in agreement with RECIST 1.0 criteria. The 
definitions and the details on the derivation are given in Novartis internal guidelines version 2 
[Protocol Appendix 2]. 


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For each treatment line, only tumor assessments performed before the start of any further 
antineoplastic therapies (Section 3.1.2.2) will be considered in the assessment of BOR.
The best overall response is defined with regard to the tumor assessment schedule adopted in 
this study (i.e., every 8 weeks, ± 1 week). The study day within each line (as defined in 
Section 3.1.1.6) will be used for the BOR derivation (i.e., Study Day 1 is DFirstTrt1L for first-
line treatment, and DFirstTrt2L for second-line treatment).
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. 

PR = at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR). 

SD = at least one SD assessment (or better) > 6 weeks after start of study treatment 
(and not qualifying for CR or PR). 

PD = progression ≤ 12 weeks after start of study treatment (and not qualifying for CR, 
PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD for 
more than 6 weeks or early progression within the first 12 weeks).
For each treatment line, patients with best overall response “unknown” will be summarized by 
reason for having unknown status. The following reasons will be used:

No valid post-baseline assessment

All post-baseline assessments have overall response UNK

New anti-neoplastic therapy(*) started before first post-baseline assessment

SD too early

PD too late
(*) in the analysis of 1st treatment line, this includes also the starting of the per protocol 
second-line treatment before any post baseline tumor assessment is performed
Special (and rare) cases where BOR is “unknown” due to both early SD and late PD will be 
classified as “SD too early”.
3.1.3.4
Change in imaging modality
Per RECIST 1.0, the imaging method used at baseline should be matched at all subsequent 
assessment. A strict implementation of RECIST 1.0 would mean that any change in imaging 
method compared to one used at baseline will lead to unknown overall response at given 
assessment. However, it is considered that a change in the use of contrast does not necessarily 
represent a change in the imaging method (for many tumor types, the assessment can be done 
despite the fact that contrast has changed). 
Therefore, in the calculation of overall lesion response the following groups of 
methods/modalities as listed under the same bullet point will be considered the same:

‘CT with contrast’ and ‘CT without contrast’

‘Spiral CT with contrast’ and ‘spiral CT without contrast’


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
‘MRI with contrast’, ‘MRI without contrast’, ‘Dynamic contrast – enhanced MRI’ and 
‘GD-MRI’.
3.1.3.5
Determination of missing adequate tumor assessments
The term ‘missing adequate assessment’ is defined as tumor assessments that are not done or
tumor assessments for which the overall lesion response equals to ‘Unknown’. For the sake of 
simplicity, the ‘missing adequate assessment’ is also referred as ‘missing assessment’.
As detailed in [Protocol Appendix 2], the PFS censoring and event date options depend on the 
presence and the number of missing tumor assessments. For example: 

in the primary analysis of PFS, an event occurring after two or more missing 
assessments is censored at the last adequate assessment.

in one of the sensitivity analyses of PFS, an event occurring after one or more missing 
assessments is back-dated to the date of next scheduled assessment.
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule is based on the time interval (distance) between the last adequate tumor 
assessment date and the event date. 
If the distance is greater than threshold D1 = 8+2(window) = 10 weeks then the analysis will 
assume one missing tumor assessment. If the distance is greater than D2 = (2*8) +2 =18 
weeks then the analysis will assume two missing tumor assessments. The threshold D1 is 
formed based on the protocol specified interval between the tumor assessments plus the 
protocol allowed window around the protocol assessments. Similarly, the threshold D2 is 
formed based on two times the protocol specified interval between the tumor assessments plus 
the protocol allowed window around the assessments.
Therefore, using the D2 definition above, the censoring of an event occurring after ≥2 missing
TAs (in primary PFS analysis) can be refined as follows: if the distance between the last 
adequate TA date and the PFS event date is larger than D2 then the patient will be censored 
and the censoring reason will be 'Event documented after one or more missing tumor 
assessments'.
The same definition of D2 will be used to determine the PFS censoring reason. If the distance 
between the last adequate tumor assessment date and the first of the following dates:
1. analysis cut-off date
2. start date of further anti-neoplastic therapy 
3. date of study treatment discontinuation due to consent withdrawal
4. date of study treatment discontinuation due to loss to follow-up 
is smaller or equal to D2 then the censoring reason will be 1.‘Ongoing’; 2. ‘New cancer 
therapy added’; 3. ‘Withdrew consent’; 4. ‘Loss to follow-up’, respectively, depending on the 
case. However, if this distance is larger than D2 then the censoring reason will always default 
to ‘Adequate assessment no longer available’.


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3.1.3.6
No baseline tumor assessments
If there is no baseline tumor assessment, all post-baseline overall lesion responses will be 
unknown.
Since the timing of disease progression cannot be determined for patients with missing 
baseline tumor assessment, these patients are censored in the PFS analysis at date of 
enrollment in the first-line treatment period or at DFirstTrt2L in the analyses of the second-line 
treatment period.
Patients without baseline tumor assessment in the first-line who die within D2 distance 
(Section 3.1.3.5) of enrollment will still be counted as having an event in the analysis of PFS 
during/after first-line treatment. Likewise in the analyses of the second-line treatment period, 
patients without baseline tumor assessment for the second-line who die within 18 weeks of 
DFirstTrt2L will be counted as having an event in the analysis of PFS during/after second -line 
treatment.
All deaths will be counted in the overall survival analysis regardless of the presence or 
absence of baseline tumor assessment.
3.1.3.7
Construction of waterfall graphs
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from the treatment-line specific baseline in the sum of the longest 
diameter of all target lesions for each patient. The proportions of patients with various degrees 
of tumor shrinkage or growth which can be read directly from the graph can then represent a 
useful efficacy metric. Only patients with measurable disease at baseline and valid post 
baseline assessments will be included in the waterfall graphs.
However, caution needs to be applied to assessments where an occurrence of a new lesion or 
worsening in non-target lesions results in the overall tumor assessment being PD confounding 
the outcome obtained on the target lesions. These assessments will not be displayed as bars in 
the graph. If such a “contradicting” assessment represents the only post-baseline assessment 
for a patient then the patient will be represented by a special symbol (e.g. *) in the waterfall 
graph.
Assessments with “unknown” target lesion response and assessments with unknown overall 
response will be excluded from the waterfall plots. Patients without any valid assessments will 
be completely excluded from the graphs.
The total number of patients displayed in the graph will be used as a denominator when 
calculating the percentages of patients with tumor shrinkage and tumor growth. Footnote will 
explain the reason for excluding some patients (due to absence of any valid assessment).
All possible assessment scenarios are described in Table 3-1.
Table 3-2
Inclusion/exclusion of assessments used in waterfall graph
Criteria for inclusion/exclusion
Possible sources of 
contradictions
case
Target 
response
Overall lesion 
response
Include in waterfall?
Non-target 
response
New 
lesion?


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Criteria for inclusion/exclusion
Possible sources of 
contradictions
1
CR/PR/SD
PD
Yes but as * only
PD
Any
2
CR/PR/SD
PD
Yes but as * only
Any
Yes
3
UNK
UNK or PD
No
Any
Any
4
CR/PR/SD
UNK
No
UNK
No
5
CR/PR/SD
CR/PR/SD
Yes as a bar
SD/IR
No
6
PD
PD
Yes as a bar
Any
Any
Therefore, the following algorithm will be used to construct the graph:
Select “valid” post-baseline assessments to be included, i.e. for each patient and each 
assessment repeat the following four steps.
1. Check the target lesion response and overall lesion response at each assessment. If at 
least one of them is UNK then exclude the whole assessment. Otherwise, go to step 
1.2.
2. Check the overall lesion response. If it is PD then go to step 1.3. Otherwise go to step 
1.4.
3. Check target response. If it’s PD then go to step 1.4. Otherwise flag the assessment 
with *.
4. Calculate the % change from baseline in target lesions.
For each patient, go through all valid assessments identified in step 1 and find the assessment 
with best % change from baseline in target lesions. The “best” means best for the patient, i.e. 
the largest shrinkage or if a patient only has assessments with tumor growth take the 
assessment where the growth is minimal. (Example 1: Patient 1 has the following % changes 
from baseline at assessments 1, 2, 3, 4 and 5, respectively: -10%; -25%; -13%; -4% and +6%. 
His/her best % change is then -25%. Example 2: Patient 2 has the following % changes from 
baseline at assessments 1, 2 and 3, respectively: +5%; +18% and +35%. His/her best % 
change is then +5%.
Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only * flagged assessment(s) will be displayed separately.
The waterfall graph will use the investigator reported overall lesion responses (see Source 1 in 
Table 1-1). 
The best overall response (BOR) will be shown above each of the displayed bars in the graph. 
The following conventions will be used to display the waterfall graphs:
1. Bars under the horizontal axis representing tumor shrinkage
2. Bars above the horizontal axis representing tumor growth
3. “Zero” bars with * symbol representing patients with contradiction.
The rationale for this order is that the third category (patients with contradiction) logically 
follows after the second category (patients with tumor growth).


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3.1.4
Time interval for ECOG performance status
The following time based intervals will be used to group the ECOG PS data over time for 
each treatment line. Day x is defined in Section 3.1.1.6. 
Time Interval
Baseline
on or before the first date of study treatment in first line, 
second line, respectively 
Week 4
day 2 to day 42
Weeks 8, 
12, …
+/- 2 weeks centered around the planned assessment 
date:
i.e. days 43, 70 for Week 8 (3rd assessment)
      days 71, 98 for Week 12 (4th assessment)
      days [(k-1)*28-13; (k-1)*28+14] (kth assessment, 
k>2)
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. 
3.1.5
Definition of the first occurrence of stomatitis
3.1.5.1 Based on OSDQ
Multiple occurrences of stomatitis can be recorded in the OSDQ questionnaire. To define the 
first occurrence of stomatitis based on the OSDQ data, the following rules will be applied.
Answer to the question 1b of the OSDQ questionnaire will be used to define the start and end 
dates of the first occurrence of stomatitis:
Q1b: When did you experience the first symptoms of mouth and throat soreness (only ask this 
question on Day 1 of the questionnaire)?
Start date of the first occurrence of stomatitis is defined as the first date ever recorded for 
question Q1b.
End date of the first occurrence of stomatitis is defined as the date of the last OSDQ 
questionnaire that was completed before a second date is recorded for question Q1b.
An example is provided below:
Patient
Questionnaire 
date
Date 
recorded for 
question Q1b 
Stomatitis 
occurrence 
number
101
19-Nov-14
19-Nov-14
1
101
20-Nov-14
.
1
101
21-Nov-14
.
1
101
04-Dec-14
03-Dec-14
2


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In the table above, the 3 first records belong to the first occurrence of stomatitis. This first 
occurrence started on 19-Nov-2014 and ended on 21-Nov-14.
3.1.5.2
Based on AE CRFs
Multiple AE CRF records of the AESI stomatitis can correspond to the same occurrence 
(investigators could report an end date for stomatitis and add a new record in the CRF only to 
update the grade of the current stomatitis occurrence or to use a different verbatim). In order 
to identify the first occurrence of the AESI stomatitis, it is needed to identify the AE records 
which belong to the same occurrence. 
The definition is as follows: 
If the difference between the previous AE record end date and the following AE record start 
date is less or equal to 1 day then the two records will be considered to belong to the same 
occurrence.
If this difference is greater than 1 day then the new AE record will be considered to be a new 
occurrence of the AESI stomatitis. 
In the analysis of duration of the first incidence of the AESI stomatitis, only the first 
occurrence will be considered.
Start date of the first occurrence of the AESI stomatitis is defined as the earliest start date of 
the AE records belonging to the first occurrence of the AESI stomatitis.
End date of the first occurrence of the AESI stomatitis is defined as the latest end date of AE 
records belonging to the first occurrence of the AESI stomatitis.
An example is provided below:
Patient
AE PT
AESI grouping
Start date
End date
Occurrence 
number
101
Stomatitis
Stomatitis
19-Nov-14
22-Nov-14
1
101
Stomatitis
Stomatitis
23-Nov-14
30-Nov-14
1
101
Mouth 
Ulceration
Stomatitis
30-Nov-14
07-Dec-14
1
101
Stomatitis
Stomatitis
15-Feb-15
15-Apr-15
2
In the table above, the 3 first records belong to the same occurrence of the AESI stomatitis 
(first occurrence). The 4th record is a new occurrence (second occurrence).
In this example, the start date of the first occurrence of the AESI stomatitis is 19-Nov-14 and 
the end date is 07-Dec-14.
3.2
Details of the statistical analysis
3.2.1
Baseline comparability
Appropriate descriptive summary statistics of baseline variables will be provided as in-text 
tables in the core CSR and also in Section 14 in the post-text tables. The summaries will be 
performed in first line and second line respectively, but no p-values will be provided.


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3.2.2
Time-to-event analyses
The following sections present a general methodology to be used to analyze the following 
time-to-event variables:

Progression-free survival

Overall survival

Time to definitive deterioration of the ECOG score by one category of the score from 
baseline

Time to the first incidence of AE
3.2.2.1
Kaplan-Meier estimates
The survival function will be estimated using the Kaplan-Meier (product-limit) method as 
implemented in PROC LIFETEST with method=KM option in SAS. Median survival will be 
obtained along with 95% confidence intervals calculated from PROC LIFETEST output using 
the loglog option available within PROC LIFETEST. Kaplan-Meier estimates with 95% 
confidence intervals at specific time points will be summarized. 
The Kaplan-Meier graphs as well as the statistics (hazard ratio, etc.) will be obtained from the 
SAS software.
Example code fragment
Here the input dataset, DSET, contains two variables, SURVTIME is the survival time (in months) 
for each subject, and the variable CENS indicates censoring with a value of 1 indicating a 
censored time, and 0 otherwise. The ‘(1)’ following CENS in the time statement is used to 
indicate the state that denotes censoring. The output dataset quart gives estimates for the 
quartiles (with 95% confidence intervals) of the quartiles of the survival distribution. The 
quartile with percent label 50 corresponds to the median. The output dataset OUTDATA
contains survival distribution function estimates with 95% confidence intervals constructed 
using Greenwood’s estimate of the standard error of the Kaplan-Meier estimate. To identify 
the Kaplan-Meier estimate (and corresponding 95% confidence interval) at a fixed time point, 
identify the value of SURVTIME at which there was a failure that is either at, or the last one 
before the time point of interest. The estimate and confidence interval at this time point is the 
correct one to display.
ods output Quartiles=quart;
proc lifetest data=dset method=KM outsurv=outdata CONFTYPE=LOGLOG;
   time survtime*cens(1);
run;


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3.2.3
Exact confidence intervals for response rate
Exact confidence intervals for proportions of patients with ORR and CBR will be derived 
using SAS PROC FREQ with the binomial option. Note that PROC FREQ will produce the 
confidence interval for the lowest level of the analysis variable, therefore care must be taken
that the variable be coded correctly in order to achieve the desired result, i.e. with responders 
coded as 0 and non-responders as 1. It should also be noted that if the data analyzed contains 
only non-responders that the default interval produced will be for non-responders and the 
interval for responders must be produced by subtracting both the upper and lower limits from 
1.
Example code fragment
Here the input dataset, DSET, contains a line per patient with an indicator variable, VAR, that is 
equal to zero if a patient has the response of interest and one otherwise. The required exact 
limits are in the ods output dataset BINPROP, labeled XL_BIN and XU_BIN.
proc freq data=dset order=internal;
   table var / binomial;
run;
If the input dataset contained only non-responders, then the interval produced is for non-
responders, and the required interval then needs to be derived with the following code:
data binprop2(keep=name1 nvalue1);
   set binprop(where=(name1 in ("XL_BIN", "XU_BIN")));
   if name1 eq "XL_BIN" then name1="XU_BIN";
                        else name1="XL_BIN";
   nvalue1 = 1-nvalue1;
run;


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4
References
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Brookmeyer, R. and Crowley, J. (1982): A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.
Clopper, C., Pearson, S (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika 26: 404-413.
Collet D (1994): Modeling survival data in medical research. London, Chapman & Hall
Dimitrienko A., Molenberghs G., Chuang-Stein Ch., Offen W. (2005). Analysis of clinical 
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