Clinical trial NCT01789281
Conditions: Neoplasms
Keywords: Neoplasms Carcinoid tumor Neuroendocrine tumor
Sponsor: Novartis Pharmaceuticals
Start date: 2013-05-14; Completion date: 2020-08-28
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study to allow access to everolimus for patients who are on everolimus treatment in a Novartis-sponsored study and are benefiting from the treatment as judged by the investigator

Detailed description:
This multi-center, open-label roll-over study aimed to better characterize the long-term safety of everolimus in subjects currently being treated in a Novartis-sponsored studies and who were receiving clinical benefit on the current study treatment as judged by the Investigator.

The study was designed to provide continued treatment with everolimus monotherapy to the subjects. Subjects were allowed to continue combination therapy with Sandostatin LAR® Depot if they were receiving this combination therapy on the parent protocol. Subjects were allowed to continue in this roll-over study until they no longer benefitted from the everolimus treatment as judged by the Investigator, discontinued due to toxicities, subject withdrew consent or lost to follow-up, disease progression, protocol non-compliance, or subject death, whichever occurred first. A subject was considered to have reached end of study when everolimus treatment was permanently discontinued.

As per the original protocol, it was designed to collect only serious adverse events (SAEs) and protocol defined adverse events of special interest (AESIs). However, due to the feedback received from health authorities, the protocol was amended in 2016 (3 years after study was initiated) to collect all AEs (non-serious and serious AEs, and AESIs). The protocol was also amended to include an Investigator assessment of clinical benefit at every visit for remaining subjects.

Arms: arm 1: Participants who were receiving everolimus in a Novartis-sponsored study, were not progressing on the current study treatment and were unable to access everolimus treatment outside of a clinical trial. Participants receiving everolimus treatment in combination with Sandostatin LAR Depot on the parent protocol were allowed to continue Sandostatin LAR Depot treatment.
Interventions: intervention 1: Everolimus intervention 2: Sandostatin LAR Depot
Intervention descriptions: intervention 1: Everolimus was provided by the investigator in 2.5 mg, 5 mg or 10 mg tablets for daily oral administration. The starting dose of everolimus was the same as the last dose that was given in the parent study. Dose modification thereafter was done at the discretion of the Investigator based upon what is in the subject's best interest. intervention 2: Sandostatin LAR Depot was provided by Novartis or by the investigational site considering local regulations. The dose and frequency of Sandostatin LAR Intramuscular injections was the same as the last dose that was given in the parent study.

Protocol documents:
Prot_000.pdf: 
Global Medical Affairs
RAD001 (Everolimus)
Afinitor
Oncology Clinical Protocol CRAD001C2X01B1&7
An open-label, multi-center everolimus roll-over protocol 
for patients who have completed a previous Novartis-
sponsored everolimus study and are judged by the 
investigator to benefit from continued everolimus 
treatment
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-004707-12
Version number
01 (Amendment) (Clean)
Development phase
IV
Document status
Final
Release date
18-Mar-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015
PPD


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................7
Amendment 01 (18-Mar-2016) ...........................................................................................9
Protocol summary:.............................................................................................................11
1
Background........................................................................................................................13
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............13
1.2
Introduction to investigational treatment(s) and other study treatment(s).............13
1.2.1
Overview of everolimus........................................................................13
2
Rationale............................................................................................................................16
2.1
Study rationale and purpose...................................................................................16
2.2
Rationale for the study design ...............................................................................16
2.3
Rationale for dose and regimen selection..............................................................16
2.4
Rationale for choice of combination drugs............................................................17
2.5
Rationale for choice of comparators drugs............................................................17
2.6
Risks & Benefits....................................................................................................17
3
Objectives and endpoints...................................................................................................18
4
Study design ......................................................................................................................20
4.1
Description of study design ...................................................................................20
4.2
Timing of interim analyses and design adaptations...............................................21
4.3
Definition of end of study......................................................................................21
4.4
Early study termination..........................................................................................21
5
Population..........................................................................................................................21
5.1
Patient population..................................................................................................21
5.2
Inclusion criteria ....................................................................................................21
5.3
Exclusion criteria...................................................................................................22
6
Treatment...........................................................................................................................23
6.1
Study treatment......................................................................................................23
6.1.1
Dosing regimen .....................................................................................23
6.1.2
Ancillary treatments..............................................................................24
6.1.3
Rescue medication ................................................................................24
6.1.4
Guidelines for continuation of treatment ..............................................24
6.1.5
Treatment duration................................................................................24


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6.2
Dose escalation guidelines.....................................................................................24
6.3
Dose modifications ................................................................................................24
6.3.1
Dose modification and dose delay ........................................................24
6.3.2
Follow-up for toxicities.........................................................................25
6.3.3
Anticipated risks and safety concerns of the study drug.......................26
6.4
Concomitant medications ......................................................................................26
6.4.1
Permitted concomitant therapy .............................................................26
6.4.2
Permitted concomitant therapy requiring caution and/or action...........26
6.4.3
Prohibited concomitant therapy ............................................................28
6.4.4
Use of Bisphosphonates (or other concomitant agents)........................28
6.5
Patient numbering, treatment assignment or randomization .................................28
6.5.1
Patient numbering .................................................................................28
6.5.2
Treatment assignment or randomization...............................................29
6.5.3
Treatment blinding................................................................................29
6.6
Study drug preparation and dispensation...............................................................29
6.6.1
Study treatment packaging and labeling ...............................................29
6.6.2
Drug supply and storage........................................................................30
6.6.3
Study drug compliance and accountability ...........................................30
6.6.4
Disposal and destruction .......................................................................31
7
Visit schedule and assessments .........................................................................................31
7.1
Study flow and visit schedule................................................................................31
7.1.1
Molecular pre-screening........................................................................33
7.1.2
Screening...............................................................................................33
7.1.3
Run-in period ........................................................................................33
7.1.4
Treatment period ...................................................................................33
7.1.5
Discontinuation of study treatment .......................................................33
7.1.6
Follow up for safety evaluations...........................................................35
7.1.7
Lost to follow-up...................................................................................35
7.2
Assessment types...................................................................................................35
7.2.1
Efficacy assessments.............................................................................35
7.2.2
Safety and tolerability assessments.......................................................35
7.2.3
Pharmacokinetics ..................................................................................35
7.2.4
Biomarkers ............................................................................................35
7.2.5
Resource utilization...............................................................................36
7.2.6
Patient reported outcomes.....................................................................36
8
Safety monitoring and reporting........................................................................................36


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8.1
Adverse events.......................................................................................................36
8.1.1
Definitions and reporting ......................................................................36
8.1.2
Laboratory test abnormalities................................................................37
8.1.3
Adverse events of special interest.........................................................38
8.2
Serious adverse events...........................................................................................38
8.2.1
Definitions.............................................................................................38
8.2.2
Reporting...............................................................................................39
8.3
Emergency unblinding of treatment assignment ...................................................40
8.4
Pregnancies............................................................................................................40
8.5
Warnings and precautions......................................................................................40
8.6
Data Monitoring Committee..................................................................................40
8.7
Steering Committee ...............................................................................................41
9
Data collection and management.......................................................................................41
9.1
Data confidentiality ...............................................................................................41
9.2
Site monitoring ......................................................................................................41
9.3
Data collection.......................................................................................................42
9.4
Database management and quality control............................................................42
10 Statistical methods and data analysis ................................................................................42
10.1
Analysis sets ..........................................................................................................42
10.1.1
Full Analysis Set ...................................................................................42
10.1.2
Safety set ...............................................................................................42
10.1.3
Dose-determining analysis set...............................................................43
10.2
Patient demographics/other baseline characteristics .............................................43
10.3
Treatments (study treatment, compliance) ............................................................43
10.4
Primary objective...................................................................................................43
10.4.1
Variable.................................................................................................43
10.4.2
Statistical hypothesis, model, and method of analysis..........................43
10.4.3
Handling of missing values/censoring/discontinuations.......................43
10.4.4
Supportive and Sensitivity analyses......................................................43
10.5
Secondary objectives .............................................................................................43
10.5.1
Key secondary objective(s)...................................................................43
10.5.2
Other secondary efficacy objectives .....................................................43
10.5.3
Safety objectives ...................................................................................43
10.6
Exploratory objectives...........................................................................................44
10.7
Interim analysis......................................................................................................44
10.8
Sample size calculation..........................................................................................44


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10.9
Power for analysis of key secondary variables......................................................44
11 Ethical considerations and administrative procedures ......................................................45
11.1
Regulatory and ethical compliance........................................................................45
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................45
11.3
Informed consent procedures.................................................................................45
11.4
Discontinuation of the study..................................................................................46
11.5
Publication of study protocol and results...............................................................46
11.6
Study documentation, record keeping and retention of documents.......................46
11.7
Confidentiality of study documents and patient records .......................................47
11.8
Audits and inspections...........................................................................................47
11.9
Financial disclosures..............................................................................................47
12 Protocol adherence ............................................................................................................47
12.1
Amendments to the protocol..................................................................................47
13 References (available upon request)..................................................................................48
List of figures
Figure 4-1
Study design..........................................................................................20
List of tables
Table 3-1
Objectives and related endpoints ..........................................................19
Table 6-1
Dose and treatment schedule.................................................................23
Table 6-2
Combination therapy dose and treatment schedule...............................23
Table 6-3
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A................................................................................27
Table 6-4
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors ...............................28
Table 6-5
Preparation and dispensing ...................................................................29
Table 6-6
Packaging and labeling .........................................................................29
Table 6-7
Supply and storage of study treatments ................................................30
Table 7-1
Visit evaluation schedule ......................................................................32


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List of abbreviations
AE
Adverse Event
BSC
Best Supportive Care
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
EC
European Commission
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IIT
Investigator-initiated Trial
IRB
Institutional Review Board
mTOR
mammalian Target of Rapamycin
OGD&GMA
Oncology Global Development and Global Medical Affairs 
o.d.
omnia die/once a day
PI
Principal Investigator
p.o.
per os/by mouth/orally
REB
Research Ethics Board
SAE
Serious Adverse Event
SOP
Standard Operating Procedure


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational 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 Number (Patient No)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Roll-over study
A roll-over study allows patients from multiple parent studies spanning 
multiple indications to continue to be treated within one study after the 
completion of the parent study(ies)
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the 
size of the tumor, whether lymph nodes contain cancer, and whether 
the cancer has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
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.


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Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further visits 
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Amendment 01 (18-Mar-2016)
Amendment rationale 
The main purpose of the amendment is to change the primary endpoint to safety to better 
characterize the long-term safety of the compound.  In addition, the protocol has been 
amended to include the collection of all AEs (including non-serious AEs) and an investigator 
attestation of continued clinical benefit.
This roll-over study has been opened since 13-May-2013 with 32 patients enrolled and 21
patients ongoing.
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 following changes have been implemented: 
Section 1.1: Removed the purpose of the study as this was redundant to Section 2.1.
Section 1.2.1: Overview language updated based on IB update.
Section 1.2.1.2: Clinical experience language updated based on IB update.
Section 2.1: Updated purpose to reflect new primary endpoint.
Section 2.2: Updated rationale to reflect new primary endpoint.
Table 3-1: Updated with revised study objectives.  The primary objective is to evaluate long 
term safety data. The secondary objective is to evaluate clinical benefit as assessed by the 
investigator.
Section 4.1: Updated description of study to reflect new primary endpoint and to clarify that 
all adverse events and serious adverse events will be collected continuously throughout the 
study.  Visit frequency updated to quarterly.  Updated to specify that at every visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment. 
Section 4.2: Updated to reflect that interim analyses are not applicable.
Section 4.3: Updated definition of the end of study.
Section 5.3: Updated contraception languagebased 
on 
new 
guidelines 
on 
pregnancy 
prevention.
Section 6.1: Removed reference to drug shipments to sites.
Section 6.1.5: Updated to specify that at every visit, the investigator is required to confirm 
that the patient continues to have clinical benefit and may continue receiving study treatment.
Section 6.3.1: Added reference to IB for dose modifications.
Section 6.3.2: Added that patients will be followed for adverse events in addition to serious 
adverse events.


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Section 6.3.2.1: New section added for drug-induced liver toxicity language.
Section 6.4: Added reference to IB for use concomitant medications.
Table 6-3: Updated inducers, and inhibitors of isoenzyme CYP3A based on IB update.
Table 6-4: Updated substrates, inducers, inhibitors of PgP and PgP/CYP3A dual inhibitors 
based on IB update.
Section 6.4.2: Updated vaccination languagebased on IB update.
Table 6-5: Updated to reflect change to quarterly visits.
Table 7-1: Updated to include investigator attestation of clinical benefit at every quarterly 
visit, collection of all adverse events, relevant medical history, monthly at home pregnancy 
testing for female patients of child bearing potential and the study evaluation completion 
eCRF page at the end of the 30 day safety follow up.
Section 7.1.2.3: Updated to reflect collection of demographics and relevant medical history.
Section 7.1.4: Updated to specify amount of drug supply to be provided, visits are quarterly, 
and that the investigator is required to confirm that the patient continues to have clinical 
benefit at every visit and may continue receiving study treatment.
Section 7.1.5: Section name updated.  
Section 7.1.5.1: Section name updated in addition to adding new language.
Section 7.1.6: Section name updated.  Added stipulation that adverse events be collected.
Section 7.1.6.1: Added new section for study evaluation completion.
Section 7.1.7: Added Lost to follow up language.
Section 7.2.1: Updated to specify that the investigator is required to confirm that the patient 
continues to have clinical benefit at every visit and may continue receiving study treatment.
Section 7.2.2: Updated pregnancy testing language.
Section 8: Updated with new AE/SAE reporting process.
Section 10: Updated statistical analysis section based on revised study objectives.
Section 11.4: Added reference to Section 4.4.
Section 13: Removed references no longer used.
References to the parent protocol have been removed in favor of a newer source that can be 
used (for example, the IB), as applicable.  The protocol summary has also been updated to 
reflect the above changes, as applicable.
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.


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Protocol summary: 
Title
An open label, multi-center everolimus roll-over protocol for patients who have 
completed a previous Novartis-sponsored everolimus study and are judged by the 
investigator to benefit from continued everolimus treatment.
Sponsor and Clinical Phase
Novartis, IV.
Investigation type
Drug.
Study type
Interventional.
Purpose and rationale
The purpose of this study is to better characterize the long- term safety of
everolimus in patients who are on everolimus treatment in a Novartis-sponsored, 
Oncology Global Development & Global Medical Affairs (OGD&GMA) study and 
are benefiting from the treatment as judged by the investigator.
Primary Objective
To evaluate long term safety data.
Secondary Objectives
To evaluate clinical benefit as assessed by the investigator 
Study design
This is a multi-center, open label study to better characterize the long-term safety
of everolimus in patients being treated in current Novartis-sponsored OGD&GMA
studies and who are benefiting from treatment with everolimus as judged by the 
investigator. There will be no screening period for this study. Eligible patients are to 
be consented and can start their treatment with everolimus as soon as they enter 
the study. All patients must report to the study site for their first visit at which time, 
a quarterly supply of everolimus can be dispensed to the patient/or as per local 
practice.
Patients must return to the study center on a quarterly basis 12 weeks +/- 1 week) 
for resupply of study medication at which time drug dispensing information and 
adverse events will be collected. The patient may return to the clinic at any given 
time as per standard of care, however, only four study visits per year will be 
recorded. All adverse events and serious adverse events will be collected 
continuously throughout the study.
Patients will continue to be treated until they are no longer benefiting from 
everolimus as judged by the investigator (disease progression), develop 
unacceptable toxicities, withdraw consent, are non-compliant to the protocol, or the 
patient dies, whichever comes first.
A patient will reach the end of study when everolimus treatment is permanently 
discontinued and the end of treatment visit has been performed. All patients must 
be followed for adverse events and serious adverse events for 30 days after the 
last dose of study treatment. Following this there are no further follow-up study 
visits.
The study is expected to remain open for 10 years or until such time that enrolled 
patients no longer need treatment with everolimus or are able to obtain commercial 
supply according to local regulations for their medical conditions. 
Population
Male and female patients, who are currently enrolled in a Novartis-sponsored, 
OGD&GMA everolimus study, are benefiting from treatment with everolimus and 
have fulfilled all their requirements in the parent study. All objectives of the parent 
study must have been reached, and the study must be in the process of being 
completed & reported. Approximately 50 patients may enroll into this study.
Inclusion criteria
Patient is currently enrolled in a Novartis- sponsored, Oncology Clinical 
Development & Medical Affairs study receiving everolimus and has fulfilled all their 
requirements in the parent study.
Patient is currently benefiting from the treatment with everolimus, as determined by 
the parent study criteria.
Patient has demonstrated compliance, as assessed by the investigator, with the 
parent study protocol requirements.


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Exclusion criteria
Patient has been permanently discontinued from everolimus study treatment in the 
parent study due any reason.
Patient has participated in a Novartis sponsored combination trial where 
everolimus was dispensed in combination with unapproved or experimental 
treatments and is still receiving the unapproved or experimental treatment. 
Investigational and 
reference therapy
Everolimus, 2.5 - 10 mg/day.
Efficacy assessments
At every quarterly visit, the investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment.
Safety assessments
All adverse events and serious adverse events will be collected continuously 
throughout the study.
Other assessments
Not applicable.
Data analysis
Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits. The assessment of safety will be based mainly on 
the frequency of AEs and SAEs.
Key words
Everolimus roll-over study to better characterize the long term-term safety of 
everolimus in patients receiving everolimus in a Novartis-sponsored OGD&GMA
study which has reached its objectives and who are benefiting from treatment with 
everolimus.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
The roll-over study is designed to accept patients with varied disease origins. Please refer to 
the parent protocol for the disease background information and rationale for use of everolimus 
in their individual indications.  See Section 1.2.1.2.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of everolimus
Everolimus is a signal transduction inhibitor (STI) targeting mTOR, or more specifically, 
mTORC1 (mammalian 'target of rapamycin' complex 1). mTOR is a key serine-threonine 
kinase playing a central role in the regulation of cell growth, proliferation and survival. The 
regulation of mTORC1 signaling is complex, being modulated by mitogens, growth factors, 
energy and nutrient availability. mTORC1 is an essential regulator of global protein synthesis 
downstream on the PI3K/AKT/mTOR pathway, which is dysregulated in the majority of 
human cancers (Boulay and Lane 2007). Consistent with the known activity of mTORC1, its 
inhibition by everolimus has been shown to reduce cell proliferation, glycolysis and 
angiogenesis in solid tumors in vivo, both through direct antitumor cell activity and inhibition 
of the tumor stromal compartment.
mTOR is a key regulatory protein affecting various cell functions (Boulay and Lane 2007). 
The main known functions of mTOR include:

Function as a sensor of mitogens, growth factors, energy and nutrient levels, facilitating 
cell-cycle progression through the G1 to- S- phase in appropriate growth conditions.

Regulation of protein synthesis important for tumor cell proliferation and angiogenesis 
through inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S 
ribosomal S6 kinases (e.g. p70S6K1). For example, activation of the mTOR pathway 
leads to:

Increased production of pro-angiogenic factors (e.g. VEGF) in tumors.

Tumor, endothelial and smooth muscle cell growth and proliferation.
1.2.1.1
Non-clinical experience
For latest information on the pre-clinical pharmacology and toxicology of everolimus please 
refer to the current Investigator Brochure (IB).
1.2.1.2
Clinical experience
In oncology, everolimus has been in clinical development since 2002 for patients with various 
hematologic and non-hematologic malignancies; as a single agent or in combination with 
antitumor agents. Malignancies that are currently being evaluated in Novartis sponsored 


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studies include the following: metastatic renal cell carcinoma (mRCC), breast cancer, 
pancreatic neuroendocrine tumors (pNET/NET), diffuse large B cell lymphoma (DLBCL), 
and hepatocellular cancer (HCC). In addition, treatment of patients with tuberous sclerosis 
complex (TSC) associated subependymal 
giant cell astrocytoma (SEGA),
renal 
angiomyolipoma, and epilepsy are also being evaluated.
Phase I dose escalating studies, exploratory Phase I/II/III studies with everolimus as single 
agent or in combination with other anti-cancer agents, Phase II/III studies of everolimus in 
different indications, Phase III double-blind studies and Phase IV studies are contributing to 
the extensive clinical database.
Approximately 27,399 patients, (excluding those patients who received marketed 
Afinitor®/Votubia®, those on planned and roll over studies as well as excluding investigator-
sponsored studies) have been enrolled in studies with everolimus as of 31-Mar-2015.
Oncology
Everolimus was approved by FDA on 30-Mar-2009 under the trade name Afinitor® for the 
treatment of patients with advanced 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. As of 31-Mar-2015, Afinitor® has been 
approved in 121 countries worldwide for the treatment of patients with advanced RCC.
On 05-May-2011, FDA approved Afinitor® for the “treatment of progressive pNET in patients 
with unresectable, locally advanced or metastatic disease. Afinitor is not indicated for the 
treatment of patients with functional carcinoid tumors”. 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. As of 31-Mar-
2015, Afinitor® has been approved in >115 countries worldwide for the treatment of patients 
with pNET/neuroendocrine tumors.
On 20-Jul-2012, FDA approved Afinitor® for the treatment of postmenopausal women with 
advanced hormone receptor-positive, HER2-negative 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 hormone receptor-positive, HER2/neu negative 
advanced breast cancer, in combination with exemestane, in postmenopausal women without 
symptomatic visceral disease after recurrence or progression following a non-steroidal 
aromatase inhibitor. As of 31-Mar-2015, Afinitor® has been approved in >115 countries for 
the treatment of patients with advanced hormone receptor-positive, HER2-negative breast 
cancer.
Tuberous sclerosis complex
Afinitor® received accelerated approval from FDA on 29-Oct-2010 for the “treatment of 
patients with SEGA associated with tuberous sclerosis complex (TSC) who require 
therapeutic intervention but are not candidates for curative surgical resection. The EC granted 
conditional approval on 02-Sep-2011 for everolimus under the trade name Votubia® for the 
“treatment of patients aged 3 years and older with SEGA associated with TSC who require 


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therapeutic intervention but are not amenable to surgery.  Afinitor® received accelerated 
approval from FDA on 26-Apr-2012 for the “treatment of adult patients with renal 
angiomyolipoma and TSC, not requiring immediate surgery
For further details please refer to the current everolimus IB.
Pharmacokinetics
Everolimus is rapidly absorbed after oral administration, with a median time to peak blood 
levels (tmax) of 1-2 hours postdose. The extent of absorption is estimated at above 11%. The 
area under the blood concentration-time curve (AUC) is dose-proportional over the dose range 
of 5 to 70 mg tested while maximum blood concentration Cmax appears to plateau at dose 
levels higher than 20 mg. The terminal half-life in cancer patients averaged 30 hours, which is 
similar to that in healthy subjects. A high-fat meal altered the absorption of everolimus with 
1.3 hour delay in tmax, a 60% reduction in Cmax and a 16% reduction in AUC. In whole blood, 
approximately 80% of everolimus is contained in red blood cells. Of the fraction of drug 
contained in plasma, 74% is protein-bound. The apparent distribution volume (Vz/F) after a 
single dose was 4.7 L/kg. Everolimus is eliminated by metabolism, mainly by hydroxylation, 
then excreted into the feces >80%.
Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal 
wall. Everolimus is also a substrate of P-glycoprotein (PgP). Therefore, absorption and 
subsequent elimination of systematically absorbed everolimus may be influenced by 
medicinal products that interact with CYP3A4 and/or P-glycoprotein. In vitro studies showed 
that everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6 substrates, potentially 
increasing the concentrations of medicinal products eliminated by these enzymes. In two 
phase III clinical trials in patients following kidney transplantation, strong inhibitors of 
CYP3A4 (azoles, antifungals, cyclosporine, erythromycin) have been shown to reduce the 
clearance of everolimus therapy thereby increasing everolimus blood levels. Similarly, 
Rifampin, a strong inducer of CYP3A4, increases the clearance of everolimus thereby 
reducing everolimus blood levels. Another drug-drug interaction study of everolimus 
administered with a sensitive CYP3A4 substrate midazolam showed that while everolimus did 
not influence the hepatic metabolism of midazolam, it led to minor increases in bioavailability 
of midazolam likely due to influences of pre-systemic metabolism. Caution should be 
exercised when co-administering everolimus with CYP3A4 inhibitors, inducers, or substrates 
with a narrow therapeutic index.
Pharmacodynamic studies
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral biomarker 
(S6 kinase inhibition in peripheral blood mononuclear cells) suggests that 5 to 10 mg daily 
should be an adequate dose to produce a high-degree of sustained target inhibition. 
Furthermore, molecular pharmacodynamic (MPD) studies using IHC in biopsied tumor tissue 
assessed the degree of inhibition and its duration (for p-S6, p-4E-BP1 and p-Akt expression) 
with the daily and weekly dosing. The pathologist was blinded for the biopsy sequence. There 
was almost complete inhibition of p-S6 at all doses and schedules studied (p=0.001). 
Preliminary results suggest a dose-related decrease in p-4E-BP1 and increase in p-Akt 
expression with maximal effect at 10 mg daily and ≥50 mg weekly. 


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For further details please refer to the current everolimus IB.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to better characterize the long-term safety of everolimus in 
patients who are currently receiving everolimus treatment in a Novartis-sponsored, 
OGD&GMA study that has reached its study objectives and are not progressing on the current 
study treatment as judged by the investigator. Parent studies eligible to participate in the roll-
over study will be decided by Novartis. Investigator initiated trials (IITs) will not be included. 
The primary objective of the parent study must have been reached and the parent study must 
be in the process of being completed and reported.
Patients will continue to receive everolimus until one of the following occurs: no treatment 
benefit (disease progression) as judged by the investigator, unacceptable toxicity develops, 
consent withdrawal, protocol non-compliance, the investigator feels it is no longer in the 
patient’s best interest to continue therapy, or the patient’s death.
The roll-over protocol is designed to provide continued treatment with everolimus 
monotherapy to patients. If patients are receiving treatment of everolimus in combination with 
other approved therapies, they can participate in the roll-over study, but it is not intended for 
combination with unapproved or experimental treatments.  Therefore, patients may be 
allowed to continue combination therapy with Sandostatin LAR® Depot if they are currently 
receiving this combination therapy on the parent protocol and at the discretion of the 
investigator. Sandostatin LAR® Depot is a formulation of octreotide which can be 
administered on a once monthly schedule and is available commercially worldwide. 
Sandostatin LAR® Depot has been used to treat the symptoms associated with metastatic 
carcinoid tumors (flushing and diarrhea), and vasoactive intestinal peptide (VIP) secreting 
adenomas (watery diarrhea).  For additional details please refer to the national prescribing 
information.
2.2
Rationale for the study design
This is a multi-center, open-label, phase IV study to better characterize the long-term safety of
everolimus in patients being treated in a current Novartis-sponsored, OGD&GMA study and 
who are benefiting from treatment with everolimus. Patients may be allowed to continue 
combination therapy with Sandostatin LAR® Depot if they are currently receiving this 
combination therapy on the parent protocol and at the discretion of the investigator.
This study will not include a screening phase as patients will transfer directly from the parent 
study and will commence with everolimus as soon as they are consented and meet the 
inclusion criteria of the roll-over protocol.
2.3
Rationale for dose and regimen selection
Everolimus will be provided as 2.5 mg, 5 mg or 10 mg tablets. At the time of transition to the 
roll-over study, the starting dose of everolimus should be the same as the last dose that was 


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given in the parent study. Dose modification thereafter may be done at the discretion of the 
investigator based upon what is in the patient’s best interest.  
The roll-over protocol is designed to provide continued treatment with everolimus 
monotherapy to patients. If patients are receiving treatment of everolimus in combination with 
other approved therapies, they can participate in the roll-over study but it is not intended for 
combination with unapproved or experimental treatments.  Therefore, for patients receiving 
everolimus in combination with Sandostatin LAR® Depot, Sandostatin LAR® Depot will be 
provided by Novartis or by the investigational site considering local regulations. At the time 
of transition to the roll-over study, the starting dose of Sandostatin LAR® Depot should be the 
same as the last dose that was given in the parent study.
2.4
Rationale for choice of combination drugs 
Patients may be allowed to continue combination therapy with everolimus and Sandostatin 
LAR® Depot at the discretion of the investigator if they are currently receiving this 
combination therapy on the parent protocol and are deriving benefit as defined in the criteria 
of the parent protocol.
2.5
Rationale for choice of comparators drugs
Not applicable.
2.6
Risks & Benefits
Postmenopausal women with hormone receptor-positive advanced breast 
cancer in combination with aromatase inhibitors, after prior endocrine therapy
Overall, everolimus + exemestane is considered to have a positive benefit-risk profile for 
postmenopausal women with hormone receptor-positive advanced breast cancer in 
combination with an aromatase inhibitor, after prior endocrine therapy; the benefits of therapy 
with everolimus + exemestane outweigh any potential risks.
Advanced neuroendocrine tumors of pancreatic origin 
Everolimus has a positive benefit-risk profile for patients with advanced pancreatic
neuroendocrine tumors (pNET). Prior study results support the use of everolimus for the 
treatment of patients with advanced pNET. Results provided evidence that everolimus, in 
combination with octreotide depot, improved PFS in patients with advanced carcinoid tumors. 
The primary endpoint of the study was not met. More data is needed to better assess the 
benefit-risk of everolimus in this patient population.
Renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib
Overall, everolimus is considered to have a positive benefit-risk profile for patients with 
advanced renal cell carcinoma after treatment failure with sunitinib or sorafenib. The benefits 
of therapy with everolimus outweigh any potential risks.


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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
To evaluate long term safety data
Frequency and severity of AEs/SAEs
Refer to Section 10.4
Secondary
To evaluate clinical benefit as assessed by the 
investigator
Proportion of patients with clinical benefit as 
assessed by the investigator at scheduled visits
Refer to Section 10.5


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4
Study design
4.1
Description of study design
This is a multi-center, open label study to better characterize the long-term safety of 
everolimus in patients currently being treated in a Novartis-sponsored OGD&GMA study and
who are not progressing on the current study treatment as judged by the investigator. Parent 
studies eligible to participate in the roll-over study will be decided by Novartis. Investigator 
initiated trials (IIT) will not be included.
There will be no screening period for this study. Eligible patients can start their treatment with 
everolimus as soon as they enter the study. All patients must report to the study site for their 
first visit and commence study participation. At that time, a quarterly supply of everolimus 
may be dispensed to the patient/or as per local practice.  
Patients must return to the study center at least on a quarterly basis (± 1 week) for resupply of 
study medication.  Drug dispensing information and adverse events will be collected. The 
patient may return to the clinic at any given time as per standard of care or treating physician 
recommendation; however only the quarterly study visits will be recorded. Study medication 
dispensed will be recorded on the dose administration page. 
All reported adverse events and serious adverse events will be collected throughout the study.
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from their everolimus treatment as judged by the investigator (disease progression), they 
develop unacceptable toxicities, they withdraw consent, they are non-compliant to the 
protocol, the investigator feels it is no longer in the patient’s best interest to continue 
everolimus therapy or the patient dies, whichever comes first. At every quarterly visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment.
A patient will reach the end of study when everolimus treatment is permanently discontinued.
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with everolimus or are able to obtain commercial supply according to 
local regulations for their medical condition.
Figure 4-1
Study design
*Note: The starting everolimus (and Sandostatin LAR® Depot, if applicable) dose will be the same as 
the last dose received in the parent study.
Parent Novartis 
Oncology CD&MA 
study:
Everolimus
(tolerable effective dose)
Roll-over study:
*Everolimus
(at assigned dose)
End of roll-over study:
Everolimus is 
permanently 
discontinued 


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4.2
Timing of interim analyses and design adaptations
Not applicable.
4.3
Definition of end of study
End of study is defined as either 10 years duration or when all patients on this study have 
permanently discontinued everolimus treatment and the end of treatment visit has been 
performed for each patient, whichever comes earlier.
4.4
Early study termination
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with everolimus or are able to obtain commercial supply according to 
local regulations for their medical condition.
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the prematurely withdrawn patient should be seen as soon as possible. The investigator may 
be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient is currently enrolled in a Novartis-sponsored, Oncology Global Development & 
Global Medical Affairs (OGD&GMA) study receiving everolimus or everolimus plus 
Sandostatin LAR® Depot and has fulfilled all their requirements in the parent study.
2. Patient is currently benefiting from the treatment with everolimus, as determined by the 
guidelines of the parent protocol. 
3. Patient has demonstrated compliance, as assessed by the investigator, with the parent 
study protocol requirements.
4. Willingness and ability to comply with scheduled visits and treatment plans.
5. Written informed consent obtained prior to enrolling into the roll-over study.

If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness.


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5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has been permanently discontinued from everolimus study treatment in the parent 
study.
2. Patients who are receiving everolimus in combination with unapproved or experimental 
treatments.
3. Sexually active males, unless they use a condom during intercourse while taking drug and 
for 8 weeks after stopping study medication. Males also should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
4. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
5. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 8 weeks after stopping study treatment. 

Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to randomization. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential
Highly effective contraception methods include:

Total abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception].

Female Sterilization: Have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male partner sterilization (at least 6 months prior to enrolling). [For female study 
subjects, the vasectomized male partner should be the sole partner for that patient] 

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.

In case of use of oral contraception, women should have been stable on the same pill 
before taking study treatment.
If a study patient becomes pregnant or suspects being pregnant during the study or within 30 
days after the final dose of everolimus, the investigator needs to be informed immediately 
and ongoing study treatment with everolimus has to be stopped immediately.


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6
Treatment
6.1
Study treatment
Study treatment and investigational treatment refer to everolimus.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
RAD001/everolimus
Tablet for oral use
2.5 – 10 mg/day
Daily
Everolimus will be provided as 2.5 mg, 5 mg or 10 mg tablets. The investigational treatment 
is to be stored in a secure locked area while under the responsibility of the investigator. 
Receipt and dispensing of investigational treatment must be recorded by an authorized person 
at the investigator’s site. Everolimus for the roll-over study can be provided as local 
commercial material or global supply where appropriate. 
At the time of transition to the roll-over study, the starting dose of everolimus should be the 
same as the last dose that was given in the parent study. Dose modification thereafter may be 
done at the discretion of the investigator based upon what is in the patient’s best interest.  
Patients will be instructed to take everolimus orally with a glass of water, once daily at the 
same time each day, either consistently with food or consistently without food. Dietary habits 
at the time of enrolling in the study from the parent study should be kept as consistent as 
possible throughout the study.  The tablet should be swallowed as a whole and should not be 
chewed or crushed. 
Please refer to the current everolimus IB and Section 6.3 for further important information on 
potential dosing precautions regarding concomitant medication interaction with cytochrome 
p450, p-glycoprotein, and CYP3A4 and the recommended dosing guidance.
6.1.1.1
Dosing regimen for combination therapy treatment
The roll-over protocol is designed to provide continued treatment with everolimus 
monotherapy to patients. If patients are receiving treatment of everolimus in combination with 
other approved therapies, they can participate in the roll-over study, but it is not intended for 
combination with unapproved or experimental treatments.  Therefore, for patients receiving 
everolimus in combination with Sandostatin LAR® Depot on the parent protocol, Sandostatin 
LAR® Depot will continue to be provided by Novartis or by the investigational site 
considering local regulations.  At the time of transition to the roll-over study, the starting dose 
of Sandostatin LAR® Depot should be the same as the last dose that was given in the parent 
study.
Table 6-2
Combination therapy dose and treatment schedule
Study treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or 
Regimen


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Study treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or 
Regimen
Sandostatin LAR® (if 
applicable)
Intramuscular injection
At discretion of treating 
physician 
At discretion of treating 
physician
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment
The starting dose of everolimus should be the same as the last dose that was given in the 
parent everolimus study. Following the starting dose, patient’s may have their dose of 
everolimus (2.5-10 mg/day) adjusted based on the investigator’s judgment of what dose is in 
the patient’s best interest.
6.1.5
Treatment duration
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from their everolimus treatment as judged by the investigator (disease progression), they 
develop unacceptable toxicities, they withdraw consent, they are non-compliant to the 
protocol, the investigator feels it is no longer in the patient’s best interest to continue 
everolimus therapy or the patient dies, whichever comes first. At every quarterly visit the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment. A patient will reach the end of the roll-over study when 
everolimus treatment is permanently discontinued.
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with everolimus or are able to obtain commercial supply according to 
local regulations for their medical condition.
6.2
Dose escalation guidelines
Not applicable.
6.3
Dose modifications 
6.3.1
Dose modification and dose delay
Patients will begin the roll-over study at the same dose as the last dose administered in the 
parent protocol. Dose adjustments are permitted to allow the patient to continue the study 
treatment at the investigator’s discretion. Dose modifications may be applied at the 
investigator’s discretion in conjunction with the most current IB.
Everolimus and Sandostatin LAR Depot® dose changes must be recorded on the Dosage 
Administration Record eCRFs.


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6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, should be followed up at least once a week (or more 
frequently if clinically indicated) for 4 weeks, and subsequently at approximately 4-week 
intervals, until resolution or stabilization of the event, whichever comes first.
Appropriate clinical experts such as ophthalmologist, endocrinologist, dermatologist, 
psychiatrists etc. should be consulted as deemed necessary. Patients must be followed for 
adverse events and serious adverse events for 30 days following the last dose of everolimus.
6.3.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 


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5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3.3
Anticipated risks and safety concerns of the study drug
It is anticipated that the patients entering the roll-over protocol have tolerated everolimus 
treatment and are anticipated to benefit from continued treatment. 
Guidelines and recommendations for the management of specific everolimus study drug 
induced toxicities (hyperglycemia, hyperlipidemia, stomatitis, infectious pneumonitis, 
reactivation of Hepatitis B and C) are provided in the current everolimus Investigator 
Brochure.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
In general, concomitant medications/therapies deemed necessary for the supportive care of the 
patient is permitted.
6.4.2
Permitted concomitant therapy requiring caution and/or action
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) inhibitor should be avoided.

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 study drug 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 study drug 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.

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 study drug 
up to twice the currently used daily dose should be considered, 5mg increments. Enzyme 
induction usually occurs within 7-10 days; therefore study drug 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 


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to a maximum of twice the daily dose used prior to initiation of the strong CYP3A4 
inducer.

This dose adjustment of study drug 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 
study drug dose should be returned to the dose used prior to initiation of the strong 
CYP3A4/PgP inducer.
Please refer to Table 6-3 listing relevant inducers and inhibitors of CYP3A and to Table 6-4
for a list of relevant substrates, inducers, and inhibitors of PgP.  Please refer to the most recent 
Investigator’s Brochure for a complete list.
Table 6-3
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A
Inducers
Strong inducers:
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum)
Moderate inducers:
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, tipranavir
Weak inducers:
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, Echinacea, 
garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, 
pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, 
topiramate, [troglitazone] , vinblastine
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole (Krishna et al 2009), ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandamycin, voriconazole
Moderate inhibitors:
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, diltiazem, 
dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit juice), imatinib, 
schisandra sphenanthera, tofisopam, verapamil


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Table 6-4
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A dual inhibitors
Substrates
colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, vincristine, everolimus
Inducers
rifampin, St John’s wort
PgP Inhibitors and PgP/CYP3A Dual Inhibitors
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, 
mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, 
ranolazine, rifampin, ritonavir, saquinavir, Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, 
Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated 29-Oct-2012 which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine's Drug 
Interaction Table.
Vaccinations
The use of live vaccines and close contact with those who have received live vaccines should 
be avoided during treatment with everolimus. Examples of live vaccines are: intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a 
typhoid vaccines.
For further details refer to the current everolimus Investigator’s Brochure.
6.4.3
Prohibited concomitant therapy
Treatment with systemic anticancer agents (chemotherapy, hormone therapy, targeted or 
biologic agents) other than everolimus is not permitted until disease progression is 
documented and everolimus is permanently discontinued.
6.4.4
Use of Bisphosphonates (or other concomitant agents)
Not applicable.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled in the roll-over study and is retained as the primary identifier 
for the patient throughout his/her entire participation in the trial. The Subject 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 Subject No. available to the investigator through the Oracle Clinical RDC interface 
(OCRDC). 


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Additionally an eCRF will be completed that identifies the patient by gender and date of birth 
and previous study, site/center and subject number.
6.5.2
Treatment assignment or randomization
All consented patients who meet all the inclusion criteria and none of the exclusion criteria 
are eligible to receive everolimus.
6.5.3
Treatment blinding
Not applicable.
6.6
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 everolimus dosages prescribed to the patient and all dose changes during 
the study must be recorded on the Everolimus Dosage Administration Record eCRF.
Table 6-5
Preparation and dispensing
Study treatments
Dispensing
Preparation
Everolimus
Blister packed tablets (2.5 – 10 mg) including instructions for 
administration will be dispensed by study personnel on an 
outpatient basis.
Patients will be provided with an adequate supply of study 
treatment for self-administration at home until at least their next 
scheduled quarterly (12 weeks ± 1 week) study visit. 
If study drug is supplied by Novartis Drug Supply Management, 
the supply may be dispensed more frequently if required based 
on local practice or drug expiration date.
Not applicable
6.6.1
Study treatment packaging and labeling
Everolimus for the roll-over study can be provided where appropriate as local commercial 
material or as global open-label supply, packed and labeled under the responsibility of 
Novartis Drug Supply Management. Study treatment labels will be in the local language and 
comply with the legal requirements of each country. They will include storage conditions for 
the drug but no information about the patient.
If everolimus is provided and labeled in-country, the locally-approved form and packaging of 
everolimus will be used.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Everolimus
Tablets in blisters*
As per local requirements
* For centrally supplied medication. If everolimus is sourced and labeled in-country/locally, the locally-approved 
form, packaging and labeling of everolimus will be used.


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6.6.2
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, everolimus should be stored according to 
the instructions specified on the drug labels and in the Investigator’s Brochure. 
Table 6-7
Supply and storage of study treatments
Study treatments
Supply
Storage
Everolimus
Centrally or locally supplied by 
Novartis
Refer to study treatment label or local product 
information
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form and other relevant source documents.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
6.6.3.3
Handling of other study treatment
If the patient was receiving a combination therapy with an approved, commercially available 
treatment with everolimus in the parent protocol, and is eligible for the roll-over study, this 
combination therapy will be allowed until the patient permanently discontinues everolimus. 
All Sandostatin LAR® Depot dosages prescribed to the patient and all dose changes during the 
study must be recorded on the Sandostatin Dosage Administration Record eCRF.
Dispensation, compliance and accountability of any combination therapy administered to the 
patient is under the supervision and discretion of the investigator. Sandostatin LAR® Depot 
will be provided by Novartis or by the investigational site considering local regulations. 
Sandostatin LAR® Depot will be distributed in country-specific approved packaging.


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6.6.4
Disposal and destruction
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
The study drug can only be destroyed once the study drug accountability check has been done 
by the monitor. The study drug can be destroyed at the local Novartis facility or by a third 
party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. A visit window of ± 1 week is allowed. All data obtained from these assessments 
must be supported in the patient’s source documentation.  
The table indicates in the “Category” column which assessments produce data to be entered in 
the database (D) or documented at the site level in the source documents (S).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
reference
section
Enrolment
Quarterly (every 12 weeks± 1 
week) visits during treatment 
phase
End of 
treatment (EoT)
30 day safety
follow-up post last 
dose of study drug/
End of Study
Visit Number
1
Visit 2, 3, 4 etc.
777
Obtain informed consent
D
7.1.2
x
Patient’s previous study,site, and 
subject number
D
7.1.2.3
x
Demography
D
7.1.2.3
x
Relevant medical history/current 
medical conditions
D
7.1.2.3
x
Inclusion/exclusion criteria
D
5.2 / 5.3
x
Serum pregnancy testing
D
7.2.2
x
x
Urine pregnancy testing
S/D
7.2.2
monthly 
Adverse events and Serious 
adverse events
D
8.1 / 8.2
x
continuous
x
x
Everolimus dosing administration 
D
6.6
x
continuous
Sandostatin LAR®  Depot dosing 
administration (if applicable)
D
6.6
x
continuous
Confirmation of Clinical Benefit from 
Study Treatment
D
6.1.5
x
continuous
End of study treatment
D
7.1.5
x
Study evaluation completion
D
7.1.5
x


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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
At the enrollment visit the patient will complete a written informed consent. There will be no 
screening period for this study. Once consented, patients will be evaluated for eligibility via 
the inclusion and exclusion criteria.
7.1.2.1
Eligibility screening 
Not applicable.
7.1.2.2
Information to be collected on screening failures
Not applicable.
7.1.2.3
Patient demographics and other baseline characteristics
For patients that are eligible to participate in this roll-over study, the patients’ gender, date of 
birth, previous study, site/center and subject number, and relevant medical history will be 
collected.
7.1.3
Run-in period 
Not applicable.
7.1.4
Treatment period
The starting dose of everolimus on this roll-over protocol will be the same as the last dose that 
was given in the parent everolimus study. A 3 month supply of everolimus will be dispensed 
to the patient, or what is allowed according to local practice/regulations.
Patients must return to the study center on a quarterly basis (12 weeks ± 1 week) for resupply 
of study medication at which time drug dispensing information and adverse event information 
will be collected. At this time the dose of everolimus is based on the investigator’s judgment. 
At every quarterly visit, the investigator is required to confirm that the patient continues to 
have clinical benefit and may continue treatment with study drug.
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with everolimus or are able to obtain commercial supply according to 
local regulations for their medical condition.
7.1.5
Discontinuation of study treatment
Patients will continue to be treated until they are no longer benefiting from everolimus 
treatment, develop unacceptable toxicities, withdraw consent, are non-compliant to the 
protocol, or the patient dies, whichever comes first.
At the time the patient discontinues study treatment, a visit should be scheduled as soon as 
possible, at which time the End of Treatment visit will be performed. End of Treatment 


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information will be completed in the eCRF giving the date and reason for stopping the study 
treatment (see Section 7.1.5.1).
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for the required safety evaluation during the 30 days 
following the last dose of study treatment. The completion of the Study Evaluation 
Completion eCRF page is required any time a patient discontinues from the study and must be 
completed 30 days after the end of treatment.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s withdrawal from the study and record this 
information on the appropriate eCRF page.
A patient will reach the end of study when everolimus treatment is permanently discontinued 
and there will be no further follow-up study visits.
7.1.5.1
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone,
e-mail, letter) to understand the primary reason for this decision and record this information.
Everolimus must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
Patients may be withdrawn from the study if any of the following occur:
1. Adverse event(s).
2. Subject withdrew consent.
3. Lost to follow-up.
4. Administrative problems.
5. Death.
6. Disease progression.
7. Treatment duration completed as per protocol.
8. Protocol deviation
9. Sponsor decision


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7.1.5.2
Replacement policy 
Not applicable.
7.1.6
Follow up for safety evaluations 
All patients must be followed up for safety evaluations for 30 days after the last dose of 
everolimus. At the end of this period, the investigator should contact the patient to inquire 
about any adverse events or serious adverse events observed during this period. This could be 
done via a phone contact. Following this there are no further follow-up study visits.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
At every quarterly visit, the investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment.
7.2.2
Safety and tolerability assessments
Safety will be monitored by collecting Adverse Events throughout the study on a continuous 
basis. See Section 8.
Women of child-bearing potential must complete the following pregnancy tests:

Baseline/Enrollment - serum pregnancy test done locally

Every 4 weeks during treatment - urine pregnancy test. Can be administered at patient’s 
home.

End of Treatment visit - serum pregnancy test done locally
Women of child-bearing potential who administer urine pregnancy testing at home should 
complete a simple diary with the dates and the outcome of the urine pregnancy test while on 
study treatment. In case of a positive pregnancy test, the instructions in Section 8.4 should be 
followed.
7.2.3
Pharmacokinetics
Not applicable.
7.2.4
Biomarkers
Not applicable.


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7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes
Not applicable.
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.
Adverse events of special interest as noted in Section 8.1.3 will be reported as serious adverse 
events.
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).
Any ongoing adverse events from the parent study will be captured as medical history in the 
roll-over database. Any AE that begins (or worsens) after signing of the informed consent for 
the rollover and during the 30-day (or 28-day) safety follow up period defined in the parent 
protocol should be reported in both clinical databases.
Adverse event monitoring should be continued for at least 30 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 current version of the Common Terminology 
Criteria for Adverse Events (CTCAE). If CTCAE grading does not exist for an adverse event, 
the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, 
will be used. CTCAE Grade 5 (death) will not be used in this study; rather, information about 
deaths will be collected on the EOT page.
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 
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1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.  
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 criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 


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required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
In addition to all serious adverse events reported on a continuous basis throughout the study, 
the investigator should use the SAE form to report the following medically significant 
potential risks noted in the Novartis Risk Management Plan for everolimus:

Development toxicity

Reproductive (teratogenicity) toxicity

Intestinal obstruction /ileus

Male infertility

Pancreatitis

Cholelithiasis

Muscle-wasting/Muscle-loss
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 
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
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAE that begins or worsens after signing of the informed consent for the roll-over and 
during the 30-day (or 28-day) safety follow up period defined in the parent protocol should be 
reported as an adverse event in both clinical databases; however, only one SAE report will be 
sent to Novartis.

Any SAE that begins or worsens during the 30-day (or 28-day) safety follow up period
specified in the parent study, should have an SAE report submitted to Novartis with the 
parent protocol study number. 

Any SAE that begins or worsens after the 30-day (or 28-day) safety follow-up period 
specified in the parent study, should have an SAE report submitted to Novartis with the 
roll-over protocol study number.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over 
protocol but follow up information is reported for the previous SAEs in the parent protocol, it 
must be clearly labeled that this is for the parent protocol number.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis.  Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each 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.


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
Preclinical data regarding reproductive toxicity is described in the most recent Investigator 
Brochure. The potential reproductive risk for humans is unknown.  Women of childbearing 
potential should be advised to use highly effective contraception methods while they are 
receiving everolimus and up to 8 weeks after treatment has been stopped.  If a pregnancy 
occurs while on study treatment, the newborn will be followed for at least 12 months.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
Not applicable. 


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8.7
Steering Committee
Not applicable. 
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 
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 


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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 in eCRFs 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 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.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the Global Head of Biostatistics and Data Management and the 
Global Head of Clinical Development.
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
10.1
Analysis sets
The following sets will be used for statistical analysis and data reporting.
10.1.1
Full Analysis Set
Not applicable.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol.


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10.1.3
Dose-determining analysis set
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data characteristics will be summarized descriptively for the 
Safety Set.
10.3
Treatments (study treatment, compliance)
Dose administration data will be summarized using the Safety Set.
10.4
Primary objective
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs.
10.4.1
Variable
See Section 10.5.3.
10.4.2
Statistical hypothesis, model, and method of analysis
No hypothesis will be tested.
10.4.3
Handling of missing values/censoring/discontinuations
Not applicable.
10.4.4
Supportive and Sensitivity analyses
No supportive analysis will be performed.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
The secondary objective 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.
10.5.3
Safety objectives
The assessment of safety will be based mainly on the frequency of AEs and SAEs.
10.5.3.1 Analysis set and grouping for the analyses
The overall observation period will be divided into two mutually exclusive segments:


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1. on-treatment period: from day of first dose of study medication in the roll-over study to 30
days after last dose of study medication
2. post-treatment period: starting at day 30+1 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the post-treatment periods) will be listed and those collected during the 
post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
10.5.3.3 Other safety data
Not applicable.
10.5.3.4 Supportive analyses for secondary
Not applicable.
10.5.3.5 Tolerability
Not applicable.
10.5.3.6 Pharmacokinetics
Not applicable.
10.6
Exploratory objectives 
Not applicable.
10.7
Interim analysis
Not applicable.
10.8
Sample size calculation
Not applicable.
10.9
Power for analysis of key secondary variables
Not applicable.


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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 Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form 
Not applicable.


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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 
4.4.
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 
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.


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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 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Boulay A, Lane HA (2007) The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124.
Krishna G, Moton A, Lei Ma L, et al (2009) Effects of oral posaconazole on the 
pharmacokinetic properties of oral and intravenous midazolam: A phase I, randomized, 
openlabel, crossover study in healthy volunteers. Clinical Therapeutics; 31(2): 286-98.

SAP_001.pdf: 
Clinical Development
RAD001/Everolimus/Afinitor®
Oncology Clinical SAPCRAD001C2X01B1&7
An open-label, multi-center everolimus roll-over protocol 
forpatients who have completed a previous Novartis-
sponsored everolimus study and are judged by the 
investigator to benefit from continued everolimus 
treatment
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final version 2.0
Release date:
09-Jun-2020
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
PPD


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Document History – Changes compared to previous version of SAP
Version
Date
Changes
1.0
08Nov2013
Final version
2.0
07Feb2020
To update the SAP per protocoal amendment 1

To change the primary endpoint from number of patients receiving 
everolimus to frequency and severity of AEs/SAEs to better 
characterize the long-term safety of the compound  

To include the collection of all AEs (including non-serious AEs) 
and an investigator attestation of continued clinical benefit. 
In addition, SAP is also updated to follow Novartis SAP 
template.
09Jun2020
To update the SAP on the basis of amendment 1 and the change of 
safety data collection in protocol amendment 1

Safety data from both ARGUS safety database and RDC clinical 
database will be analyzed seperately for comprehensive and 
transparent safety data reporting in final CSR.

To include global protocol amendment date 18-Mar-2016 as a 
general cutoff date to analyze safety data from RDC clinical
database.


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Table of contents
Document History – Changes compared to previous version of SAP.................................2
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................10
2.3
Patient disposition, demographics and other baseline characteristics ...................10
2.3.1
Patient disposition.................................................................................10
2.3.2
Patient demographics and other baseline characteristics ......................10
2.3.3
Protocol deviation .................................................................................10
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................11
2.4.1
Study treatment/compliance..................................................................11
2.4.2
Prior, concomitant, and post therapies..................................................11
2.5
Analysis of the primary objective..........................................................................12
2.5.1
Primary endpoint...................................................................................12
2.5.2
Statistical hypothesis, model, and method of analysis..........................12
2.5.3
Handling of missing values/censoring/discontinuations.......................12
2.5.4
Supportive analyses...............................................................................12
2.6
Analysis of the key secondary objective ...............................................................12
2.7
Analysis of secondary efficacy objective(s)..........................................................12
2.7.1
Secondary endpoints .............................................................................12
2.7.2
Statistical hypothesis, model, and method of analysis..........................12
2.7.3
Handling of missing values/censoring/discontinuations.......................12
2.8
Safety analyses.......................................................................................................12
2.8.1
Exposure to study treatment..................................................................13
2.8.2
Adverse events (AEs)............................................................................13
2.8.3
Deaths....................................................................................................16
2.8.4
Laboratory data .....................................................................................16
2.8.5
Other safety data ...................................................................................16
2.9
Pharmacokinetic endpoints....................................................................................16
2.10
PD and PK/PD analyses.........................................................................................17


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2.11
Patient-reported outcomes .....................................................................................17
2.12
Biomarkers.............................................................................................................17
2.13
Other Exploratory analyses....................................................................................17
2.14
Interim analysis......................................................................................................17
3
Sample size calculation .....................................................................................................17
4
Change to protocol specified analyses ..............................................................................17
5
Appendix ...........................................................................................................................17
5.1
Imputation rules.....................................................................................................17
5.1.1
Study drug.............................................................................................17
5.1.2
AE date imputation ...............................................................................17
5.1.3
Concomitant medication date imputation .............................................18
5.2
AEs coding/grading ...............................................................................................18
5.3
Laboratory parameters derivations ........................................................................18
5.4
Statistical models...................................................................................................19
5.4.1
Primary analysis....................................................................................19
5.4.2
Key secondary analysis.........................................................................19
5.5
Rule of exclusion criteria of analysis sets..............................................................19
6
Reference (available upon request) ...................................................................................19


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List of abbreviations
AE
AESI
Adverse event
Adverse events of special interest
BSC
Best Supportive Care
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or 
Paper
CRO
CSP
Contract Research Organization
Clinical Study Protocol
CSR
CTCAE
Clinical Study Report
Common Terminology Criteria for Adverse Events
EC
European Commission
eCRS
Electronic Case Retrieval Strategy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IIT
Investigator-initiated Trial
IRB
Institutional Review Board
OGD&GMA
Oncology Global Development and Global Medical Affairs 
PI
Principal Investigator
PT
Preffered Term
REB
Research Ethics Board
SAE
SAP
SOC
Serious Adverse Event
Statistical Analysis Plan
System Organ Class
SOP
Standard Operating Procedure


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1
Introduction
This document provides the detailed statistical analysis plan (SAP) for the data from study 
CRAD001C2X01B. Data analysis will be performed by Novartis personnel or a designated 
third party.
The original RAP Module 3 for study CRAD001C2X01B was finalized in November 2013 after 
the initial protocol was released. Subsequently clinical study protocol (CSP) amendment 1 was 
released in March 2016 to change the primary endpoint from number of patients receiving 
everolimus to frequency and severity of AEs/SAEs to better characterize the long-term safety 
of the compound.  In addition, the CSP has been amended to include the collection of all AEs 
(including non-serious AEs) and an investigator attestation of continued clinical benefit. This 
SAP amendment is to incoporate the impact of CSP amendment 1 on the analysis.
1.1
Study design
This is a multi-center, open label study to better characterize the long-term safety of everolimus 
in patients currently being treated in a Novartis-sponsored Oncology Global Development and 
Global Medical Affairs (OGD&GMA) study and who are not progressing on the current study 
treatment as judged by the investigator. 
Parent studies eligible to participate in the roll-over study will be decided by Novartis. 
Investigator initiated trials (IIT) will not be included. The primary objective of the parent study 
must have been reached and the parent study must be in the process of being completed and 
reported. Patients may be allowed to continue combination therapy with Sandostatin LAR®
Depot if they are currently receiving this combination therapy on the parent protocol and at the 
discretion of the investigator.
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from their everolimus treatment as judged by the investigator (disease progression), they 
develop unacceptable toxicities, they withdraw consent, they are non-compliant to the protocol, 
the investigator feels it is no longer in the patient’s best interest to continue everolimus therapy 
or the patient dies, whichever comes first. At every quarterly visit, the investigator is required 
to confirm that the patient continues to have clinical benefit and may continue receiving study 
treatment. A patient will reach the end of study when everolimus treatment is permanently 
discontinued.
The study is expected to remain open  until such time that enrolled patients no longer need 
treatment with everolimus or are able to obtain commercial supply according to local 
regulations for their medical condition.


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Figure 1-1
Study design
*Note: The starting everolimus (and Sandostatin LAR® Depot, if applicable) dose will be the same as 
the last dose received in the parent study.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Parent Novartis 
Oncology CD&MA 
study:
Everolimus
(tolerable effective dose)
Roll-over study:
*Everolimus
(at assigned dose)
End of roll-over study:
Everolimus is 
permanently 
discontinued 


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Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To evaluate long term safety data
Frequency and severity of AEs/SAEs
Refer to Section 2.5 & 2.8
Secondary
To evaluate clinical benefit as assessed by the 
investigator
Proportion of patients with clinical benefit as 
assessed by the investigator at scheduled visits
Refer to Section 2.7


2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis using SAS Version 9.3. Only data reported in the database 
of this protocol will be included in the analyses. Patient data from the parent study will not be 
taken into account. 
Summary tables will be provided for patient disposition, demographic data and treatment 
exposure. All data collected on the database will be listed, using all patients enrolled in this 
study.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented, unless otherwise stated. 
The original protocol was released on 07-Dec-2012. Protocol amendment 1 (PA1) was released 
on 18-Mar-2016. In this amendment the primary endpoint was changed to safety to better 
characterize the long-term safety of the compound.  In addition, the protocol has been amended
to include the collection of all AEs (including non-serious AEs) and an investigator attestation 
of continued clinical benefit. Additional eCRFs were added to collect data related to

Investigator attestation of clinical benefit at every quarterly visit

All adverse events (based on original protocol only SAEs were collected and all SAEs 
were only collected in ARGUS safety database)

Relevant medical history/current medical conditions

Monthly at home pregnancy testing for female patients of child bearing potential
(serum/urine)

Study evaluation completion at the end of the 30 day safety follow up

Related imaging, drug use 6 months prior to liver event, pathology,  medical history 
possibly contributing to liver dysfunction, local laboratory results (viral serology, 
autoimmune, immunoglobulin, liver function tests), overview, potential impact of 
alcohol use, acetaminophen/paracetamol pertaining to liver event (only when drug-
induced liver injury (DILI) cases occur)
However, at the time of global protocol amendment was released, 32 out of 34 patients were 
enrolled; 21 patients ongoing; 11 patients had already discontinued the study. Only 2 patients 
consented after PA1 approval. Therefore, 32/34 patients did not have AEs collected in eCRFs
before PA1, ~30% of enrolled patients had AEs reported in RDC clinical database after PA1, 
and ~50% of SAEs occurred before PA1 were not reported in RDC. Due to this, safety data 
from both ARGUS safety database and RDC clinical database will be analyzed seperately for 
comprehensive and transparent safety data reporting in final CSR. See section 2.8.2 in detail.


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2.1.1
General definitions
Study drug = RAD001 = everolimus = Afinitor®.
Study treatment is defined as everolimus or everolimus + Sandostatin LAR if patients are
allowed to continue combination therapy.  
Date of first administration of study drug is defined as the first date when a nonzero dose of 
study drug was administered and recorded on eCRF. For the sake of simplicity, the date of first 
administration of study drug will also be referred as start of study drug.
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 database of this protocol. 
The date of first and last administration of sandostatin LAR is defined in the same way.
Date of first administration of study treatment is defined as the first date when a nonzero 
dose of study treatment was administered and recorded on the database of this protocol.
Date of last administration of study treatment is defined as the last date when a nonzero dose 
of study drug was administered and recorded on the database of this protocol.
Study day is calculated as: date of the event (onset date of an event, assessment date...) – first
date of the first administration of study treatment + 1. Therefore, the first day of study treatment 
is study day 1. 
Baseline is defined when appropriate as the the non-missing record with the latest assessment 
date on or before the date of first administration of study treatment.
2.2
Analysis sets
The safety set will be used for statistical analysis and data reporting.
The Safety Set includes all patients who received at least one dose of study drug after enrolling 
into the roll-over protocol.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number of patients ongoing, completed and discontinued from the treatment at the time of 
analysis as well as the primary reason for end of treatment will be summarized. 
2.3.2
Patient demographics and other baseline characteristics
For patients that are eligible to participate in this roll-over study, demographic data, like gender, 
age, previous study, site/center and subject number, and relevant medical history will be 
summarized descriptively. 
2.3.3
Protocol deviation
Protocol deviation data will be summarized.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment/compliance
Exposure to everolimus and sandostatin LAR will be summarized for all treated patients and 
will be based only on dose administered within this protocol. Study treatment administered 
during the parent study will not be taken into account.
The following algorithm will be used to calculate the duration of exposure in days:
-
Duration of exposure to everolimus (days) = (date of last administration of everolimus) 
– (date of first administration of everolimus) + 1.
-
Duration of exposure to sandostatin LAR (days) = (date of last administration of 
sandostatin LAR + 27 days) – (date of first administration of sandostatin LAR) + 1. 
-
Duration of exposure to everolimus + sandostatin LAR (days) = max(date of last 
administration of everolimus, date of last administration of sandostatin LAR + 27 days) 
– min(date of first administration of everolimus, date of first administration of 
sandostatin LAR) + 1.
The date of first administration of everolimus is derived as the first date when a nonzero dose 
of everolimus was administered and recorded on the database of this protocol. The date of last 
administration of everolimus is defined as is the last date when a nonzero dose of study drug 
was administered and recorded on the database of this protocol. The date of first and last 
administration of sandostatin LAR is defined in the same way.
The duration of exposure in years is calculated by dividing the duration of exposure in days by 
365.25. The duration includes the periods of temporary interruption. 
-
Duration of exposure in years for everolimus = (Last dosing date – First dosing date + 
1)/365.25
-
Duration of exposure in years for sandostatin LAR = (Last dosing date + 27– First 
dosing date + 1)/365.25
-
Duration of exposure in years for everolimus + sandostatin LAR (days) = [max(date of 
last administration of everolimus, date of last administration of sandostatin LAR + 27 
days) – min(date of first administration of everolimus, date of first administration of 
sandostatin LAR) + 1] /365.25.
2.4.2
Prior, concomitant, and post therapies 
Prior and post medication/thearpies are not applicable in this roll-over study. The information 
of concomitant medication is not collected.


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2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs.
Varaibles see Section 2.8
2.5.2
Statistical hypothesis, model, and method of analysis
No hypothesis will be tested.
2.5.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.5.4
Supportive analyses
No supportive analysis is planned.
2.6
Analysis of the key secondary objective
No key secondary efficacy objectives are analyzed.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
The secondary objective of the study is to evaluate clinical benefit as assessed by the 
investigator.  The secondary endpoint is the proportion of patients with clinical benefit as 
assessed by the investigator at scheduled visits.
2.7.2
Statistical hypothesis, model, and method of analysis
No statistical analyses will be performed on secondary endpoint. Data will be used only for 
descriptive summary of patients remaining on drug – as needed during the conduct of the study. 
SAEs reported to the safety database will be reviewed and reported as part of the regular 
pharmacovigilance activities. 
2.7.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.8
Safety analyses
The assessment of safety will be based mainly on the frequency of AEs and SAEs.
Analysis set and grouping for the analyses:
The overall observation period will be divided into two mutually exclusive segments:
1. on-treatment period: from day of first dose of study medication in the roll-over study to 30
days after last dose of study medication


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2. post-treatment period: starting at day 30+1 after last dose of study medication.
2.8.1
Exposure to study treatment
Exposure will be assessed for both Everolimus and Everolimus + Sandostatin LAR.  
The following analyses will be performed to assess study treatment exposure:

Duration of study drug exposure in years;

Cumulative dose;

Actual dose intensity;

Dose adjustments and discontinuation;
Seperate table and plot for on-treatment period and AEs/SAEs collection period in clinical 
database on patient level will be generated to reflect the proportion of safety data collection 
within the overall treatment period.
2.8.2
Adverse events (AEs)
Verbatim terms will be coded to lower-level terms in the Medical Dictionary for Regulatory 
Activities (MedDRA). AEs will be coded to MedDRA. An assessment of severity grade will be 
made using NCI-CTCAE v4.03.Summary tables for adverse events (AEs) will include only 
AEs that started or worsened during the on-treatment period, the treatment-emergent AEs. The 
incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by System Organ Class (SOC) and or Preferred Term (PT), severity (CTC Grade 
1-4, 5 Death is exluded), type of adverse event, relation to study treatment.
Since safety data collection was changed in the protocol amendment released on 18-Mar-2016, 
CTC grade were captured in the RDC clinical database only after the protocol amendment. All 
SAEs including AESIs reported as SAEs were captured in ARGUS safety database throughtout 
the study.
Thorough manual review was implemented to ensure SAEs reported both in ARGUS and RDC 
databases were uniquetly matched without any missing or overlapped inputs. 
Hence, AEs/SAEs from both ARGUS safety database and RDC clinical database will be 
summarized seperately to ensure comprehensive and transparent safety data reporting. Global 
protocol amendment date (18-Mar-2016) as a general cutoff date will be applied to analyze
safety data from RDC clinical database.
The following AE summary tables will be provided:
I. from Safety Database (ARGUS):
-
All SAEs throughout the study

SAEs regardless of study treatment relationship by primary system organ class and 
preferred term

SAEs suspected to be study treatment relationship by primary system organ class 
and preferred term


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-
All AESI reported as SAEs as per protocol throughout the study

Serious AESIs regardless of study treatment relationship by safety topic and 
preferred term
II. from Clinical Database (RDC):
-
AEs (non-serious AE and AESI) after protocol amendment

AEs regardless of study treatment relationship
a.
by primary system organ class, preferred term and maximum CTC grade
b. by primary system organ class and preferred term

AEs suspected to be study treatment related
a.
by primary system organ class, preferred term and maximum CTC grade
b. by primary system organ class and preferred term

AEs leading to study drug discontinuation regardless of study drug relationship by 
primary system organ class and preferred term

AEs resulting in dose adjustment or interruption regardless of study drug 
relationship by primary system organ class and preferred term

AEs requiring additional therapy and concomitant medication regardless of study 
drug relationship by primary system organ class and preferred term

AESIs regardless of study treatment relationship
c.
by primary system organ class, preferred term and maximum CTC grade
d. by primary system organ class and preferred term

AESIs suspected to be study treatment related
c.
by primary system organ class, preferred term and maximum CTC grade
d. by primary system organ class and preferred term

AESIs leading to study drug discontinuation regardless of study drug relationship
by primary system organ class and preferred term

AESIs resulting in dose adjustment or interruption regardless of study drug 
relationship by primary system organ class and preferred term

AESIs requiring additional therapy and concomitant medication regardless of study 
drug relationship by primary system organ class and preferred term
-
SAEs after protocol amendment

SAEs regardless of study treatment relationship by primary system organ class and 
preferred term

SAEs suspected to be study treatment relationship by primary system organ class 
and preferred term
For legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment-
emergent non-serious AEs with an incidence greater than 5% in clinical database, and on-
treatment deaths and treatment-emergent SAEs in ARGUS safety database will be provided by 


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system organ class and preferred term using the safety set. The rule for the calculation of the 
number of occurrences is detailed in the Appendix section 5.2.
All of these tables will display the number and percent of patients that experience the given 
event and will display events by MedDRA. Events will be displayed alphabetically for SOC 
and PT. All safety data (including those from the post-treatment periods) will be listed and 
those collected during the post-treatment period are to be flagged.The following listings will
also be generated:

Listing of AEs leading to study drug discontinuation

Listing of AEs leading to dose adjustment or interruption

Listing of SAEs in ARGUS safety database

Listing of SAEs in RDC clinical database
2.8.2.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest (AESI) will be summarized by risk group and preferred term
defined below. AESIs in RDC clinical database and serious AESI in ARGUS safety database 
will also be listed.
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
In addition to all serious adverse events reported on a continuous basis throughout the study, 
the investigator should use the SAE form to report the following medically significant potential 
risks noted in the Novartis Risk Management Plan for everolimus:

Development toxicity

Reproductive (teratogenicity) toxicity

Intestinal obstruction /ileus

Male infertility

Pancreatitis

Cholelithiasis

Muscle-wasting/Muscle-loss
All AESIs are defined through the use of MeDRA terms,  Standardized MedDRA Queries 
(SMQ), Preferred Terms (PT), System Organ Classes (SOC), or through a combination of 
these components. At the project level, a SAS dataset named Case Retrieval Strategy (eCRS) 
contains the exact composition of the adverse events groupings will be used to map reported 
adverse events to the adverse events groupings of special interest. This dataset may be 
updated (i.e., it is a living document) based on review of accumulating trial data, and it is the 
most up to date version at the time of DBL that will be used. Safety topics flagged in the 


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eCRS are adjusted to use RMP update flag (RM) instead of core safety flag (SP), with 2 
study-specific groupings of “Cholelithiasis” and “Intestinal obstruction ileus” using other flag 
(OS) to generate protocol-defined AESIs from both RDC clinical and ARGUS safety 
databases. Note that certain adverse events may be reported within multiple groupings.
For each specified AESI, the number and percentage of patients with at least one event of the 
AESI occurring during the on-treatment period will be summarized. Summaries of these 
AESIs will be provided grouped by CTCAE grades, relationship, leading to treatment 
discontinuation, resulting in dose adjustment/interruption, etc.
2.8.3
Deaths
CTC Grade 5 will not be used in this study; rather, information about deaths will be collected 
on the CRF End of Treatment (EOT) page. Deaths reportable as SAEs will be listed by patient 
and tabulated by type of adverse event.
All deaths will be summarized. Following summaries will be provided:

On-treatment death in RDC clinical database by primary system organ class and 
preferred term

All deaths in ARGUS safety database by system organ class and preferred term
Listing of all deaths in ARGUS safety database will also be provided.
2.8.4
Laboratory data
Lab data of hepatic laboratory values will be listed only when DILI cases occur.
2.8.5
Other safety data
Pregnancy test results for safety monitoring is collected locally and will be listed.
Following liver event data will be listed only when DILI cases occur.

Related imaging of liver event 

Pathology of liver event

Overview of liver event

Liver event associated with clinical signs/symptoms

Potential impact of alcohol use of liver event
2.9
Pharmacokinetic endpoints
Not applicable.


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2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
Not applicable.
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
No exploratory analyses are planned.
2.14
Interim analysis
No interim analyses are planned for this study. Nevertheless it may be possible that different 
analyses may be necessary to descriptively summarize patients on drug at regular intervals.
3
Sample size calculation
The sample size is not based on any statistical considerations. 
The purpose of this study is to allow continued use of everolimus in patients who are currently 
receiving everolimus treatment in a Novartis-sponsored, Oncology Clinical Development & 
Medical Affairs (CD&MA) study that has reached its study objectives, are not progressing on 
the current study treatment as defined by the parent protocol and are unable to access everolimus 
treatment outside of a clinical study. 
The total sample size will be determined by the number of patients entering the study.
4
Change to protocol specified analyses
No change from protocol specified analysis is planned.
5
Appendix
5.1
Imputation rules
Not applicable.
5.1.1
Study drug
Not applicable.
5.1.2
AE date imputation
Not applicable.


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5.1.3
Concomitant medication date imputation
Not applicable.
5.1.3.1
Prior therapies date imputation
Not applicable.
5.1.3.2
Post therapies date imputation
Not applicable.
5.1.3.3
Other imputations
Not applicable.
5.2
AEs coding/grading
AEs will be coded using the latest MedDRA version available at time of database lock while 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.03 will be used for reporting AE severity.
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). 
CTCAE grade 5 (death) will not be used in this study; rather, this death information will be 
collected on the EOT CRF page (Panel: CMP). Grading is applicable in dada collected in RDC 
clinical database but not ARGUS safety database.
The rule for the calculation of the number of occurrences that is provided in the summary of 
serious and non serious adverse events required for the legal requirements of ClinicalTrials.gov 
and EudraCT is the following:
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence of SAE, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
5.3
Laboratory parameters derivations
Not applicable.


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5.4
Statistical models
5.4.1
Primary analysis
Not applicable.
5.4.2
Key secondary analysis
Not applicable.
5.5
Rule of exclusion criteria of analysis sets 
Not applicable.
6
Reference (available upon request)
Not applicable.