Clinical trial NCT02017860
Conditions: Neoplasms
Keywords: RAD001, everolimus, roll-over
Sponsor: Novartis Pharmaceuticals
Start date: 2014-01-16; Completion date: 2019-04-25
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to collect and assess long-term safety of everolimus in patients who were currently receiving everolimus treatment in a Novartis-sponsored, Oncology CD\&MA study that had reached its study objectives, were not progressing on the current study treatment as defined by the parent protocol, and were unable to access everolimus treatment outside of a clinical study. Parent studies eligible to participate in the roll-over study were decided by Novartis. Investigator initiated trials (IITs) were not included. The primary objective of the parent study must have been reached and the parent study must have been in the process of being completed and reported.

Detailed description:
This was a multi-center, open label study to collect and assess long-term safety of everolimus in patients being treated in current Novartis-sponsored studies and who were benefiting from treatment with everolimus judged by the investigator.There was no screening period for this study. Eligible patients were consented and started their treatment with everolimus as soon as they entered the study. Patients had to return to the study center on a yearly basis (± 3 months), but for resupply of study medication, the frequency of the receipt and dispensing followed local practice (e.g., every 2 to 3 months). The dose of everolimus was based on the investigator's judgment.

Adverse events (AEs) were collected continuously throughout the study. For the safe and effective use of everolimus, patient could return to the clinic at any given time following local practice. When AEs were observed, additional visits were arranged by investigator's discretion.

Patients continued to be treated until they were no longer benefiting from everolimus as defined in the parent protocol (disease progression), developed unacceptable toxicities, withdrew consent, were non-compliant to the protocol, the investigator felt it is no longer in the patient's best interest to continue everolimus therapy or the patient died, whichever came first.

A patient reached the end of study when everolimus treatment was permanently discontinued and the end of treatment visit had been performed. All patients were followed for AEs for 30 days after the last dose of everolimus.

The study remained open for approximately 5 years; until such time that enrolled patients no longer needed treatment with everolimus, whichever came first.

Arms: arm 1: Patients who received everolimus in a Novartis-sponsored, Oncology Clinical Development \& Medical Affairs (CD\&MA) study that had reached its study objectives, were not progressing on the current study treatment as defined by the parent protocol and were unable to access everolimus treatment outside of a clinical trial were enrolled.
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Everolimus was provided by the investigator in 2.5 mg or 5 mg tablets for daily oral administration.

Protocol documents:
Prot_001.pdf: 
Clinical Development 
RAD001, everolimus 
Clinical Trial Protocol CRAD001C1X01B / NCT02017860
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 
Not applicable 
Version number 
01 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
30-Aug-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 15-Feb-2012 


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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 (30-Aug-2016) ........................................................................................... 8 
Protocol summary: ............................................................................................................... 9 
1 
Background ........................................................................................................................ 11 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 11 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 11 
1.2.1 
Overview of everolimus (RAD001) ...................................................... 11 
2 
Rationale ............................................................................................................................ 14 
2.1 
Study rationale and purpose ................................................................................... 14 
2.2 
Rationale for the study design ............................................................................... 14 
2.3 
Rationale for dose and regimen selection .............................................................. 14 
2.4 
Rationale for choice of combination drugs ............................................................ 15 
2.5 
Rationale for choice of comparators drugs ............................................................ 15 
3 
Objectives and endpoints ................................................................................................... 15 
4 
Study design ...................................................................................................................... 15 
4.1 
Description of study design ................................................................................... 15 
4.2 
Timing of interim analyses and design adaptations ............................................... 16 
4.3 
Definition of end of the study ................................................................................ 16 
4.4 
Early study termination .......................................................................................... 16 
5 
Population .......................................................................................................................... 16 
5.1 
Patient population .................................................................................................. 16 
5.2 
Inclusion criteria .................................................................................................... 16 
5.3 
Exclusion criteria ................................................................................................... 17 
6 
Treatment ........................................................................................................................... 18 
6.1 
Study treatment ...................................................................................................... 18 
6.1.1 
Dosing regimen ..................................................................................... 18 
6.1.2 
Ancillary treatments .............................................................................. 18 
6.1.3 
Rescue medication ................................................................................ 19 
6.1.4 
Guidelines for continuation of treatment .............................................. 19 
6.1.5 
Treatment duration ................................................................................ 19 
6.1.6 
Other study treatment ............................................................................ 19 
6.2 
Dose escalation guidelines ..................................................................................... 19 


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6.3 
Dose modifications ................................................................................................ 19 
6.3.1 
Dose modifications and dose delay ....................................................... 19 
6.3.2 
Follow-up for toxicities ......................................................................... 19 
6.3.3 
Anticipated risks and safety concerns of everolimus ............................ 21 
6.4 
Concomitant medications ...................................................................................... 21 
6.4.1 
Permitted concomitant therapy ............................................................. 21 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 21 
6.4.3 
Prohibited concomitant therapy ............................................................ 23 
6.5 
Patient numbering, treatment assignment or randomization ................................. 23 
6.5.1 
Patient numbering ................................................................................. 23 
6.5.2 
Treatment assignment or randomization ............................................... 23 
6.5.3 
Treatment blinding ................................................................................ 23 
6.6 
Study drug preparation and dispensation ............................................................... 23 
6.6.1 
Study drug packaging and labeling ....................................................... 23 
6.6.2 
Drug supply and storage ........................................................................ 24 
6.6.3 
Study drug compliance and accountability ........................................... 24 
6.6.4 
Disposal and destruction ....................................................................... 25 
7 
Visit schedule and assessments ......................................................................................... 25 
7.1 
Study flow and visit schedule ................................................................................ 25 
7.1.1 
Enroll visit ............................................................................................. 27 
7.1.2 
Run-in period ........................................................................................ 27 
7.1.3 
Treatment period ................................................................................... 27 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal ............................................................................................. 27 
7.1.5 
Follow up for safety evaluations ........................................................... 29 
7.1.6 
Lost to follow-up ................................................................................... 29 
7.2 
Assessment types ................................................................................................... 29 
7.2.1 
Efficacy assessments ............................................................................. 29 
7.2.2 
Safety and tolerability assessments ....................................................... 29 
7.2.3 
Pharmacokinetics .................................................................................. 29 
7.2.4 
Biomarkers ............................................................................................ 29 
7.2.5 
Resource utilization ............................................................................... 29 
7.2.6 
Patient reported outcomes ..................................................................... 30 
8 
Safety monitoring and reporting ........................................................................................ 30 
8.1 
Adverse events ....................................................................................................... 30 
8.1.1 
Definitions and reporting ...................................................................... 30 
8.1.2 
Laboratory test abnormalities ................................................................ 31 


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8.1.3 
AEs of special interest ........................................................................... 31 
8.2 
Serious adverse events ........................................................................................... 32 
8.2.1 
Definitions ............................................................................................. 32 
8.2.2 
Reporting ............................................................................................... 32 
8.3 
Emergency unblinding of treatment assignment ................................................... 33 
8.4 
Pregnancies ............................................................................................................ 33 
8.5 
Warnings and precautions ...................................................................................... 34 
8.6 
Data Monitoring Committee .................................................................................. 34 
8.7 
Steering Committee ............................................................................................... 34 
9 
Data collection and management ....................................................................................... 34 
9.1 
Data confidentiality ............................................................................................... 34 
9.2 
Site monitoring ...................................................................................................... 34 
9.3 
Data collection ....................................................................................................... 35 
9.4 
Database management and quality control ............................................................ 35 
10 Statistical methods and data analysis ................................................................................ 35 
10.1 
Analysis sets .......................................................................................................... 36 
10.1.1 
Full Analysis Set ................................................................................... 36 
10.1.2 
Safety Set .............................................................................................. 36 
10.2 
Patient demographics/other baseline characteristics ............................................. 36 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 36 
10.4 
Primary objective ................................................................................................... 36 
10.4.1 
Analysis set and grouping for the analyses ........................................... 36 
10.4.2 
Adverse events (AEs) ............................................................................ 36 
10.5 
Sample size calculation .......................................................................................... 37 
11 Ethical considerations and administrative procedures ...................................................... 37 
11.1 
Regulatory and ethical compliance ........................................................................ 37 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 37 
11.3 
Informed consent procedures ................................................................................. 37 
11.4 
Discontinuation of the study .................................................................................. 38 
11.5 
Publication of study protocol and results............................................................... 38 
11.6 
Study documentation, record keeping and retention of documents ....................... 38 
11.7 
Confidentiality of study documents and patient records ....................................... 39 
11.8 
Audits and inspections ........................................................................................... 39 
11.9 
Financial disclosures .............................................................................................. 39 
12 Protocol adherence ............................................................................................................ 39 
12.1 
Amendments to the protocol .................................................................................. 39 
13 References (available upon request) .................................................................................. 40 


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List of figures 
Figure 4-1 
Study design .......................................................................................... 16 
 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 15 
Table 6-1 
Dose and treatment schedule ................................................................. 18 
Table 6-2 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A ................................................................................ 22 
Table 6-3 
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors ............................... 22 
Table 6-4 
Preparation and dispensing ................................................................... 23 
Table 6-5 
Packaging and labeling ......................................................................... 24 
Table 6-6 
Supply and storage of Investigational  treatments ................................ 24 
Table 7-1 
Visit evaluation schedule ...................................................................... 26 
 


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List of abbreviations  
AE 
Adverse event 
AUC 
Area under the drug plasma (serum/blood) concentration-time curve 
BSC 
Best supportive care 
Cmax 
Maximal drug blood concentration 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Event 
DDI 
Drug-drug interaction 
DS&E 
Drug Safety and Epidemiology 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FAS 
Full analysis set 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IIT 
Investigator initiated trial 
IN 
Investigator notification 
IRB 
Institutional review board 
mTOR 
mammalian target of rapamycin 
NET 
Neuroendocrine tumors 
PgP 
P-glycoprotein 
PHI 
Protected health information 
PI 
Principal investigator 
pNET 
Pancreatic neuroendocrine tumors 
RAD001 
Everolimus 
REB 
Research ethics board 
RECIST 
Response evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SEGA 
Subependymal giant cell astrocytoma 
Tmax 
Time to reach the maximum drug blood concentration following drug administration 
TSC 
Tuberous sclerosis complex 
VEGF 
Vascular endothelial growth factor 


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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.: every 28 days) 
Dose level 
The dose of drug given to the patient (total daily dose)  
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. 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 
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) 
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. 


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Amendment 01 (30-Aug-2016) 
Amendment rationale  
The amendment provides latest guideline of follow up toxicities such as evaluations for hepatic 
toxicities and work-up guidelines for potential Drug Induced Liver Injury (DILI) cases. In 
addition, this amendment has been implemented to provide updated information as well as 
clarification of sections of the protocol where additional guidance was required. 
Changes to the protocol 
Section 1.2.1.2: Clinical experience language updated 
Section 5.3: Updated contraception languagebased on new guidelines on pregnancy prevention. 
Section 6.1: Definition of study treatment clarified. Relevant sections were also updated. 
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 6-2: Updated inducers, and inhibitors of isoenzyme CYP3A based on IB update. 
Table 6-3: Updated substrates, inducers, inhibitors of PgP and PgP/CYP3A dual inhibitors 
based on IB update. 
Section 6.4.2: Updated vaccination language based on IB update. 
Section 7.1.4.1: Section name updated in addition to adding new language. 
Section 7.1.5: Section name updated.   
Section 7.1.6: Added Lost to follow up language. 
Section 7.2.2: Updated pregnancy testing language. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Protocol summary:  
Protocol number 
CRAD001C1X01B 
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. 
Brief title 
Study to collect and assess long-term safety of everolimus in patients who are 
on everolimus treatment in a Novartis-sponsored study and are benefiting from 
the treatment as judged by the investigator. 
Sponsor and Clinical 
Phase 
Novartis, II 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to collect and assess long-term safety of everolimus 
in patients who are on everolimus treatment in a Novartis-sponsored study and 
are benefiting from the treatment as judged by the investigator. 
Primary Objective(s) and 
Key Secondary Objective 
To collect and assess long-term safety of everolimus of patients receiving 
everolimus in a Novartis-sponsored study which has reached its objectives and 
who are benefiting from treatment with everolimus. 
Secondary Objectives 
Not applicable 
Study design 
This is a multi-center, open label study to collect and assess long-term safety of 
everolimus in patients being treated in current Novartis-sponsored studies and 
who are benefiting from treatment with everolimus 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.  
At least, patients must return to the study center on a yearly basis (± 3 months), 
but for resupply of study medication, the frequency of the receipt and dispensing 
must follow local practice (e.g., every 2 to 3 months). At this time the dose of 
everolimus is based on the investigator’s judgment.  
Adverse events (AEs) will be collected continuously throughout the study. For 
the safe and effective use of everolimus, patient may return to the clinic at any 
given time following local practice.  When AEs are observed, additional visits will 
be arranged by investigator’s discretion.  
Patients will continue to be treated until they are no longer benefiting from 
everolimus as defined in the parent protocol (disease progression), develop 
unacceptable toxicities, withdraw consent, 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. 
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 AEs for 30 days after the last dose of everolimus.  
The study is expected to remain open for 5 years or until such time that enrolled 
patients no longer need treatment with everolimus, whichever comes first.  
Population 
Male and female patients, who are currently enrolled in a Novartis-sponsored 
everolimus study, are benefiting from treatment with everolimus and have 
fulfilled all their requirements in the parent study. 
Inclusion criteria 
Patient is currently enrolled in a Novartis- sponsored everolimus 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 guidelines of the parent protocol. 
Patient has demonstrated compliance, as assessed by the investigator, with the 
parent study protocol requirements. 
Exclusion criteria 
Patient has been permanently discontinued from everolimus study treatment in 
the parent study due any reason. 
Investigational and 
reference therapy 
Everolimus, 2.5 – 10 mg/day. 
Efficacy assessments 
Not applicable 


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Safety assessments 
Reported AEs will be collected continuously throughout the study. For the safe 
and effective use of everolimus, medical monitoring should be performed as 
clinically indicated at the physician’s discretion. 
Other assessments 
Not applicable 
Data analysis 
Statistical analysis will be performed when all patients discontinued the trial or 
the 30-day safety follow-up was completed, whichever comes earlier. Those 
analyses results will be used to document the summary of the safety. Data will 
be used only for descriptive summary of patients remaining on drug.  
Key words 
Everolimus, roll-over study 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
The purpose of this study is to allow continued use of everolimus in patients who are currently 
receiving everolimus treatment in a Novartis-sponsored 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 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 also Section 1.2.1.2.  
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of everolimus (RAD001) 
Everolimus is a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) 
drug class. The mTOR pathway activity is modulated by the PI3K/AKT pathway, a pathway 
known to be dysregulated in numerous human cancers. 
Everolimus is being investigated as an anticancer agent based on its potential to act 
• directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity [via potent 
inhibition of tumor cell vascular endothelial growth factor (VEGF) production and VEGF-
induced proliferation of endothelial cells]. 
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR, a key protein kinase which regulates cell growth, proliferation and 
survival. The mTOR kinase is mainly activated via the phosphatidylinositol 3-kinase (PI3-
Kinase) pathway through AKT/PKB and the tuberous sclerosis complex (TSC). Mutations in 
these components or in phosphatase and tensin homolog, a negative regulator of PI3-kinase, 
may result in their dysregulation. Abnormal functioning of various components of the signaling 
pathways contributes to the pathophysiology of numerous human cancers. Various preclinical 
models have confirmed the role of this pathway in tumor development (Cohen et al 2005). 
The main known functions of mTOR include the following (Bjornsti and Houghton 2004): 
• mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels; 
• Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions; 
• The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors; 
• The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) 
and inhibition of endothelial cell growth and proliferation; 
• Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including 


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the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of 
HIF-1. 
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’s 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 studies 
include the following: metastatic renal cell carcinoma, breast cancer, pancreatic neuroendocrine 
tumors (pNET/NET), diffuse large B cell lymphoma, and hepatocellular cancer. In addition, 
treatment of patients with 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 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 including Japan 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. In Japan, Afinitor was approved in pNET in 2011 and 
approved in NET in 2016 based on the additional results from the study for patients with GI or 
lung NET. 
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® 


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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 
including Japan 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 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  
In Japan, Afinitor® was approved for adult patients with SEGA associated with TSC as well as 
AML associated with TSC.  
For further details please refer to the current everolimus IB. 
Pharmacokinetics 
Everolimus is rapidly absorbed after oral administration, with a time to reach the maximum 
drug blood concentration (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 drug 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 


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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.  
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 collect and assess long-term safety of everolimus in patients who 
are currently receiving everolimus treatment in a Novartis-sponsored 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. 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 defined in the parent protocol, 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. 
2.2 
Rationale for the study design 
This is a multi-center, open-label, phase II study to collect and assess long-term safety of 
everolimus for patients being treated in a current Novartis-sponsored study and who are 
benefiting from treatment with everolimus. 
The study will not include a screening phase as patients will transfer directly from the parent 
studies and will commence treatment with everolimus as soon as they are consented and meet 
the inclusion criteria of this roll-over study protocol.  
2.3 
Rationale for dose and regimen selection 
The selected doses and regimen will be based on the dose ranges and regimen available in the 
parent studies. Everolimus will be provided as 2.5 or 5 mg tablets to be administered using 
every day. See more details in Section 6.1.1.  


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2.4 
Rationale for choice of combination drugs  
Patients may be allowed to continue combination with everolimus in combination with other 
therapies if they are currently receiving the therapies on the parent protocol and are driving 
benefit judged by the investigator.   
2.5 
Rationale for choice of comparators drugs  
Not applicable.  
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below.  
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To collect and assess long term safety 
of everolimus 
Frequency and nature of AEs 
 
4 
Study design 
4.1 
Description of study design 
This is a multi-center, open label study to collect and assess long-term safety of everolimus in 
patients currently being treated in a Novartis-sponsored Oncology CD & MA study, who 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. Parent studies eligible to participate 
in the roll-over study will be decided by Novartis. Investigator initiated trials (IITs) 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. Patients must return to the study center at least on 
a yearly basis (± 3 months) for resupply of study medication.  Limited drug dispensing 
information will be collected. The patient may return to the clinic at any given time as per 
standard of care or be treated by physician’s recommendation, however at least one study visit 
every year will be scheduled and AEs reported at general medical care will be collected 
continuously throughout the study.  When AEs are observed, additional visits will be arranged 
by investigator’s discretion (see Section 6.3.2).  
Patients entering the roll-over protocol should be followed at the investigator’s discretion for 
known or clinically notable AEs that occur on everolimus treatment as described in the current 
version of the everolimus IB. 
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from their everolimus treatment as defined in the parent protocol (disease progression), they 
develop unacceptable toxicities, they withdraw consent, they are non-compliant to the protocol, 


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the investigator feels it is no longer in the patient’s best interest to continue everolimus therapy 
or the patient dies, whichever comes first.  
A patient will reach the end of study when everolimus treatment is permanently discontinued. 
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with everolimus, whichever comes first.  
Figure 4-1 
Study design 
 
4.2 
Timing of interim analyses and design adaptations 
Not applicable.  
4.3 
Definition of end of the study  
The end of the study is defined as when the patient permanently discontinues treatment with 
everolimus and the end of treatment visit has been performed for each patient. 
4.4 
Early study termination  
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with everolimus, whichever comes first.  
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be informed as soon as possible and should stop taking study labeled drug. 
Assessments should be performed as described in Section 7.1.4 for a prematurely withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
5 
Population 
5.1 
Patient population 
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: 
Parent study
Novartis Oncology CD&MA 
study
Everolimus (tolerable and 
effective dose)
RAD001C1X01B
Roll-over study
Everolimus (at assigned dose)
Starting dose = the same as the last 
dose received in the parent study
End of roll-over 
study
Everolimus is 
permanently 
discontinued


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1. Patient is currently enrolled in a Novartis-sponsored study, receiving everolimus 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. 
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. 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. 
3. 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. 
4. 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 everolimus last dose. 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 sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject. 


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• 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 
for a minimum of 3 months before taking study treatment. 
If a study patient or partner becomes pregnant or suspects being pregnant during the study or 
within 30 days after the last dose of everolimus, the investigator needs to be informed 
immediately and ongoing study treatment with everolimus has to be stopped immediately.  
6 
Treatment 
6.1 
Study treatment 
For study treatment refer to everolimus plus combination drugs used in the parent study and for 
investigational treatment refer to everolimus. 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule  
Investigational 
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 or 5 mg tablets. The investigational treatment is to be 
stored in a secure locked area while under the responsibility of the investigator. The investigator 
should assess compliance of study drug at each patient visit (see Section 6.6.3.1). Receipt and 
dispensing of investigational drug must be recorded by an authorized person at the 
investigator’s site (see Section 6.6.3.2).  
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. 
6.1.2 
Ancillary treatments  
Not applicable.  


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6.1.3 
Rescue medication  
Not applicable.  
6.1.4 
Guidelines for continuation of treatment  
Please refer to the Section 6.3.1.  
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 defined in the parent protocol (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. 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 5 years or until such time that enrolled patients no 
longer need treatment with everolimus, whichever comes first. 
6.1.6 
Other study treatment 
Please refer to the parent protocol and Package Insert for treatment, management of toxicities 
and dose modifications. 
6.2 
Dose escalation guidelines  
Not applicable.  
6.3 
Dose modifications 
6.3.1 
Dose modifications 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. The same dose modifications as followed in the parent 
protocol may apply at the investigator’s discretion, but the dose of everolimus will not be over 
10 mg/day.   
6.3.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE 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 serious 
AEs for 30 days after the last dose of everolimus.   


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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.  
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. 


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6.3.3 
Anticipated risks and safety concerns of everolimus 
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 parent protocol and the current everolimus 
IB. 
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 
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. 


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Please refer to Table 6-2 listing relevant inducers and inhibitors of CYP3A and to Table 6-3 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 6-2 
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 
Table 6-3 
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A dual inhibitors 
Substrates 
digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel, talinolol, 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 please refer to the current everolimus IB. 


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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.  
6.5 
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. .  
Additionally an electronic Case Report Form (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 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 6-4 
Preparation and dispensing 
Investigational 
treatments 
Dispensing 
Preparation 
Everolimus 
Blister packed tablets (2.5 – 5 mg) including instructions for 
administration will be dispensed by study personnel on an outpatient 
basis. 
Patients will be provided with an adequate supply of everolimus for 
self-administration at home until at least their next scheduled study 
visit.  
Dispensing of investigational drug must be managed regularly 
according to local practice (e.g., every 2 to 3 months).  
Not 
applicable 
6.6.1 
Study drug packaging and labeling 
Everolimus printed description on patient kit box will be in Japanese and comply with the legal 
requirements of Japan. They will include storage conditions for the drug but no information 
about the patient. 


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Everolimus for the roll-over study can be provided where appropriate as investigational medical 
products, packed under the responsibility of Novartis Drug Supply Management in Japan.  
The remained study drugs of the parent study which satisfies the legal requirements and no 
change in the description on patient kit box can be used for this roll-over study. More details 
can be found in the study drug manual of CRAD001C1X01B.  
Table 6-5 
Packaging and labeling 
Investigational 
treatment 
Packaging 
Labeling (the printed description on patient 
kit’s box) 
Everolimus 
Tablets in blisters 
As per local requirements 
6.6.2 
Drug supply and storage 
Everolimus 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 current everolimus IB.  
Table 6-6 
Supply and storage of Investigational  treatments  
Investigational 
treatments 
Supply 
Storage 
Everolimus 
Local clinical study supply (open 
label) supplied by Novartis 
Refer to everolimus printed description on 
patient kit box 
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. This information must be captured in the source document at each patient 
visit.  
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of everolimus in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. At study close-out, and, as 
appropriate during the course of the study, the investigator will return all used and unused 
everolimus, packaging, drug labels, and a copy of the completed drug accountability log to the 
Novartis monitor or to the Novartis address provided in the investigator folder at each site.  
6.6.3.3 
Handling of other study treatment 
Not applicable. 


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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 everolimus, packaging, the patient kit’s box, and a copy of the completed 
drug accountability log to the Novartis monitor. 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.  
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Patients must return to the study center at least yearly (± 3 months) for resupply 
of study medication.  
The table indicates which assessments produce data to be entered into the clinical database (D) 
or documented at the site level in the source documents (S) (“Category” column). 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Reference 
Section 7.2 
Enrollment 
Annual Visits during 
treatment phase 
(± 3 months visits during 
treatment phase) 
End of study 
treatment 
(EoT) 
30 day safety 
follow-up post 
last dose of 
study drug 
Visit Number  
 
 
1 
2 
3 
4 
5 
777 
 
Demographic: Patients’ previous study, site, 
subject number, race, gender, date of birth,  
D 
7.1.1.3 
x 
 
 
 
 
 
 
Informed consent 
D 
7.1.1 
x 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
5.2 / 5.3 
x 
 
 
 
 
 
 
Serum pregnancy testing 
S 
7.2.2 
x 
 
 
 
 
x 
 
Urine pregnancy testing 
 
 
S 
7.2.2 
 
monthly  
 
 
AEs 
D 
8.1 
x 
Continuous 
 
Everolimus dosing administration 
D 
6.1.1 
x 
Continuous 
x 
 
End of study treatment  
D 
7.1.4 
 
 
 
 
 
x 
 


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7.1.1 
Enroll visit 
There will be no screening period for this study. At the enrollment visit, the patient will need to 
complete a written informed consent. Once consented, patients will be evaluated for eligibility 
via the inclusion and exclusion criteria.  
7.1.1.1 
Eligibility screening  
Not applicable. 
7.1.1.2 
Information to be collected on screening failures 
Not applicable. 
7.1.1.3 
Patient demographics and other baseline characteristics 
For patients who are eligible to participate in this roll over study, an eCRF will be completed 
that identifies the patients’ race, gender, data of birth and previous study, site/center and subject 
number. 
7.1.2 
Run-in period  
Not applicable. 
7.1.3 
Treatment period 
The starting dose of everolimus on this roll-over protocol should be the same dose as that which 
the patient was receiving in the parent study at roll over.  
At least, patients must return to the study center on a yearly basis (± 3 months), but for resupply 
of study medication, the frequency of the receipt and dispensing must follow local practice (e.g., 
every 2 to 3 months). At this time the dose of everolimus is based on the investigator’s judgment. 
Patient whose treatment is interrupted or permanently discontinued due to an AE 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.   
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with everolimus, whichever comes first. 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal 
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 
information will be completed in the eCRF giving the date and reason for stopping the study 
treatment. 


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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 
after the last dose of everolimus.  
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. Thirty-day safety follow-up could be done 
via a phone contact.   
7.1.4.1 
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: 
• Death 
• Lost to follow-up 
• Staying in the study would be harmful 
• Patient/guardian decision 
• Physician decision 
• Non-compliance to protocol requirements 
• Protocol deviation 
• Pregnancy 
• Study terminated by sponsor 
• Unsatisfactory therapeutic effect 
7.1.4.2 
Replacement policy  
Not applicable.  


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7.1.5 
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 AE observed during this period. This could be done via a phone contact. Following this 
there are no further follow-up study visits. 
7.1.6 
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 
Not applicable.  
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by collecting AEs 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 performed 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. 
7.2.5 
Resource utilization 
Not applicable. 


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7.2.6 
Patient reported outcomes 
Not applicable.  
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained.  
Abnormal laboratory values or test results occurring after informed consent constitute AEs 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). 
AEs that begin or worsen after informed consent should be recorded in the AEs eCRF. AE 
monitoring should be continued for at least 30 days after the last dose of everolimus. AEs 
(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 AE. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Event 
(CTCAE) version 4.03.  
If CTCAE grading does not exist for an AE, 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 in the End of Treatment 
eCRF page.  
The occurrence of AEs should be sought by non-directive questioning of the patient during the 
screening process after signing informed consent and at each visit during the study. AEs also 
may be detected when they are volunteered by the patient during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments. As far as 
possible, each AE should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or Ongoing at End of Study) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted/ 
temporarily interrupted, permanently discontinued, concomitant medication taken, non-
drug therapy given, hospitalizaion) 
5. Whether it is serious, where a SAE is defined as in Section 8.2.1 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the AE eCRF. 


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Once an AE 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. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method [for example, as per Response evaluation Criteria in Solid Tumors (RECIST) criteria 
for solid tumors or as per Cheson's guidelines for hematological malignancies], should not be 
reported as a SAE. 
AEs 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 AE 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 AEs eCRF. 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 AEs 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 AE, 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 AE, should not be reported as 
AEs. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless 
it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold or medication for the lab abnormality may be required by the protocol in which case the 
lab abnormality would still, by definition, be an AE and must be reported as such. 
8.1.3 
AEs of special interest  
The treating doctor should be aware of the important potential risks of everolimus as reported 
in the current IB. In addition, the treating doctor should report any events noted below as AEs 
which are being closely monitored by safety to rule out causality: 
Refer to preclinical toxicity and or clinical data found in the current everolimus IB. 
In addition to all serious AEs reported on a continuous basis throughout the study, the 
investigator should use the SAE form to report the following medically significant potential 
risks: 
• Postnatal development toxicity 
• Pregnant or breast-feeding women 
• Intestinal obstruction /ileus 
• Male infertility 


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• 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 SAEs: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a SAE 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. A SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the SAE 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 
Japanese, and send the completed, signed form by fax within 24 hours to the Novartis Drug 
Safety and Epidemiology (DS&E) department. 


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The telephone and telefax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the CRF 
documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the current IB or Package Insert (new occurrence) 
and is thought to be related to the Novartis study treatment, a Novartis 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 Novartis DS&E. Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the study drug for 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 IB. 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.  


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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 IB. Additional 
safety information collected between IB updates will be communicated in the form of IN. 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.  
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 contract research organization (CRO)] will review the protocol and 
eCRFs 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 eCRFs, 
the adherence to the protocol to Good Clinical Practice, the progress of enrollment, and to 
ensure that everolimus is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits. 


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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 eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (ICF) 
(a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of AEs. 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 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 (PI) is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff 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. 
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 
Statistical analysis will be performed when all patients discontinued the trial or the 30-day 
safety follow-up was completed, whichever comes earlier. Those analyses results will be used 
to document the summary of the safety.  


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10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose (partial or 
complete) of everolimus. The FAS will be used for all listings of raw data. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose (partial or complete) of 
everolimus, and have at least one valid post-baseline safety assessment. The statement that a 
patient had no AEs (on the AEs CRF) constitutes a valid safety assessment.  
10.2 
Patient demographics/other baseline characteristics 
Patient demographics and baseline characteristics will be listed by patient. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
Everolimus dose administration will be listed by patient.  
10.4 
Primary objective 
Primary objective of this trial is to collect and assess the long-term safety everolimus in patients 
who are currently receiving treatment in the parent study and who are benefiting from treatment 
with everolimus. 
10.4.1 
Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into two mutually exclusive segments: 
1. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
2. post-treatment period: starting at day 30 after last dose of study medication. 
10.4.2 
Adverse events (AEs) 
Summary tables for AEs have to 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 AEs (new or worsening from baseline) will be summarized by system organ 
class and preferred term, severity (based on CTCAE grades), type of AE and relation to study 
treatment. 
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient. 


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Specific safety event categories will be considered. Such categories consist of one or more well-
defined safety events which are similar in nature and for which there is a specific clinical interest 
in connection with the study treatment(s).  
10.5 
Sample size calculation 
No formal sample size calculation is required for this trial since only patients who are still on 
treatment in the parent study will be enrolled in this trial.  
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 
International Conference on Harmonization (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 ICF 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 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 


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duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in the clinical study 
agreement. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The study eCRF 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 eCRFs and all other required reports. Data reported on the eCRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies 
should be explained. All data requested on the eCRF must be recorded. Any missing data must 
be explained. For eCRFs an audit trail will be maintained by the system.  
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 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 ICFs 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 Clinical Study Report. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC/REB at 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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Oncology Clinical Trial Protocol v01 (Clean) 
Protocol No. CRAD001C1X01B 
 
13 
References (available upon request) 
Bjornsti MA, Houghton PJ (2004) The TOR Pathway: A target for Cancer therapy. Nat Rev 
Cancer; 4(5):335-48. 
Boulay A, Lane HA (2007) The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124. 
Cohen HT, McGovern FJ (2005) Renal Cell Carcinoma. N Engl J Med; 353(23):2477-90. 
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011 

SAP_000.pdf: 
Clinical Development 
RAD001, everolimus 
Clinical Trial Protocol CRAD001C1X01B / NCT02017860
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 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
Final 1.0 
Release date: 
20-Apr-2015
Number of pages: 
5 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
1.0 
20Apr2015 
First version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Statistical methods planned in the protocol and determination of sample size ................... 4 
1.1 
Subjects and treatments ........................................................................................... 4 
1.1.1 
Analysis sets ............................................................................................ 4 
1.1.2 
Patient disposition ................................................................................... 4 
1.1.3 
Patient demographics and other baseline characteristics ........................ 4 
1.1.4 
Treatments (study treatment, concomitant therapies, compliance) ......... 4 
1.2 
Safety evaluation ..................................................................................................... 5 
1.2.1 
Adverse events (AEs) .............................................................................. 5 
1.3 
Determination of sample size .................................................................................. 5 
2 
Clinical Study Report - Appendix 16.1.9  Documentation of statistical methods .............. 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Statistical methods planned in the protocol and 
determination of sample size 
Data will be analyzed by Novartis according to the data analysis section 10 of the study 
protocol which is available in Appendix 16.1.1 of the CSR.  Important information is given in 
the following sections and details are provided. 
Statistical analysis will be performed when all patients discontinued the trial or the 30-day 
safety follow-up was completed, whichever comes earlier. Those analyses results will be used 
to document the summary of the safety.  
1.1 
Subjects and treatments  
1.1.1 
Analysis sets 
Full Analysis Set (FAS): The Full Analysis Set (FAS) comprises all patients who received at 
least one dose (partial or complete) of everolimus. The FAS will be used for all listings of raw 
data. 
Safety Set: The Safety Set includes all patients who received at least one dose (partial or 
complete) of everolimus, and have at least one valid post-baseline safety assessment. The 
statement that a patient had no AEs (on the AEs CRF) constitutes a valid safety assessment.  
1.1.2 
Patient disposition 
The number of patients ongoing at the time of analysis as well as the primary reason for end 
of treatment will be summarized for FAS. 
1.1.3 
Patient demographics and other baseline characteristics 
Demographic data, like age and gender as well as the parent study number will be 
summarized descriptively. 
Patient demographics and baseline characteristics will be listed by patient. 
1.1.4 
Treatments (study treatment, concomitant therapies, compliance) 
Exposure to everolimus will be summarized for FAS 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. 
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.  


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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. 
Everolimus dose administration will be listed by patient.  
1.2 
Safety evaluation 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into two mutually exclusive segments: 
1. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
2. post-treatment period: starting at day 30 after last dose of study medication. 
1.2.1 
Adverse events (AEs) 
Summary tables for AEs have to 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 all treatment-emergent AEs (number and percentage) will be summarized by 
system organ class (SOC), preferred term, and maximum severity, relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient. 
1.3 
Determination of sample size 
No formal sample size calculation is required for this trial since only patients who are still on 
treatment in the parent study will be enrolled in this trial.  
2 
Clinical Study Report - Appendix 16.1.9  Documentation of 
statistical methods 
No appendix 16.1.9 will be provided.