Clinical trial NCT01206764
Conditions: Renal Cell Carcinoma
Keywords: RCC, mTOR pathway, angiogenesis, PFS, partial response [PR] + complete response [CR]) metastatic recurrent renal cell carcinoma metastatic unresectable renal cell carcinoma
Sponsor: Novartis Pharmaceuticals
Start date: 2009-11-11; Completion date: 2017-07-01
Enrollment: 143 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Renal cell carcinoma (RCC) accounts for more than 200,000 new cases of cancer and over 100,000 cancer deaths annually in the World (Ferlay, et al., 2004). It is estimated that there were about 15,000 new cases of RCC in the region that excludes the Americas, European Union and Japan. Renal cell carcinomas arise from the proximal tubal epithelium are more common in males than in females with an overall lifetime risk of 1 in 75 and a median age of diagnosis of 65 years.

Everolimus (Certican®) has been approved since 2003 in more than 60 countries for the prevention of organ rejection in patients with renal and cardiac transplantation. Everolimus (RAD001) is a derivative of rapamycin, which acts as a signal transduction inhibitor. It targets mTOR, a key protein kinase regulating cell growth, proliferation, and survival. The mTOR pathway activity is modulated by the phosphatidylinositol-3-kinase (PI3K)/protein kinase B AKT (AKT) pathway, a pathway known to be deregulated in numerous human cancers. RAD001 (Afinitor®) has been 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 hypoxia-inducible factor 1 (HIF-1) activity, VEGF production, and VEGF-induced proliferation of endothelial cells).

Primary: To evaluate the PFS rate over time.

Secondary:

* To evaluate the disease control rate (stable disease \[SD\] + partial response \[PR\] + complete response \[CR\]);
* To evaluate the objective response rate (ORR; where ORR = CR + PR) and duration;
* To describe the safety profile of RAD001.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: RAD001
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
RAD001, Everolimus 
Amendment 1 to Clinical Trial Protocol CRAD001LIC01 / NCT01206764
An Open-Label, Multi-Center Phase 2 Study to Evaluate 
Everolimus as Monotherapy Treatment for Patients with 
Metastatic Recurrent and/or Unresectable Renal Cell 
Carcinoma (EVERMORE) 
Authors 
 
Document type 
Clinical Trial Protocol for Oncology 
Version number 
01  
Development phase 
Phase 2 
Document status 
Final 
Release date 
12-May-2010
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of Contents 
Table of Contents ............................................................................................................... 2 
List of Post-Text Supplements (PTS) ............................................................................... 5 
List of Tables ...................................................................................................................... 6 
List of Abbreviations ......................................................................................................... 7 
Oncology Clinical Study Protocol Synopsis .................................................................. 10 
1 
Background ...................................................................................................................... 19 
1.1 
Overview of Metastatic Renal Cell Carcinoma ................................................. 19 
1.2 
Overview of RAD001 ........................................................................................... 20 
1.2.1 
mTor Pathway and Cancer ................................................................ 21 
1.2.2 
Preclinical Studies ............................................................................... 21 
1.2.3 
Clinical Experience ............................................................................. 23 
1.3 
History of Amendments ...................................................................................... 28 
2 
Study Rationale ................................................................................................................ 28 
3 
Objectives ......................................................................................................................... 29 
3.1 
Primary Objective ............................................................................................... 29 
3.1.1 
Endpoint for Primary Objective ........................................................ 29 
3.2 
Secondary Objectives .......................................................................................... 29 
3.2.1 
Endpoints for Secondary Objectives ................................................. 29 
4 
Study Design ..................................................................................................................... 30 
5 
Population ........................................................................................................................ 31 
5.1 
Inclusion Criteria ................................................................................................. 31 
5.2 
Exclusion Criteria ................................................................................................ 32 
6 
Treatment ......................................................................................................................... 34 
6.1 
Investigational and Control Drugs ..................................................................... 34 
6.1.1 
Study Drug ........................................................................................... 34 
6.1.2 
Known Undesirable Effects of RAD001 ............................................ 34 
6.1.3 
RAD001 Dose Level Modification/Interruption Guidelines in 
Case of Suspected Toxicity ................................................................. 34 
6.1.4 
Monitoring of RAD001 Suspected Toxicities .................................... 36 
6.1.5 
How Supplied ....................................................................................... 40 
6.1.6 
Preparation and Storage ..................................................................... 41 
6.2 
Treatment Arms ................................................................................................... 41 
6.3 
Patient Numbering ............................................................................................... 41 
6.4 
Treatment Assignment ........................................................................................ 41 
6.5 
Treatment Blinding ............................................................................................. 41 


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6.6 
Treating the Patient ............................................................................................. 41 
6.6.1 
Commencing Treatment ..................................................................... 41 
6.6.2 
Study Drug Administration ................................................................ 41 
6.6.3 
Permitted Study Drug Adjustments .................................................. 42 
6.6.4 
Concomitant Medications ................................................................... 42 
6.6.5 
Interruption or Discontinuation of Study Drug ............................... 44 
6.6.6 
Patient Withdrawal ............................................................................. 45 
6.6.7 
Emergency Unblinding of Treatment Assignment........................... 45 
7 
Visit Schedule and Assessments ..................................................................................... 46 
7.1 
Visit Windows ...................................................................................................... 50 
7.2 
Information to be Collected on Screening Failures .......................................... 50 
7.3 
Patient Demographics/Other Baseline Characteristics .................................... 50 
7.4 
Treatments ............................................................................................................ 50 
7.5 
Efficacy ................................................................................................................. 50 
7.5.1 
Radiological Assessment of Tumor(s) ............................................... 50 
7.5.2 
Imaging Procedures ............................................................................ 52 
7.6 
Safety ..................................................................................................................... 52 
7.6.1 
Adverse Events .................................................................................... 52 
7.6.2 
Physical Examination, Including a Neurological Examination ...... 54 
7.6.3 
Vital Signs ............................................................................................ 54 
7.6.4 
Karnofsky Performance Status .......................................................... 55 
7.6.5 
Laboratory Evaluations ...................................................................... 55 
8 
Safety Monitoring ............................................................................................................ 58 
8.1 
Serious Adverse Event Reporting ...................................................................... 58 
8.2 
Pregnancies ........................................................................................................... 59 
8.3 
Data Monitoring Board ....................................................................................... 59 
9 
Data Review and Data Management ............................................................................. 59 
9.1 
Site Monitoring .................................................................................................... 59 
9.2 
Data Collection ..................................................................................................... 60 
9.3 
Auditing Procedures ............................................................................................ 60 
9.4 
Database Management and Quality Control .................................................... 60 
10 Statistical Methods and Data Analysis .......................................................................... 61 
10.1 
Populations for Analysis...................................................................................... 61 
10.2 
Patient Demographics/Other Baseline Characteristics .................................... 62 
10.3 
Treatments (Study Drug, Concomitant Therapies, Compliance) ................... 62 
10.3.1 
Study Drug ........................................................................................... 62 
10.3.2 
Concomitant Therapies ...................................................................... 62 


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10.4 
Primary Objective ............................................................................................... 62 
10.4.1 
Variable:  Progression-Free Survival ................................................ 62 
10.4.2 
Statistical Hypothesis, Model, and Method of Analysis................... 63 
10.4.3 
Handling of Missing Values/Censoring/Discontinuations ............... 63 
10.4.4 
Supportive Analyses ............................................................................ 63 
10.5 
Secondary Objectives .......................................................................................... 63 
10.5.1 
Secondary Efficacy Evaluation .......................................................... 63 
10.5.2 
Safety Evaluation ................................................................................ 64 
10.5.3 
Tolerability........................................................................................... 65 
10.5.4 
Resource Utilization ............................................................................ 65 
10.5.5 
Patient-Reported Outcomes ............................................................... 65 
10.5.6 
Pharmacokinetics ................................................................................ 65 
10.5.7 
Biomarkers........................................................................................... 65 
10.6 
Interim Analysis ................................................................................................... 65 
10.7 
Sample Size Calculation ...................................................................................... 65 
10.8 
Power for Analysis of Critical Secondary Variables ........................................ 66 
11 Administrative Procedures ............................................................................................. 67 
11.1 
Administrative Structure .................................................................................... 67 
11.2 
Regulatory and Ethical Compliance .................................................................. 67 
11.3 
Responsibilities of the Investigator and IRB/IEC/REB ................................... 67 
11.4 
Informed Consent ................................................................................................ 68 
11.5 
Exploratory Biomarker Consent Form ............................................................. 68 
11.6 
Amendments to the Protocol ............................................................................... 68 
11.7 
Discontinuation of the Study............................................................................... 68 
11.8 
Study Drug Supply and Resupply, Storage, and Tracking/Drug 
Accountability ...................................................................................................... 69 
11.9 
Study Duration/Timelines ................................................................................... 69 
11.10 Publication ............................................................................................................ 69 
12 Protocol Adherence ......................................................................................................... 70 
12.1 
Signature Pages .................................................................................................... 71 
13 References (available upon request) .............................................................................. 75 
14 Post-Text Supplements .................................................................................................... 78 
 


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List of Post-Text Supplements (PTS) 
 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference: .......................... 78 
 
 


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List of Tables 
 
Table 1 Adverse Events Suspected to be Drug-Related in 10% of Patients with 
Advanced Cancers Reported in Phase 1 RAD001 Monotherapy Studies 
(C2101, C2102, and C2107) .................................................................................... 25 
Table 2 RAD001 Dose Level Modification Guidelines ........................................................ 34 
Table 3 Criteria for Dose Modification in Case of Suspected RAD001 Toxicity and 
Re-Initiation of RAD001 Treatment ........................................................................ 35 
Table 4 Management of Non-Infectious Pneumonitis ........................................................... 38 
Table 5 Clinically Relevant Drug Interaction:  Substrates, Inducers, and Inhibitors 
of Isoenzyme CYP3A .............................................................................................. 43 
Table 9 Visit Evaluation Schedule ........................................................................................ 47 
Table 7 Karnofsky Performance Scale .................................................................................. 55 
Table 8 Number of Patients Required per Cohort Depending on Desired Width of 
Confidence Interval (CI) for the 10-Month Progression-Free Survival 
Proportion ................................................................................................................. 65 
Table 9 Study Administrative Structure ................................................................................ 67 
Table 10 Study Milestones ...................................................................................................... 69 
 
 


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List of Abbreviations 
ADR 
apparent drug reactions 
AE 
adverse event 
AKT/PKB 
Protein Kinase B (a component of PI3K signaling pathway) 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
area under the blood-concentration time curve 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computerized tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450  
DLCO 
diffusion capacity of carbon monoxide 
DLT  
dose limiting toxicity 
DSMB 
Drug Safety Monitoring Board 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl-transferase 
Hb 
hemoglobin 
HIF 
hypoxia-inducible factor 
HMG CoA 
high mobility group co-enzyme A 
IB 
Investigator‟s Brochure 
IC50 
inhibitory concentration at 50% 


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Protocol No. CRAD001LIC01  
 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IMS 
Integrated Medical Safety 
IND 
Investigational New Drug 
INR 
international normal ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
iv 
intravenous(ly) 
IVRS 
Interactive Voice Response System 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPD 
molecular pharmacodynamic 
MRCC 
metastatic renal cell carcinoma 
MRI 
magnetic resonance imaging 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
mTOR 
mammalian target of rapamycin  
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
ORR 
objective response rate 
OS 
overall survival 
p-4E-BP1 
eukaryotic initiation factor 4E binding protein-1  
p-AKT 
phospho-AKT 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI 
principle investigator 
PI3K 
phosphatidylinositol 3-kinase (mTOR pathway) 
PK 
pharmacokinetics 
PKB 
protein kinase B 
po 
per os/by mouth/orally 
PR 
partial response 
PT 
prothrombin time 
PTEN 
phosphatase and tensin homolog deleted on chromosome 10 


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Protocol No. CRAD001LIC01  
 
RBC 
red blood cells  
RCC 
renal cell carcinoma 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
S6K1 
S6 kinase 1 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous 
SD 
stable disease 
SOC 
System Organ Class 
SUSARS 
Suspected Unexpected Serious Adverse Reactions 
tmax 
time to reach maximum plasma concentration 
TTP 
time to progression  
TSC 
tuberous sclerosis complex  
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor  
VHL 
Von Hippel-Lindau 
WBC 
total white blood cell count 
WHO 
World Health Organization 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Oncology Clinical Study Protocol Synopsis  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
Background 
Renal cell carcinoma (RCC) accounts for more than 200,000 new cases of 
cancer and over 100,000 cancer deaths annually in the World (Ferlay, et al., 
2004).  It is estimated that there were about 15,000 new cases of RCC in the 
region that excludes the Americas, European Union and Japan. Renal cell 
carcinomas arise from the proximal tubal epithelium are more common in 
males than in females with an overall lifetime risk of 1 in 75 and a median age 
of diagnosis of 65 years.  
The past 10 years have seen a dramatic expansion of therapeutic options in 
the treatment of metastatic renal cell carcinoma (MRCC).  Cytokine-based 
immunotherapy, the introduction of vascular endothelial growth factor (VEGF) 
targeted therapies, such as sorafenib, sunitinib, bevacizumab, and the 
mammalian target of rapamycin (mTOR) inhibitor temsirolimus have 
completely changed the treatment paradigm, with another mTOR inhibitor, 
everolimus (Afinitor®),  approved in the US and Europe.  Despite this 
progress, MRCC still remains a fatal disease; therefore, the development of 
new treatments is needed to help improve the outcome for these patients. 
Everolimus (Certican®) has been approved since 2003 in more than  
60 countries for the prevention of organ rejection in patients with renal and 
cardiac transplantation.  Everolimus (RAD001) is a derivative of rapamycin, 
which acts as a signal transduction inhibitor.  It targets mTOR, a key protein 
kinase regulating cell growth, proliferation, and survival.  The mTOR pathway 
activity is modulated by the phosphatidylinositol-3-kinase (PI3K)/protein 
kinase B AKT (AKT) pathway, a pathway known to be deregulated in 
numerous human cancers.  RAD001 (Afinitor®) has been 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 hypoxia-inducible factor 
1 (HIF-1) activity, VEGF production, and VEGF-induced proliferation 
of endothelial cells).   
The role of angiogenesis in the maintenance of solid tumor growth is well 
established, and the mTOR pathway has been implicated in the regulation of 
tumor production of proangiogenic factors as well as modulation of VEGFR 
signaling in endothelial cells. 
This activity has recently been confirmed in a Phase 3 study (RECORD-1), 
which was stopped at its interim analysis by an Independent Data Monitoring 
Committee for outstanding efficacy observed at the second interim analysis.  
The results indicated a significant difference in efficacy between the RAD001 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
group and placebo group (hazard ratio 0.30 [95% confidence interval (CI): 
0.22, 0.40], p<0.0001).  The progression-free survival (PFS) showed in favor 
of RAD001 with a median PFS of 4.0 months (95% CI: 3.7, 5.5) versus  
1.9 months (CI: 1.8, 1.9) for the placebo group (Motzer, et al, 2008).  The 
probability of being progression-free at 6 months was 26% (95% CI: 14, 37) 
for patients receiving RAD001 compared with 2% (CI: 0, 6) for patients in the 
placebo group. The medium overall survival (OS) had not been reached for 
the RAD001 group and was 8.8 months (95% CI: 7.9, ASCO2009) for the 
placebo group.  There was no significant difference between the groups in 
terms of OS (hazard ratio 0.83; 95% CI: 0.50, 1.37; p=0.23) (Motzer et al, 
2008).  Results from a further analysis in the RECORD-1 study, indicated a 
significant prolongation in PFS for the RAD001 group compared with the 
placebo group (hazard ratio 0.33; 95% CI: 0.25, 0.43; p<0.001) (Escudier, et 
al., 2008).  The PFS showed in favor of RAD001 with a median PFS of  
4.9 months versus 1.87 months for the placebo group.  The median OS was 
not reached for RAD001, (hazard ratio 0.82; 95% CI: 0.57, 1.17; p<0.137) 
versus 13 months for the placebo group. RAD0001 is generally well tolerated 
at a dose of 10mg administered daily.  The most frequent adverse events 
associated with RAD001 therapy (stomatitis, anemia, asthenia, fatigue, rash, 
mucosal inflammation, hypercholesterolemia, and headache) are effectively 
managed with drug and non-drug therapies or dietary interventions.  Non-
infectious pneumonitis has been reported with mTOR inhibitors but is 
commonly low-grade and reversible. 
A Phase 2 study reported promising information in 41 metastatic renal cell 
cancer patients (majority were previously-treated with cytokine therapy), who 
were treated with RAD001, 10 mg orally (po) daily (Amato, et al., 2009).  The 
reported response rate was 32% (12 partial responses [PRs]), the median 
time to tumor progression was 11.17 months (2.00 months to >31.53 months) 
and OS in 39 patients was 24.17+ months. 
The intravenous mTOR inhibitor, temsirolimus (Torisel), has been reported to 
have a PFS and OS advantage over interferon (IFN) alpha in Memorial Sloan-
Kettering Cancer Center (MSKCC) poor prognosis MRCC patients treated in 
the first-line setting.  The median survival in the temsirolimus arm was 
prolonged to 10.9 months versus 7.3 months for interferon alpha (p=0.0069).  
Planned and post-hoc analyses have been performed to assess the influence 
of tumor histology (clear cell versus others) on survival in patients treated with 
temsirolimus or IFN (Dutcher, et al., 2007).  The “other” subgroup category 
included non-clear cell and indeterminate histologies.  The HR analysis for OS 
suggested an advantage for temsirolimus over IFN in this sub-group category 
(11.6 months versus 4.3 months, p=0.00095), even if the group analyzed is 
small and thus the confidence interval broader. 
It is clear that novel therapies are needed for patients with advanced RCC, 
including those with metastatic disease and those whose tumors are not 
amenable to surgical resection.  Although sunitinib and temsirolimus have 
improved PFS or OS, in comparison with IFN, and the addition of 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
bevacizumab to IFN has led to improved results in comparison with single-
agent IFN, in some countries IFN remains the only available treatment option 
for patients with advanced RCC.  This trial will therefore explore the use of 
once daily oral RAD001 in patients with advanced kidney cancer of clear and 
non-clear cell histology and all MSKCC prognosis.  
Purpose/rationale 
The purpose of this study is to demonstrate the safety and efficacy of RAD001 
(everolimus), an mTOR inhibitor, as monotherapy in patients with metastatic 
carcinoma of the kidney who have not received prior systemic treatment, 
other than cytokine therapy.  The proposed dose and schedule (10 mg/day) is 
based on various Phase 1, Phase 2 studies (monotherapy and combination 
therapy) in advanced cancers, including RCC, and a large controlled Phase 3 
study (RECORD-1).   
Current standard therapies (chemotherapies and cytokine-based therapies) 
have produced few and short-lived tumor responses, and are associated with 
severe toxicities.  The efficacy of RAD001 as monotherapy in patients who 
were previously treated with cytokine therapy (Amato et al., 2009), and whose 
disease had progressed on VEGF-tyrosine kinase inhibitor therapy (Motzer et 
a., 2008l) were recently reported. 
Objectives 
Primary:  To evaluate the PFS rate over time. 
Secondary: 
 
To evaluate the disease control rate (stable disease [SD] + partial 
response [PR] + complete response [CR]); 
 
To evaluate the objective response rate (ORR; where ORR = CR + PR) 
and duration; 
 
To evaluate Overall Survival (OS) 
 
To describe the safety profile of RAD001. 
Study design 
This is an open-label, multi-center, single arm Phase 2 study to evaluate the 
safety and efficacy of RAD001 as monotherapy in patients with any MSKCC 
prognosis metastatic recurrent and/or unresectable clear cell or non-clear cell 
carcinoma of the kidney.  Patients who have received prior cytokine therapy 
are permitted to participate in the study.   
Patients will self-administer orally, 10 mg RAD001 per day.  Tumor 
assessments will be performed at 8 weeks to evaluate for inadequate 
response (progressive disease [PD]).  The visit at which PD is documented 
will be deemed the End-of-Treatment Visit.  In the absence of PD, 
assessments will continue every 12 weeks (±1 week) until the start of new 
anticancer therapy and at End-of-Treatment Visit (within 1 week of stopping 
treatment) or until death.  A partial or complete response warrants 
confirmation no sooner than 4 weeks. 
Follow-up phase:  All patients will have a follow-up visit scheduled 28 days 
after the End-of-Treatment Visit to follow for AEs and SAEs that may have 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
occurred after discontinuation from the study.   
No Data Safety Monitoring Board (DSMB) is planned. 
Population 
Adult patients who have any MSKCC prognosis metastatic recurrent and/or 
unresectable clear cell or non-clear cell carcinoma of the kidney are eligible 
for enrollment in this study.  Previous cytokine therapy is permitted.  Patients 
must have histological or cytological confirmation of clear cell or non-clear cell 
renal carcinoma or a component of these histologies.   
Inclusion/exclusion 
criteria 
Inclusion criteria:  Patients may be entered in the study only if they meet all of 
the following criteria: 
 
Age ≥18 years old; 
 
Patients with advanced renal cell carcinoma with confirmed clear or 
non-clear cell histology, with or without nephrectomy, and with any 
MSKCC prognosis;   
 
Prior cytokine therapy is permitted; 
 
Patients with at least one measurable lesion at baseline as per the 
Response Evaluation Criteria in Solid Tumors (RECIST) criteria.  If skin 
lesions are reported as target lesions, they must be documented (at 
baseline and at every physical exam) using color photography and a 
measuring device (such as a caliper) in clear focus to allow the size of 
the lesion(s) to be determined from the photograph; 
 
Life expectancy ≥3 months.  Life expectancy should be judged in 
relation to other determining patient eligibility factors such as laboratory 
results, Karnofsky Performance Status, etc.; 
 
Patients with a Karnofsky Performance Status ≥70%; 
 
Adequate bone marrow function as shown by:  absolute neutrophil 
count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, hemoglobin (Hb)  
>9 g/dL; 
 
Adequate liver function:  serum bilirubin ≤1.5 x upper limit of normal 
(ULN), alanine transaminase (ALT), and aspartate transaminase (AST) 
≤2.5 x ULN.  Patients with known liver metastases:  AST and ALT ≤5 x 
ULN; 
 
Adequate renal function: serum creatinine ≤1.5 x ULN; 
 
Females of childbearing potential must have had a negative serum or 
urine pregnancy test 7 days prior to the administration of the study 
treatment start; 
 
Patients who give a written informed consent obtained according to 
local guidelines. 
 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
 
Exclusion criteria:  Patients may not be entered into the study if they meet any 
of the following criteria: 
 
Patients within 2 weeks post-minor surgery (e.g., herniorrhaphy),  
4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal, or 
intra-pelvic) to avoid wound healing complications.  Percutaneous 
biopsies require no waiting time prior to study entry; 
 
Patients with a recent history of hemoptysis, ≥0.5 teaspoon of red 
blood; 
 
Patients who have received prior systemic treatment for their metastatic 
RCC other than with cytokine therapy; 
 
Patients who received prior therapy with a VEGF pathway inhibitor, 
such as sunitinib, sorafenib, and bevacizumab; 
 
Patients who have previously received mTOR inhibitors (sirolimus, 
temsirolimus, everolimus, deferolimus); 
 
History or clinical evidence of central nervous system (CNS) 
metastases. Note: Subjects who have previously-treated CNS 
metastases (surgery±radiotherapy, radiosurgery, or gamma knife) and 
meet all 3 of the following criteria are eligible: 
 
Are asymptomatic;  
 
Have had no evidence of active CNS metastases for ≥ 6 
months prior to enrollment and; 
 
Have no requirement for steroids or enzyme-inducing 
anticonvulsants (EIAC); 
 
Clinically significant gastrointestinal abnormalities including, but not 
limited to: 
 
Malabsorption syndrome; 
 
Major resection of the stomach or small bowel that could 
affect the absorption of study drug; 
 
Active peptic ulcer disease; 
 
Inflammatory bowel disease; 
 
Ulcerative colitis, or other gastrointestinal conditions with 
increased risk of perforation; 
 
History of abdominal fistula, gastrointestinal perforation, or 
intra abdominal abscess within 28 days prior to beginning of 
study treatment; 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
 
Patients receiving chronic systemic treatment with corticosteroids (dose 
of ≥10 mg/day methylprednisone equivalent) or another immune-
suppressive agent.  Inhaled and topical steroids are acceptable, as well 
as opotherapy after bilateral adrenal gland removal; 
 
Patients with a known history of human immunodeficiency virus 
seropositivity; 
 
Patients with autoimmune hepatitis; 
 
Patients with an active, bleeding diathesis.  Patients may use coumadin 
or heparin preparations; 
 
Patients who have any severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study;  
 
Patients who have a history of another primary malignancy ≤3 years, 
with the exception of non-melanoma skin cancer and carcinoma in situ 
of uterine; 
 
Female patients who are pregnant or breastfeeding, or adults of 
reproductive potential who are not using effective birth control methods.  
If barrier contraceptives are being used, these must be continued 
throughout the study by both sexes.  Oral contraceptives are not 
acceptable as the only contraception method. However they can 
be used in combination with other methods such as barrier 
contraceptives; 
 
Patients who are using other investigational agents or who had received 
investigational drugs ≤4 weeks prior to study treatment start; 
 
Patients unwilling or unable to comply with the protocol. 
Patient numbering 
The patient number is a 9-digit number.  The first part is the site number (first 
4 digits) and the second part (last 5 digits) is one of a series of numbers 
allocated to patients at that site.  The site number is assigned by Novartis. 
There will be no Interactive Voice Response System (IVRS) used. 
Investigational and 
control drugs 
Study drug refers to any Novartis investigational drug(s) or any Novartis 
marketed drug(s) being used for an unapproved indication.   The 
investigational drug used in this study is RAD001.  The study drug will be self-
administered (by the patients themselves).  The investigator will instruct the 
patient to take the study drug exactly as specified in the protocol. 
Dose, regimen, 
treatment cycle 
Patients will be instructed to take two 5 mg RAD001 tablets (one tablet after 
another) orally, with a glass of water at the same time each day in a fasting 
state or with a light fat-free meal. 
RAD001 will be taken daily from Visit 2 (Day 1) until disease progression, 
unacceptable toxicity, or death or discontinuation from the study for any other 
reason. 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
Each treatment cycle is 28 days. 
Supply, preparation, 
and administration 
RAD001 will be provided by Novartis.  RAD001 is formulated as tablets of  
5 mg strength for oral administration.  The starting dose for Cycle 1 is  
10 mg/day.  Tablets should be opened only at the time of administration, as 
the drug is both hygroscopic and light sensitive.  Patients will be supplied with 
enough tablets for a complete 28-day cycle.  Tablets should be stored in a 
secure, dry, light-proof medicine cabinet. 
Visit schedule and 
assessments 
Patients will present to the clinic on Day 1 and Day 15 of treatment Cycles 1, 
2, and 3 and Day 1 of each subsequent treatment cycle for assessments.  
Please see Section 7 and Table 9 for details of assessments.   
Efficacy 
assessment(s) 
Tumor response, SD, and progression will be assessed using the RECIST 
criteria.  A computerized tomography (CT) scan or magnetic resonance image 
(MRI) of the chest/abdomen and pelvis will be obtained at screening (≤35 
days) prior to the first dose of RAD001.  Tumor response will be assessed at 
8 weeks (±1 week), and every 12 weeks (±1 week) thereafter, until 
determination of disease progression (by the local radiologist) and at the end 
of the study.  The same imaging modality used at screening must be used for 
all subsequent follow-up assessments.  
Ultrasound scans cannot be used to measure tumor lesions. 
Special safety 
assessment(s) 
Safety assessments will consist of monitoring and recording all AEs, including 
SAEs, the regular monitoring of hematology, serum chemistry, routine 
monitoring of vital signs (heart rate, blood pressure, and body temperature), 
and chest x- rays, electrocardiograms, and physical condition. 
Toxicity will be assessed using the National Institutes of Health (NIH)-National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), version 3.0. 
During the screening period, ALL patients must be screened for HBV and 
HCV (current or past history of infection). Careful medical history must be 
taken for all patients to look for risk factors (family history of HBV and HCV, 
intravenous drug abuse, unprotected sex, dialysis, blood transfusions, etc), 
and any past or present HBV symptoms (e.g., jaundice, dark urine, light-
colored stools, right upper quadrant pain). In addition, ALL patients will be 
tested at screening for: 
 
HBV-DNA levels 
 
Hepatitis B surface antigen (HBsAg) 
 
Hepatitis B core antibody (HBcAb) 
 
Hepatitis B surface antibody (HBsAb) 
Based on the results of the screening HBV tests, the patients may be given 
prophylactic antiviral treatment and  will be monitored throughout the study 
according to Table 6-5. 
ALL patients will be tested for quantitative HCV RNA-PCR at the screening 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
visit. 
Monitoring for HCV RNA-PCR levels every six weeks is required for: 
 
patients known to have a history of HCV infection, despite a negative viral 
load test at screening (including those that were treated and are 
considered „cured‟) 
 patients positive for viral load on HCV RNA-PCR test at screening. 
Patient reported 
outcomes 
There are no patient reported outcomes. 
Pharmacokinetics 
Not applicable. 
DSMB 
No Data Safety Monitoring Board is planned for this study. 
Statistical methods 
and data analysis 
Study Populations 
The Full Analysis Set (FAS) consists of all patients treated with RAD001.  
Following the intent-to-treat (ITT) principle, patients are analyzed according to 
the treatment and stratum they were in at the start of the study. 
The Safety population consists of all patients who received at least one dose 
of the study drug and who have at least one post-baseline safety assessment.  
Patients 
are 
analyzed 
according 
to 
the 
treatment 
received 
 
Efficacy: 
The primary endpoint of this study, PFS, is defined as the time from the date 
of the start of RAD001 treatment to the date of the first documented disease 
progression or death due to any cause.  
A patient who has not progressed or died at the date of the analysis cut-off, or 
when he/she receives any further anticancer therapy, would have his/her PFS 
censored at the time of the last tumor assessment, before the first of the cut-
off date or the anticancer therapy date.  
The primary analysis, PFS, will be based on the review by the local radiologist 
and/or the investigator, who will determine tumor response and progression 
according to the RECIST criteria. 
Secondary endpoints include OS, disease control rate, duration of response, 
ORR, and frequency of AEs and SAEs.  The disease control rate will be 
based on the data as per radiological review, following the RECIST criteria.  
The disease control rate is defined as the proportion of patients with CR, PR, 
or SD.  The disease control rate (CR + PR + SD) will be summarized in terms 
of percentage with a 95% confidence interval (CI).  The overall response rate 
is defined as the proportion of patients with CR or PR.  The overall response 
rate (CR + PR) will be summarized in terms of percentage with a 95% CI. 
The sample size for this study will be determined with reference to estimating 
a CI for the PFS rate at 10 months, assuming (for simplicity) the use of the 


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Oncology Clinical Study Protocol (Version No. 01) (AM 1) 
Protocol No. CRAD001LIC01  
 
Investigational drug 
RAD001 (everolimus) 
Protocol no. 
CRAD001LIC01 
Study phase 
Phase 2 
Study title 
An open-label, multi-center phase 2 study to evaluate everolimus as 
monotherapy treatment for patients with metastatic recurrent and/or 
unresectable renal cell carcinoma (EVERMORE) 
normal approximation to the binomial distribution and assuming that a CI for a 
proportion is based on this normal approximation.  To be able to estimate a 
95% CI for the PFS rate, centered at 0.50, and having an expected total 
interval width of approximately 0.27, requires a sample size of 55 patients in 
each cohort (first- and second-line). With 95% confidence, the expected total 
interval width is approximately 0.19 for all 110 patients (both cohorts 
combined). 
Study Recruitment 
and duration 
Recruitment:  Approximately 18 months. 
Treatment period: Patients will receive study treatment until: (a) there is 
evidence of disease progression; (b) the patient develops 
unacceptable toxicity; or (c) the patient withdraws 
informed consent.  
Follow-up: 28 days 
Key dates 
FPFV: 
31 July 2009 
LPLV: 
30 January 2012 
Number of patients, 
sites and location 
Total number of patients:  110 
Number of sites:  25 
Location of sites:  Algeria, Morocco, Tunisia, Egypt, Saudi Arabia, Thailand, 
Jordan, Lebanon, India, Russia, and South Africa. 


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1 
Background 
1.1 
Overview of Metastatic Renal Cell Carcinoma 
Renal cell carcinoma (RCC) accounts for more than 200,000 new cases of cancer and over 
100,000 cancer deaths annually in the World (Ferlay, et al., 2004).  It is estimated that there 
were about 15,000 new cases of RCC in the region that excludes the Americas, European 
Union and Japan.  
Renal cell carcinomas arise from the tubular epithelium.  Alternatively known as clear-cell 
cancer or renal adenocarcinoma, RCC is characterized by a distinct clear or granular cell 
appearance visible by light microscopy (Amato, 2000; George and Kaelin, 2003).  Renal cell 
carcinoma can occur in different cellular types (Storkel and van den Berg, 1995): 
 
conventional RCC (also known as clear cell) (75% of cases); 
 
RCC of papillary cell type (also known as chromophilic) (10% of cases); 
 
chromophobe cell carcinoma (5% of cases); 
 
Others (10% of cases). 
The most common molecular abnormality in clear cell RCC is loss of Von Hippel-Lindau 
(VHL), which is found in about 50%-70% of sporadic cases (Kim and Kaelin, 2004).  
Sporadic somatic and hereditary germ cell mutations cause the loss of the VHL protein 
(Gnarra and Dressler, 1995) and VHL negatively regulates hypoxia inducible genes, such as 
those encoding hypoxia inducible factor-1 alpha (HIF 1-alpha), vascular endothelial growth 
factor (VEGF), and platelet-derived growth factor B and the glucose transporter GLUT-1 
(Iliopoulus, et al., 1996).  An animal model of VHL-deficient tumors showed increased 
uptake of the positron emission tomography tracer fluorodeoxyglucose in an mTOR 
dependent manner (Thomas, et al., 2006). 
As with clear cell cancers, papillary tumors originate from the tubular epithelium, but they are 
morphologically and genetically distinct malignancies.  Multiple genetic abnormalities have 
been described.  Among 29 malignant papillary RCCs, for example, trisomy 16 was present in 
20 tumors, and trisomy 12 and trisomy 20 were each identified in 8 cases (Kovacs, et al., 
1989).  No tumor had an abnormality in 3p, which is the typical finding in clear cell 
carcinomas.  While inherited papillary RCCs have been associated with mutations in the  
c-met oncogene, such mutations have not been routinely detected in sporadic cases. 
Papillary carcinomas have been subdivided into two subtypes, based upon histologic criteria 
and distinctive gene expression profiles (Delahunt and Eble, 1997).  Type 1 tumors tend to be 
low-grade and have a better prognosis, while type 2 lesions generally are high-grade and have 
a poorer prognosis.  An analysis of 130 cases of papillary carcinomas at a median follow-up 
of 48 months found that patients with type 1 tumors had a significantly better overall and 
disease-free survival than patients with type 2 tumors (89% and 92% versus 55%  and 44%, 
respectively; Pignot, et al., 2007).  
Approximately 25% of the patients present with advanced disease at the time of diagnosis, 
including locally invasive or metastatic renal cell carcinoma, and 50% of the patients 


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Protocol No. CRAD001LIC01  
 
undergoing curative surgery can be expected to experience relapse at distant sites (Figlin, 
1999; Linehan, 2001).  Median survival for patients with metastatic disease is about  
13 months (Cohen and McGovern, 2005). 
Renal cell carcinoma is characterized by a high degree of resistance to chemotherapy. 
Interferon-α and interleukin-2 were for many years standard therapies for patients with 
metastatic RCC (MRCC).  Both achieve complete plus partial responses in 10% to 20% of 
patients.  Only a minority of patients achieve long-term survival.  Recently developed VEGF 
targeted therapies, both receptor tyrosine kinase inhibitors (sunitinib, sorafenib) and VEGF-A 
ligand antibodies (bevacizumab), have demonstrated activity in clear-cell MRCC (Motzer, et 
al., 2007; Awada, et al., 2005; Escudier, et al., 2007; Yang, et al., 2003); however, there is 
limited data regarding their efficacy in papillary RCC. 
The mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, reported both a PFS 
and overall survival (OS) advantage over interferon alpha in Memorial Sloan-Kettering 
Cancer Center (MSKCC) poor prognosis MRCC patients treated in the first-line setting 
(Hudes, et al., 2006).  This study demonstrated a statistically significant improvement in PFS 
(3.7 months) for patients who received 25 mg intravenous (iv) temsirolimus on a weekly 
schedule versus 1.9 months for patients who received interferon alpha (p=0.0001).  The 
median survival in the temsirolimus arm was prolonged to 10.9 months versus 7.3 months for 
interferon alpha (p=0.0069).  Planned and post-hoc analyses have been performed to assess 
the influence of tumor histology (clear cell versus others) on survival in patients treated with 
temsirolimus or interferon (IFN) (Dutcher, et al., 2007).  The “other” subgroup category 
included non-clear cell and indeterminate histologies.  The HR analysis for OS suggested an 
advantage for temsirolimus over IFN in this sub-group category (11.6 months versus  
4.3 months, p=0.00095), even if the group analyzed was small and thus the confidence 
interval broader (Dutcher, et al., 2007).  
It is clear that novel therapies are needed for patients with advanced RCC, including those 
with metastatic disease and those whose tumors are not amenable to surgical resection. 
Although sunitinib and temsirolimus have improved PFS or OS, in comparison with IFN, and 
the addition of bevacizumab to IFN has led to improved results in comparison with single-
agent IFN, in some countries IFN remains as the only available treatment option for patients 
with advanced RCC.  This trial will therefore explore the use of oral RAD001 daily in both 
clear cell and non-clear cell carcinoma of the kidney.  
1.2 
Overview of RAD001 
RAD001 (everolimus) is a novel derivative of rapamycin.  RAD001 has been in clinical 
development since 1996 as an immunosuppressant in solid organ transplantation.  Since 2003, 
RAD001 has been approved in Europe (trade name: Certican®) via the Mutual Recognition 
Procedure for the prevention of organ rejection in patients with renal and cardiac 
transplantation.  Certican® is also approved in Australia, South Africa, the Middle East, 
Central and South America, the Caribbean, and some Asian countries. 
RAD001 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;  


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Protocol No. CRAD001LIC01  
 
 
indirectly, by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF production and VEGF-induced proliferation of 
endothelial cells). 
1.2.1 
mTor Pathway and Cancer 
At the cellular and molecular level, RAD001 acts as a signal transduction inhibitor.  RAD001 
selectively inhibits mTOR, a key protein kinase present in all cells, which regulates cell 
growth, proliferation, and survival.  mTOR is mainly activated via the phosphatidylinositol 3-
kinase (P13K) pathway through AKT/protein kinase B (PKB) and the tuberous sclerosis 
complex (TSC1/2).  Mutations in these components, or in PTEN (phosphatase and tensin 
homolog deleted on chromosome 10), a negative regulator of PI3K, 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. 
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 the HIF-1 proteins.  Inhibition of mTOR is expected to lead to decreased 
expression of HIF-1. 
1.2.2 
Preclinical Studies 
RAD001 inhibits the proliferation of a range of human tumor cell lines in vitro, including 
lines originating from lung, breast, prostate, colon, melanoma, and glioblastoma.  The  
50% inhibitory concentration (IC50) ranges from sub/low nM to μM.  RAD001 also inhibits 
the proliferation of human umbilical vein endothelial cells in vitro, with particular potency 
against VEGF-induced proliferation, suggesting that RAD001 may also act as an 
antiangiogenic agent.  
The antiangiogenic activity of RAD001 was confirmed in vivo.  RAD001 selectively inhibited 
VEGF-dependent angiogenic responses at well tolerated doses.  Mice with primary and 
metastatic tumors treated with RAD001 showed a significant reduction in blood vessel density 
when compared with controls. 
The potential of RAD001 as an anticancer agent was shown in rodent models.  RAD001 is 
orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous (sc) 
mouse xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor 
model.  The pharmacokinetic (PK) profile of RAD001 indicates sufficient tumor penetration, 


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Protocol No. CRAD001LIC01  
 
above that needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed 
sensitive to RAD001 in vitro. 
RAD001 administered daily orally (po) was a potent inhibitor of tumor growth, at well-
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung, and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic 
melanoma).  These models included tumor lines considered sensitive and “relatively resistant” 
in vitro.  In general, RAD001 was better tolerated in mouse xenograft models than standard 
cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar antitumor 
activity.  Additionally, in a VEGF-impregnated sc implant model of angiogenesis, RAD001 
antiangiogenic activity was demonstrated by reduced vascularity in RAD001-treated tumors 
(murine melanoma). 
It is not clear which molecular determinants predict responsiveness of tumor cells to RAD001. 
Molecular analysis has revealed that relative sensitivity to RAD001 in vitro correlates with 
the degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 
ribosomal protein; in some cases (i.e., glioblastoma multiforme) there is also a correlation 
with PTEN status. 
In vivo studies investigating the antitumor activity of RAD001 in experimental animal tumor 
models showed that RAD001 monotherapy typically reduced tumor cell growth rates rather 
than regression or stable disease.  These effects occurred within the dose range of 2.5 mg/kg 
to 10 mg/kg, po once a day. 
In preclinical models, the administration of RAD001 was associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) 
and eukaryotic initiation factor 4E binding protein-1 (p-4E-BP1), and occasionally with an 
increase in phosphorylation of AKT, a protein upstream of mTOR in the signaling pathway.  
Study CRAD001A2107 explored molecular pharmacodynamic (MPD) changes in tumors at 
different doses and schedules of RAD001 (weekly 20, 50, and 70 mg or daily 5 and 10 mg). 
All significant adverse events (AEs) observed in toxicology studies with RAD001 in mice, 
rats, monkeys, and minipigs were consistent with its anticipated pharmacological action as an 
antiproliferative and immunosuppressant and, at least in part, were reversible after a 2- or  
4-week recovery period, with the exception of the changes in male reproductive organs, most 
notably the testes. 
Thomas, et al. (2006), have published on the preclinical rationale for using mTOR inhibitors 
in kidney cancer.  Their work showed that HIF mutants rescue growth suppression caused by 
treatment of CCI-779, a rapamycin prodrug, in mice, and supports that the effect of mTOR 
inhibitors in renal cell carcinoma are mediated primarily via direct effects on tumor cells.  
However, the effect of mTOR inhibitors on the carcinoma‟s microenvironment requires 
further study.  The mTOR inhibitors have a distinct mechanism of action from the VEGF 
pathway inhibitors such as VEGF receptor tyrosine kinase inhibitors (sunitinib and sorafenib) 
and VEGF ligand antibodies (bevacizumab).  Therefore, resistance to VEGF inhibitors does 
not imply resistance to mTOR inhibitors. 


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1.2.3 
Clinical Experience 
1.2.3.1 
RAD001 Pharmacokinetics 
The PK characteristics of RAD001 have been extensively investigated in the context of the 
drug‟s development as an immunosuppressant in solid organ transplantation, where RAD001 
was administered twice daily as a part of an immunosuppressant, multi-drug regimen, 
consistently including cyclosporin A and glucocorticoids.  
Recent Phase 1 studies provide steady-state PK for both the weekly and daily schedules at 
varying dose levels in patients with advanced cancers.  RAD001 is rapidly absorbed after oral 
administration, with a median time to peak plasma levels (tmax) of 1-2 hours postdose.  The 
extent of absorption is estimated at above 11%.  
The area under the blood concentration-time curve (AUC) is dose-proportional over the dose 
range tested, while maximum blood concentration (Cmax) appears to plateau at dose levels 
higher than 20 mg.  The terminal half-life in cancer patients averaged 30 hours, which is 
similar to that in healthy subjects.  Inter-patient variability is moderate with the coefficient of 
variation (CV) of approximately 50%.  A high-fat meal altered the absorption of RAD001 
with 1.3 hour delay in tmax, a 60% reduction in Cmax, and a 16% reduction in AUC.  In whole 
blood, approximately 80% of RAD001 is contained in red blood cells (RBC).  
Of the fraction of drug contained in plasma, 74% is protein-bound.  The apparent distribution 
volume after a single dose was 4.7 L/kg.  RAD001 is eliminated by metabolism, mainly by 
hydroxylation, then excreted into the feces (>80%). RAD001 is mainly metabolized by 
cytochrome P450 (CYP) 3A4 isoenzyme in the liver and to some extent in the intestinal wall.  
RAD001 is also a substrate of P-glycoprotein (P-gp).  Therefore, absorption and subsequent 
elimination of systematically absorbed RAD001 may be influenced by medicinal products 
that interact with CYP3A4 and/or P-gp.  In vitro studies showed that RAD001 is a 
competitive inhibitor of CYP3A4 and of CYP2D6 substrates, potentially increasing the 
concentrations of medicinal products eliminated by these enzymes.  
In two Phase 3 clinical studies in patients following kidney transplantation, strong inhibitors 
of CYP3A4 (azoles, antifungals, cyclosporine, erythromycin) have been shown to reduce the 
clearance of RAD001, thereby increasing RAD001 blood levels.  Similarly, rifampin, a strong 
inducer of CYP3A4, increases the clearance of RAD001, thereby reducing RAD001 blood 
levels.  Caution should be exercised when co-administering RAD001 with CYP3A4 inhibitors 
or inducers. 
Pharmacokinetic drug to drug interactions with cancer agents are being evaluated in ongoing 
Phase 1b studies.  Based on currently available results, gemcitabine (Study 2101 part 2) and 
paclitaxel (Study 2104) did not alter RAD001 PK to a clinically relevant extent, whereas 
imatinib notably increased RAD001 exposure with a mean increase in AUC by a multiple of 
3.7 for RAD001 administered weekly and 2-fold for RAD001 administered daily (Study 
2206).  Exposure to RAD001 in the presence of letrozole did not exceed that in monotherapy 
(Study 2108).  
Co-administration of RAD001 did not influence the PK of gemcitabine, imatinib, or letrozole.  
Exposure to paclitaxel in the presence of RAD001 was slightly decreased (average by 23%). 


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RAD001 PK in transplant patients were investigated in special populations, such as patients 
with hepatic or renal impairment, various ethnic groups, and pediatric renal transplant 
patients.  In patients with mild to moderate hepatic impairment, mean AUC for RAD001 was 
increased by 2-fold whilst renal impairment did not affect the PK of RAD001.  Age, weight 
(both over the adult range), and gender did not affect the PK of RAD001 to a clinically 
relevant extent.  Also, the PK were not altered in Asian patients, whereas black patients had 
21% higher clearance compared with non-blacks. 
A single, escalating-dose study in Japanese subjects did not show a significant difference in 
systemic exposure relative to the Caucasian population. 
1.2.3.2 
Pharmacodynamic Studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral biomarker 
(S6 kinase inhibition in peripheral blood mononuclear cells [PBMCs]) suggests that 5 mg to 
10 mg daily should be an adequate dose to produce a high degree of sustained target 
inhibition. 
Furthermore, MPD studies using immunohistochemistry in biopsied tumor tissue assessed the 
degree of inhibition and its duration (for p-S6, p-4E-BP1, and p-AKT expression) with 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. 
In the first part of Study C2101/C2102, the inhibition of S6K1 activity in PBMCs was 
measured in patients on a weekly regimen (5, 10, 20, and 30 mg) by radioimmunoassay 
(Lane, et al., 2003).  Subsequently, PK/pharmacodynamic modeling was carried out, 
extrapolating from preclinical findings in order to predict the likely inhibitory effect of 
RAD001 on its known target in the tumor of patients at these doses in the weekly regimen, as 
given, at postulated higher weekly doses, and in a postulated daily regimen.  For the weekly 
regimen, the modeling suggested 20 mg/week as a minimum inhibitory dose, but with a 
decline of inhibition (over 50%) between administrations, which was only marginally 
improved by increasing the dose.  The model indicated that a greater degree of sustained 
inhibition should be obtained with a daily regimen at comparable total drug consumption. 
A daily regimen of RAD001 (5 mg/day) was associated with a high inhibition of p-S6 and  
p-eIF4G, which was complete at 10 mg daily.  In patients on the weekly schedule, p-S6 
inhibition was complete and sustained at all dose levels, while that of p-eIF4G was complete 
and sustained at 50 mg weekly, but not at 20 mg weekly.  On both regimens, numerous 
patients demonstrated apparent up-regulation of AKT, which tended not to persevere in the 
patients at 50 mg weekly.  The proliferation index was reduced in most patients, recovering in 
some of those on the 50 mg weekly regimen.  Please refer to the Investigator‟s Brochure (IB) 
for further details.  
1.2.3.3 
Phase 1 Oncology Studies 
Data are available from Phase 1 clinical studies of RAD001 given as a single agent to  
147 patients with advanced solid tumors.  Such studies included various doses and schedules 
(weekly dosing, range 5 mg to 70 mg and daily dosing 5 mg to 10 mg).  Approximately 46% 


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Protocol No. CRAD001LIC01 
of patients reported rash or erythema and 40% of the patients presented with 
stomatitis/mucositis.  The most frequent AEs suspected to be drug-related observed in 
3 studies using RAD001 as a single-agent are listed in Table 1. 
Table 1 
Adverse Events Suspected to be Drug-Related in 10% of Patients with 
Advanced Cancers Reported in Phase 1 RAD001 Monotherapy Studies 
(C2101, C2102, and C2107) 
Weekly 
Daily 
5-30 mg 
n=30 
50 mg 
n=18 
70 mg 
n=38 
5 mg 
n=16 
10 mg 
n=45 
Total 
n=147 
Number of Patients with 
Adverse Event 
Any event 
23 (1) 
17 (2) 
38 (10) 
14 (1) 
43 (14) 
135 (28) 
By event 
Rash 
5 
8 
18 
10 
27 (1) 
68 (1) 
Stomatitis/mucositis 
6 
8 (2) 
16 (2) 
6 (1) 
23 (3) 
59 (8) 
Fatigue 
8 
7 (1) 
14 (1) 
1 
17 (1) 
47 (3) 
Nausea 
5 
4 
8 
2 
18 (1) 
37 (1) 
Anorexia  
1 
6 
10 
3 
15 
35 
Diarrhea 
1 
7 
7 
- 
9 
24 
Vomiting 
4 
5 
5 
- 
10 
24 
Headache 
7 
4 
6 
6 
4 
20 
Pruritis 
2 
1 
6 
3 
4 
16 
Infections 
1 
3 
2 
1 
4 (1) 
14 (1) 
Constipation 
- 
1 
2 
2 
9 
14 
The number of patients (by dose level and dose schedule) who have reported grade 3 toxicities is given in brackets.  There 
were no RAD001 suspected grade 4 adverse events. 
Infections noted as drug-related included: 
Herpes simplex 
Oral candidiasis 
Pneumonia (grade 3) 
Rhinitis 
Upper respiratory tract infection 
Urinary tract infection 
 
4 patients (1 at 50 mg/week; 1 at 5 mg/day; 2 at 10 mg/day) 
5 patients (1 at 20 mg/week; 1 at 50 mg/week; 2 at 70 mg/week; 1 at 10 mg/day) 
1 patient (10 mg/day) 
2 patients (50 mg/week) 
1 patient (50 mg/week) 
1 patient (50 mg/week) 
Reduced blood cell counts at the initiation of treatment are frequent, but remain mostly within 
the normal range or limited to grade 1, although a grade 3 neutropenia was a dose-limiting 
toxicity (DLT) in one patient, as was a grade 3 thrombocytopenia in a patient receiving 
RAD001 with letrozole, where pharmacodynamic interaction is unlikely.  This suggests that 
some patients may be particularly sensitive to the myelosuppressive effect of RAD001, 
making it necessary to carefully monitor blood cell counts at the initiation of treatment.  
Metabolic changes (hyperlipidemia and hyperglycemia) may be observed during treatment 
with RAD001.  Both events may be medically managed.  Hyperlipidemia has been reported as 
an apparent drug reaction (ADR) in 10% of patients, although review of the laboratory values 
suggests that as many as a quarter of the patients developed grade 1 to grade 2 hyperlipidemia 
on treatment, mostly hypercholesterolemia.  Hyperglycemia has been reported as an AE in 7% 
of patients.  Grade 3 hyperglycemia has been observed, especially in diabetics receiving 
RAD001 treatment. Therefore, patients with diabetes should have their blood glucose 
monitored carefully and their medications adjusted, as needed, to maintain adequate control of 
their blood glucose levels. 


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1.2.3.4 
Clinical Studies with RAD001 in MRCC Patients 
RAD001 has shown single agent responses in patients with MRCC.  Porter, et al. (2006), 
reported data from 12 RCC patients enrolled in two Phase 1 studies who received RAD001 on 
a weekly or a daily schedule.  Seven patients received doses ranging from 
20 mg to 70 mg po weekly and 5 patients received 10 mg po daily.  Ten of the 12 patients had 


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received prior treatment (7 patients had received bevacizumab and erlotinib, 2 patients had 
received IL-2, and 1 patient received other drugs).  
The results of tumor assessments using Response Evaluation Criteria in Solid Tumors 
(RECIST) showed one confirmed and one unconfirmed partial response (PR), the latter 
having progressed on bevacizumab therapy.  Overall, 6 patients had stable disease (SD) for  
≥6 months and 4 patients were progression-free beyond 12 months (maximum 20 months).  
Two of the latter patients had previously received bevacizumab therapy. 
In a Phase 2 study (Amato, et al., 2006) of RAD001 in patients with MRCC involving no 
more than 1 prior therapy, an oral daily dose of 10 mg without an interruption (28-day cycle) 
and response rate determined using RECIST criteria with re-assessment every 3 cycles, 
RAD001 had promising anti-tumor activity as demonstrated by a 33% PR rate.  Anti-tumor 
activity was further suggested by prolonged time to progression (TTP) of 3 months for 86% 
of patients. The antitumor effect was also demonstrated when RAD001 was used as a second-
line therapy.   
In a second Phase 2 study, RAD001 (10 mg po daily) demonstrated promising anti-tumor 
activity in 41 previously-treated patients with metastatic RCC.  The reported response rate 
was 32% (12 PRs), the median TTP was 11.17 months (2.00 months to >31.53 months) and 
OS in 39 patients was >24.17+ months (Amato, et al., 2009). 
This activity has recently been confirmed in a Phase 3 study, RECORD-1, which was stopped 
at its interim analysis by an Independent Data Monitoring Committee for outstanding efficacy 
observed at the second interim analysis.  The results indicated a significant difference in 
efficacy between the RAD001 group and placebo group (hazard ratio 0.30 [95% confidence 
interval (CI): 0.22, 0.40], p<0.0001).  The progression-free survival (PFS) showed in favor of 
RAD001 with a median PFS of 4.0 months (95% CI: 3.7, 5.5) versus 1.9 months (CI: 1.8, 1.9) 
for the placebo group (Motzer, et al, 2007).  The probability of being progression-free at 6 
months was 26% (95% CI: 14, 37) for patients receiving RAD001 compared with 2% (CI: 0, 
6) for patients in the placebo group. The medium OS had not been reached for the RAD001 
group and was 8.8 months (95% CI: 7.9, not available) for the placebo group.  There was no 
significant difference between the groups in terms of OS (hazard ratio 0.83; 95% CI: 0.50, 
1.37; p=0.23) (Motzer et al, 2008).  Results from a further analysis in the RECORD-1 study, 
indicated a significant prolongation in PFS for the RAD001 group compared with the placebo 
group (hazard ratio 0.33; 95% CI: 0.25, 0.43; p<0.001) (Kay, et al., 2008).  The PFS showed 
in favor of RAD001 with a median PFS of 4.9 months versus 1.87 months for the placebo 
group.  The median overall survival was not reached for RAD001, (hazard ratio 0.82;  
95% CI: 0.57, 1.17; p<0.137) versus 13 months for the placebo group. 
RAD001 (Afinitor) was recently approved by the US FDA for the treatment of patients with 
advanced renal cell cancer after failure of treatment with sunitinib or sorafenib. 
It is clear that novel therapies are needed for patients with advanced RCC, including those 
with metastatic disease and those whose tumors are not amenable to surgical resection.  
Although sunitinib (Motzer, et al., 2007) and temsirolimus (Hudes, et al., 2007) have 
improved PFS or OS, in comparison with IFN, and the addition of bevacizumab to IFN has 
led to improved results in comparison with single-agent IFN (Escudier, et al., 2007), in some 
countries IFN remains the only available treatment option for patients with advanced RCC.  


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This trial will therefore explore the use of oral RAD001 daily in clear and non-clear cell 
advanced kidney cancer. 
1.3 
History of Amendments 
Changes in paragraphs: 
1. Section 4: Hepatitis B and C Screeening. 
2. Section 5.2: Exclusion Criteria # 14. 
3. Table 3: Criteria for Dose Modification in Case of Suspected RAD001 Toxicity. 
4. Table 5: Action to be taken based on Screening Hepatitis B Results. 
5. Table 6: Guidelines for the management of Hepatitis B reactivation. 
6. Table 9: Visits Evaluation Schedule: 
CT scan or MRI of chest, abdomen, and pelvis- If the CT scan was performed during the 
screening (in the range of 35 days) it does not need to be performed again at baseline.  
Pulmonary Function Test- will be peformed at screening per investigator discretion. 
7. Section 7.5.1: Radiological Assessment of Tumor(s). 
8. Section 7.6.5.8: Chest X-Ray/Chest Computed Scans/Pulmonary Function Tests. 
9. Section 10.5.1.3: Overall Survival Definition. 
10. Table 10: Updated country, # of patients, and #of sites. 
11. Section 10.1: Population for Analysis. 
12. Section 10.5.1.3: Overall Survival. 
 
2 
Study Rationale 
Current standard therapies (chemotherapies and cytokine-based therapies) have produced few 
and short-lived tumor responses, and are associated with severe toxicities. It is clear that novel 
therapies are needed for patients with advanced RCC, including those with metastatic disease 
and those whose tumors are not amenable to surgical resection.  Although sunitinib and 
temsirolimus have improved PFS or OS, in comparison with IFN, and the addition of 
bevacizumab to IFN has led to improved results in comparison with single-agent IFN, in some 
countries IFN remains the only available treatment option for patients with advanced RCC.    
A smaller sub-group analysis of patients with “other” subgroup category (non-clear and 
indeterminate histologies), the HR analysis for OS suggested an advantage for temsirolimus 
(an iv mTOR inhibitor) over IFN (Dutcher, at al., 2007).  
The oral formulation of RAD001 presents an improvement in the delivery of anticancer 
therapy, with direct impact on the patient and the health care delivery system.  RAD001 is 
generally well tolerated at 10 mg daily doses (see Table 1).  


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RAD001 has been studied extensively in solid organ transplantation (renal and cardiac) where 
over 1000 patients have received RAD001 for ≥3 years, with the drug being given as a 
constituent of an immunosuppressive regimen, which included cyclosporine (a CYP3A4 
inhibitor) and glucocorticoids. 
Pharmacodynamic modeling indicates that downstream effectors of mTOR are completely 
suppressed by RAD001 at the 10 mg/day.  Preliminary results of MPD studies in biopsied 
tumor tissue suggest a dose-related decrease in p-4E-BP1 and increase in p-AKT expression, 
with maximal effect at 10 mg daily. 
The proposed dose and schedule (10 mg/day) is based on various Phase 1 and Phase 2 studies 
(monotherapy and combination therapy) in advanced cancers, including RCC.  This dose and 
schedule also showed significant efficacy in a large placebo-controlled Phase 3 study in 
patients with MRCC who previously progressed on anti-VEGF targeted therapy. 
The purpose of this open-label, multi-center, Phase 2 study is to demonstrate the safety and 
efficacy of RAD001 10 mg po daily dose, as monotherapy, in patients with metastatic 
carcinoma of the kidney with clear cell and non-clear cell histology and all MSKCC 
prognosis, who have not received prior systemic treatment other than cytokine therapy. 
3 
Objectives 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the PFS rate over time. 
3.1.1 
Endpoint for Primary Objective 
The primary efficacy endpoint is PFS (i.e., remaining free from disease progression and 
death). 
3.2 
Secondary Objectives 
The secondary objectives of the study are: 
1. To evaluate the disease control rate (stable disease [SD] + partial response [PR] + 
complete response [CR]) (SD + PR + CR); 
2. To evaluate the objective response rate (ORR; where ORR = CR + PR); 
3. To evaluate duration of response; 
4. To evaluate OS; 
5. To describe the safety profile of RAD001. 
3.2.1 
Endpoints for Secondary Objectives 
Secondary endpoints include: 
 
Disease control rate (SD + PR + CR); 
 
ORR; 


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 
Response duration; 
 
OS; 
 
Safety will be assessed using CTCAE version 3.0. Safety parameters include AEs, 
laboratory , and other safety parameters as appropriate. 
4 
Study Design 
This is an open-label, multi-center, single arm Phase 2 study to evaluate the safety and 
efficacy of RAD001 as monotherapy in patients with any MSKCC prognosis metastatic 
recurrent and/or unresectable clear cell or non-clear cell carcinoma of the kidney.  Patients 
who have received prior cytokine therapy are permitted to participate in the study.   
Tumor assessments will be performed at 8 weeks to evaluate for inadequate response 
(progressive disease [PD]).  The visit at which PD is documented will be deemed the End-of-
Treatment Visit.   
In the absence of PD, assessments will continue every 12 weeks (±1 week) until the start of 
new anticancer therapy and at the End-of-Treatment Visit (within 1 week of stopping 
treatment) or until death.  A PR or CR warrants confirmation no sooner than 4 weeks. 
Follow-up phase:  All patients will have a follow-up visit scheduled 28 days after the End-of-
Treatment Visit to follow for AEs and SAEs that may have occurred after discontinuation 
from the study.  Any patient who is discontinued from study treatment for any reason will 
continue to have tumor assessments every 12 weeks (±1 week) until the patient is switched to 
another anticancer therapy or until death.  The investigator or his/her designee will continue 
collecting information on the initiation of additional anticancer therapies until the date of data 
cutoff for the final analysis (see Section 10.6).  All new anticancer therapies after the last dose 
of study treatment will be recorded on the appropriate case report form (CRF) page. 
Study drug refers to RAD001.  All patients who meet the study entry criteria will receive 
RAD001.  It is anticipated that approximately 110 patients will be enrolled in the study. 
Hepatitis B and C Screening 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of HBV reactivation and associated 
HBV morbidity and mortality (Loomba et al. 2008; Sorrell et al. 2009). 
During the screening period, ALL patients must be screened for HBV and HCV (current or 
past history of infection). Careful medical history must be taken for all patients to look for 
risk factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, 
dialysis, blood transfusions, etc), and any past or present HBV symptoms (e.g., jaundice, dark 
urine, light-colored stools, right upper quadrant pain). All patients will be tested for HBV-
DNA and serological markers, and HCV viral load by quantitative RNA-PCR. It is highly 
recommended that patients at risk of HBV reactivation are treated prophylactically with 
antivirals for 1-2 weeks prior to receiving study drug and for at least 4 weeks after last dose of 
study drug. The management guidelines, in Section 6.1.4.4, are provided according to the 
results of the screening assessment of viral load and serological markers for HBV and HCV. 


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5 
Population 
Adult patients who have metastatic recurrent and/or unresectable renal cell carcinoma are 
eligible for enrollment in this study.  Previous cytokine therapy is permitted.  Patients must 
have histological or cytological confirmation of clear cell or non-clear cell renal carcinoma or 
a component of these histologies.  The treating oncologist is advised to consider biopsy of 
lesions to establish the diagnosis of MRCC if there is substantial clinical ambiguity regarding 
the nature or source of primary disease. 
Inclusion/exclusion criteria 
The investigator or his/her designee must ensure that all patients who meet the following 
inclusion and exclusion criteria are offered enrollment in the study.  No additional exclusions 
can be applied by the investigator, in order that the study population will be representative of 
all eligible patients. 
Patients must have screening evaluations performed to ensure potential patients being 
considered by the investigator meet all inclusion and exclusion criteria.  Results of all 
screening evaluations, which assure that all inclusion and exclusion criteria have been 
satisfied, must be reviewed by the Principal Investigator or his/her designee, prior to 
enrollment of that patient into the study.  Local laboratory results will be used to determine 
patient eligibility for the study. 
All study patients must be thoroughly informed about all aspects of the study, including the 
study visit schedule, required evaluations, and all regulatory requirements for informed 
consent.  The written informed consent must be obtained prior to the performance of any 
screening evaluations.  If the patient is unable to read, an impartial witness should be present 
during the entire informed consent discussion.  The following criteria apply to all patients 
enrolled into the study, unless otherwise specified. 
5.1 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following criteria: 
1. Age ≥18 years old; 
2. Patients with advanced renal cell carcinoma with confirmed clear or non-clear cell 
histology, with or without nephrectomy, and with any MSKCC prognosis;   
3. Prior cytokine therapy is permitted; 
4. Patients with at least one measurable lesion at baseline as per the RECIST criteria.  If 
skin lesions are reported as target lesions, they must be documented (at baseline and at 
every physical exam) using color photography and a measuring device (such as a 
caliper) in clear focus to allow the size of the lesion(s) to be determined from the 
photograph; 


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5. Life expectancy ≥3 months.  Life expectancy should be judged in relation to other 
determining patient eligibility factors such as laboratory results,  Performance Status, 
etc.; 
6. Patients with a Karnofsky Performance Status ≥70%; 
7. Adequate bone marrow function as shown by:  absolute neutrophil count (ANC) 
 ≥1.5 x 109/L, platelets ≥100 x 109/L, hemoglobin (Hb) >9 g/dL; 
8. Adequate liver function:  serum bilirubin ≤1.5 x upper limit of normal (ULN), alanine 
transaminase (ALT) and aspartate transaminase (AST) ≤2.5 x ULN.  Patients with 
known liver metastases:  AST and ALT ≤5 x ULN; 
9. Adequate renal function: serum creatinine ≤1.5 x ULN; 
10. Females of childbearing potential must have had a negative serum or urine pregnancy 
test 7 days prior to the administration of the study treatment start; 
11. Patients who give a written informed consent obtained according to local guidelines. 
5.2 
Exclusion Criteria 
Patients may not be entered into the study if they meet any of the following criteria: 
1. Patients within 2 weeks post-minor surgery (e.g., herniorrhaphy), 4 weeks post-major 
surgery (e.g., intra-thoracic, intra-abdominal, or intra-pelvic) to avoid wound healing 
complications.  Percutaneous biopsies require no waiting time prior to study entry; 
2. Patients with a recent history of hemoptysis, ≥0.5 teaspoon of red blood; 
3. Patients who have received prior systemic treatment for their metastatic RCC other 
than cytokine therapy; 
4. Patients who received prior therapy with a VEGF pathway inhibitor, such as sunitinib, 
sorafenib, and bevacizumab; 
5. Patients who have previously received mTOR inhibitors (sirolimus, temsirolimus, 
everolimus, deferolimus); 
6. History or clinical evidence of central nervous system (CNS) metastases. Note: 
Subjects who have previously-treated CNS metastases (surgery±radiotherapy, 
radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible: 
 
Are asymptomatic;  
 
Have had no evidence of active CNS metastases for ≥ 6 months prior to 
enrollment and; 
 
Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC); 
7. Clinically significant gastrointestinal abnormalities including, but not limited to: 
 
Malabsorption syndrome; 
 
Major resection of the stomach or small bowel that could affect the absorption 
of study drug; 


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 
Active peptic ulcer disease; 
 
Inflammatory bowel disease; 
 
Ulcerative colitis, or other gastrointestinal conditions with increased risk of 
perforation; 
 
History of abdominal fistula, gastrointestinal perforation, or intra abdominal 
abscess within 28 days prior to beginning of study treatment; 
8. Patients receiving chronic systemic treatment with corticosteroids or another 
immunosuppressive agent.  Inhaled and topical steroids are acceptable; 
9. Patients with a known history of human immunodeficiency virus seropositivity; 
10. Patients with autoimmune hepatitis; 
11. Patients with an active, bleeding diathesis.  Patients may use coumadin or heparin 
preparations; 
12. Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
 
unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac 
arrhythmia; 
 
uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN;  
 
any active (acute or chronic) or uncontrolled infection/disorders that impair the 
ability to evaluate the patient or for the patient to complete the study; 
 
non-malignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the study treatment, such as severe hypertension that is not 
controlled with medical management and thyroid abnormalities whose thyroid 
function cannot be maintained in the normal range by medication; 
 
liver disease such as cirrhosis, decompensated liver disease, chronic active 
hepatitis, or chronic persistent hepatitis; 
 
fatal or life-threatening autoimmune and ischemic disorders; 
13. Patients who have a history of another primary malignancy ≤3 years, with the 
exception of non-melanoma skin cancer and carcinoma in situ of uterine; 
14. Female patients who are pregnant or breastfeeding, or adults of reproductive potential 
who are not using effective birth control methods.  If barrier contraceptives are being 
used, these must be continued throughout the study by both sexes.  Oral contraceptives 
are  not acceptable as the only contraception method. However they can be used in 
combination with other methods such as barrier contraceptives; 
15. Patients who are using other investigational agents or who had received investigational 
drugs ≤4 weeks prior to study treatment start; 
16. Patients unwilling or unable to comply with the protocol. 


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6 
Treatment 
6.1 
Investigational and Control Drugs 
6.1.1 
Study Drug 
The investigational drug used in this study is RAD001.  The study drug will be self-
administered (by the patients themselves).  The investigator will instruct the patient to take the 
study drug exactly as specified in the protocol. 
Patients will be instructed to take two 5 mg RAD001 tablets (one tablet after another) orally, 
with a glass of water at the same time each day, in a fasting state or with a light fat-free meal. 
If vomiting occurs, no attempt should be made to replace the vomited dose.  Any dietary 
habits around the time of RAD001 intake should be as consistent as possible throughout the 
study. 
RAD001 will be taken daily from Visit 2 (Day 1) until disease progression, unacceptable 
toxicity, or death or discontinuation from the study for any other reason. 
6.1.2 
Known Undesirable Effects of RAD001 
Adverse events most frequently observed with RAD001 are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, diarrhea, ocular toxicity, and infections.  Non-
infectious pneumonitis has also been observed as indicated in Section 1.2.3.3.  
Overall, the most frequently observed laboratory abnormalities include neutropenia, 
thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia.  The majority of these 
AEs have been of mild to moderate severity (CTC grade 1 to grade 2).  Refer to Table 3 for 
management of laboratory abnormalities. 
6.1.3 
RAD001 Dose Level Modification/Interruption Guidelines in Case of 
Suspected Toxicity 
Dose adjustments are permitted in those patients who are unable to tolerate the protocol-
specified dosing schedule.  If administration of RAD001 must be interrupted because of 
unacceptable toxicity, drug dosing will be interrupted or modified according to rules 
described in Table 2, Table 3, and Table 4.  
If the toxicity is tolerable to the patient, the initial dose should be maintained.  If the toxicity 
is intolerable to the patient, RAD001 treatment is to be interrupted until recovery to grade ≤1, 
then reintroduced at the initial dose or a lower dose level, depending on toxicity type and 
grade (see Table 3).  All interruptions or dose modifications must be recorded on the Dosage 
Administration Record CRF. 
Table 2 
RAD001 Dose Level Modification Guidelines 
Dose Level 
Dose Schedule 
0 
10 mg daily 
1 
5 mg daily 
2 
5 mg every other day 
 


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Table 3 provides the procedure to be followed for dose modification and re-initiation of 
RAD001 in the event of toxicities suspected to be related to the study drug. 
Table 3 
Criteria for Dose Modification in Case of Suspected RAD001 Toxicity  
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 1 
No dose modification. 
Grade 2 (except pneumonitis): 
If the toxicity is tolerable to the patient, maintain the same 
dose.  If toxicity is intolerable to the patient, interrupt RAD001 
until recovery to grade ≤1, then re-introduce RAD001 at the 
same dose.  If the event returns to grade 2, interrupt RAD001 
until recovery to grade ≤1, then re-introduce at the lower dose 
level.  
Grade 3 (except hyperlipidemia):  
Interrupt RAD001 until recovery to grade ≤1, then re-introduce 
at the lower dose level.  For pneumonitis, consider the use of a 
short course of corticosteroids. 
Grade 3 hyperlipidemia (hypercholesterolemia 
and/or hypertriglyceridemia): 
Should be managed using standard medical therapies. 
Grade 4: 
Discontinue RAD001. 
Reactivation of HBV or HCV 
Please refer to Tables 6 and 7.   
Hematological toxicity 
 
Grade 1 
No dose modification. 
Grade 2 thrombocytopenia  
(platelets <75 x 109/L, ≥50 x 109/L): 
Interrupt RAD001 until recovery to grade ≤1 (platelets  
≥75 x 109/L), then re-introduce RAD001 at the initial dose.  If 
thrombocytopenia returns to grade 2, interrupt RAD001 until 
recovery to grade ≤1, then re-introduce at the lower dose level. 
Grade 3 thrombocytopenia   
(platelets <50 x 109/L, ≥25 x 109/L): 
Interrupt RAD001 until recovery to grade ≤1 (platelets  
≥75 x 109/L), then resume RAD001 at 1 dose level lower.  If 
grade 3 thrombocytopenia recurs, discontinue RAD001. 
Grade 4 thrombocytopenia  
(platelets <25 x 109/L): 
Discontinue RAD001. 
Grade 3 neutropenia  
(neutrophils <1 x 109/L, ≥0.5 x 109/L): 
Interrupt RAD001 until recovery to grade ≤1 (neutrophils ≥1.5 
x 109/L), then resume RAD001 at initial dose.  If absolute 
neutrophil count (ANC) returns to grade 3, hold RAD001 until 
recovery to grade 1 (ANC ≥0.5 x 109/L), then resume RAD001 
at the lower dose level.  Discontinue patient from study therapy 
for a third episode of grade 3 neutropenia. 
Grade 4 neutropenia  
(neutrophils <0.5 x 109/L): 
Interrupt RAD001 until recovery to grade ≤1 (neutrophils ≥1.5 
x 109/L), then resume RAD001 at the lower dose level.  If 
grade 3 or grade 4 neutropenia occurs despite this dose 
reduction, discontinue RAD001. 
Grade 3 febrile neutropenia  
(not life-threatening): 
Interrupt RAD001 until resolution of fever and neutropenia to 
grade 
≤1. 
 
Hold 
further 
RAD001 
until 
the  
ANC ≥1500/mm3 and fever has resolved.  Resume RAD001 at 
the lower dose level.  If febrile neutropenia recurs, discontinue 
RAD001. 
Grade 4 febrile neutropenia (life-threatening): 
Discontinue RAD001. 
Any hematological or non-hematological toxicity 
Discontinue RAD001. 


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requiring interruption for ≥3 weeks: 
6.1.4 
Monitoring of RAD001 Suspected Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
abnormal laboratory value suspected to be related to RAD001 must be followed at least 
weekly until the AE or abnormal laboratory value resolves or returns to grade 1.  
If a patient requires a dose delay of >21 days from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study. 
6.1.4.1 
Management of Stomatitis/Oral Mucositis/Mouth Ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local 
supportive care.  Please note that investigators in earlier studies have described the oral 
toxicities associated with RAD001 as mouth ulcers, rather than mucositis or stomatitis.  
If examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
the AE should be classified as such.  Please follow the paradigm below for the treatment of 
stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (grade 1), conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution should be used. 
2. For more severe toxicity (grade 2, in which case patients have pain, but are able to 
maintain adequate oral alimentation, or grade 3, in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 
mouth treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, 
such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers.  It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed.  In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
RAD001 metabolism, leading to higher RAD001 exposures. Therefore, topical 
antifungal agents are preferred if an infection is diagnosed.  Similarly, antiviral agents 
such as acyclovir should be avoided unless a viral infection is diagnosed. 
Note: Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the National Cancer Institute- (NCI) CTC for Adverse Events (CTCAE), version 3.0. 
6.1.4.2 
Management of Hyperlipidemia and Hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient.  Blood tests to monitor hyperlipidemia must be taken in the fasting state.  
Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 or higher 
hypertriglyceridemia (>2.5 x ULN) should be treated with a statin or appropriate lipid-
lowering medication, in addition to diet.  Patients should be monitored clinically and through 


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serum biochemistry for the development of rhabdomyolysis and other AEs as required in the 
product label/data sheets for HMG-CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare, but serious, skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase levels and myoglobinuria, acute 
renal failure, and sometimes death.  The risk versus benefit of using this therapy should be 
determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia. 
Grade 3 hyperglycemia has been observed in patients receiving RAD001 therapy.  In many 
cases in Study RAD001C2222, the affected patients had an abnormal fasting glucose at 
baseline.  Based on this finding, it is recommended that optimal glucose control be achieved 
before starting a patient on RAD001.  Study patients should have their glucose levels 
monitored during RAD001 therapy. 
6.1.4.3 
Management of Non-Infectious Pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = interfering 
with activities of daily living and oxygen indicated) have been noted in patients receiving 
RAD001 therapy.  Non-infectious pneumonitis has been associated with RAD001 and other 
mTOR inhibitors (Atkins, et al., 2004).  
In order to monitor for asymptomatic (grade 1) non-infectious pneumonitis, a chest x-ray or 
CT scan is required in addition to the 3-monthly CT or magnetic resonance imaging (MRI) 
tumor examinations.  
Additional chest x-rays or CT scans may be performed, when clinically necessary.  If non-
infectious pneumonitis develops, a consultation with a pulmonologist should be considered.  
If the patient develops grade 3 pneumonitis, treatment with RAD001 should be interrupted 
and the patient should be treated as medically indicated (short course corticosteroids, oxygen, 
etc.). 
Chest x-ray/chest CT scans obtained during the study should be readily accessible at the site 
and must be kept with the patient‟s source documents. 
Dose modification instructions and Management of non-infectious pneumonitis suspected to 
be associated with RAD001 and are provided in Table 3 and Table 4. 
 
 
 
 
 
 
 
 
 
 
 


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Table 4 
Management of Non-Infectious Pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows. 
Repeat every 3 cycles until return to 
within normal limits. 
No specific therapy 
is required. 
Administer 100% of RAD001 
dose. 
Grade 2 
CT scans with lung windows and 
required pulmonary function testing 
includes:  spirometry, DLCO, and 
room air O2 saturation at rest.  
Repeat each subsequent cycle until 
return to baseline.  Consider a 
bonchoscopy.a 
Symptomatic only.  
Prescribe cortico-
steroids if cough is 
troublesome. 
Reduce 
RAD001 
dose 
until 
recovery to ≤ grade 1.  RAD001 
may 
also 
be 
interrupted 
if 
symptoms 
are 
troublesome.  
Patients should be withdrawn 
from the study if they fail to 
recover to ≤ grade 1 within  
3 weeks. 
Grade 3 
CT scans with lung windows and 
required pulmonary function testing 
includes:  spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat each subsequent cycle until 
return to baseline.  Bonchoscopya is 
required. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out.  Taper as 
medically indicated. 
Hold treatment until recovery to  
≤grade 1.  May restart protocol 
treatment within 2 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Grade 4 
CT scans with lung windows and 
required pulmonary function testing 
includes:  spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat each subsequent cycle until 
return to baseline.  Bonchoscopya is 
required. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out.  Taper as 
medically indicated. 
Discontinue treatment. 
a  A bronchoscopy with a biopsy and/or broncheoalveolar lavage is required. 
Abbreviations:  CT = computerized tomography; DLCO = diffusion capacity of carbon monoxide. 
  
6.1.4.4 
Management of hepatitis reactivation 
Monitoring and Prophylactic Treatment for Hepatitis B Reactivation 
Table 5 provides details of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing. 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA  
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb  
+ or - 
+ or - 
+ 
and no prior 
HBV vaccination 
+ or - 
 
or + with prior HBV 
vaccination 


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Table 5 
Action to be taken based on Screening Hepatitis B Results 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug. For HBV reactivation definition and management guidelines, see Table 6. 
Table 6 
Guidelines for the management of Hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as:   
[Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤  grade 1 ALT (or baseline ALT, if > grade 1) and 
 ≤  baseline HBV-DNA levels 
If resolution occurs within ≤  28 days, study drug should be re-
started at one dose lower, if available (see Table 6-1 for dose levels 
available). If the patient is already receiving the lowest dose of study 
drug according to the protocol, the patient should restart at the same 
dose after resolution. Both antiviral therapies should continue at least 
4 weeks after last dose of study drug.  
If resolution occurs > 28 days, patients should discontinue study 
drug but continue both antiviral therapies at least 4 weeks after last 
dose of study drug. 
For patients with baseline 
results:  
Negative HBV-DNA and 
HBsAg  
AND  
[Positive HBsAb (with no 
prior history of vaccination 
against HBV), OR positive 
HBcAb]  
------------------------------------- 
reactivation is defined as: 
New appearance of 
measurable HBV-DNA 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until resolution: 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤  28 days, study drug should be re-
started at one dose lower, if available (see Table 6-1 for dose levels 
available). If the patient is already receiving the lowest dose of study 
drug according to the protocol, the patient should restart at the same 
dose after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of study drug. 
If resolution occurs > 28 days Patients should discontinue study 
drug but continue antiviral therapy at least 4 weeks after last dose of 
study drug. 
* All reactivations of HBV are to be recorded as grade 3 (CTCAE Version 3.0 – Metabolic 
Laboratory/Other: Viral Reactivation), unless considered life threatening by the investigator, in which 
case they should be recorded as grade 4. Date of viral reactivation is the date on which DNA (and 
ALT) criteria were met (e.g.. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT 
reached ≥  5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 
Monitoring for Hepatitis C Reactivation 
The following two categories of patients should be monitored every 6 weeks for HCV 
reactivation: 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylactic antiviral treatment 
should be started 1-2 weeks prior 
to first dose of  study drug. 
Monitor HBV-DNA every 6 weeks 
No prophylaxis 
 
Monitor HBV-DNA every 3 weeks 
No specific action 


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 Patients with detectable  HCV RNA-PCR test at baseline 
 Patients known to have a history of HCV infection, despite a negative viral load test at 
baseline (including those that were treated and are considered „cured‟)  
For definitions of HBV or HCV reactivation and actions to be taken in the event of 
reactivation, please refer to Table 7. 
Table 6 
Guidelines for the management of Hepatitis C reactivation 
HCV reactivation* 
For patients with baseline results:  
Detectable HCV-RNA 
 
reactivation is defined as: 
ALT elevation x 5 ULN 
Discontinue study drug  
 
 
For patients with baseline results: 
Knowledge of past hepatitis C infection with no 
detectable HCV-RNA 
 
reactivation is defined as: 
New appearance of detectable HCV-RNA  
Discontinue study drug 
 
* All reactivations of HCV are to be recorded as grade 3 (CTCAE Version 3.0 – Metabolic Laboratory 
/Other: Viral Reactivation), unless considered life threatening by the investigator; in which case they 
should be recorded as grade 4. 
 
 
6.1.5 
How Supplied 
6.1.5.1 
Study Drug 
RAD001 will be provided by Novartis at no charge to the study site.  RAD001 is formulated 
as tablets of 5 mg strength for oral administration.  Tablets should be opened only at the time 
of administration, as the drug is both hygroscopic and light sensitive. 
Medication labels will comply with the legal requirements of each country and are printed in 
the local language.  The labels do not contain information about the patient.  The storage 
conditions for the study drug will be described on the study drug label. 
Each study site will receive the study drug (RAD001).  After a final drug accountability/ 
reconciliation review has been performed by the study monitor, unused, used, and empty 
study drug packaging and any unused tablets will be destroyed at the end of the study 
according to local regulatory procedures.  All local regulatory procedures must be followed. 


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6.1.6 
Preparation and Storage 
6.1.6.1 
Study Drug 
RAD001 is supplied as 5 mg tablets.  Patients will be supplied with enough tablets for a 
complete 28-day cycle.  Tablets should be stored in a secure, dry, light-proof medicine 
cabinet. 
6.2 
Treatment Arms 
One treatment arm:  RAD001. 
6.3 
Patient Numbering 
Patient informed consent must be obtained before any screening testing is performed to 
determine the patient‟s eligibility.  At screening (Visit 1), upon signing the informed consent 
form, the patient is assigned a unique patient number by the investigator or his/her designee.  
The patient number is a 9-digit number.  The first part is the site number (first 4 digits) and 
the second part (last 5 digits) is one of a series of numbers allocated to patients at that site. 
The site number is assigned by Novartis.  The patient identification numbers will be assigned 
in a sequential manner.  Once assigned, the patient identification number will not be reused.  
At screening (Visit 1), the investigator or his/her designee will record the patient identification 
number appropriately on the CRFs. 
6.4 
Treatment Assignment 
This is a single arm study with one dose of study drug.  All patients will initiate treatment 
with 10 mg/day RAD001. 
6.5 
Treatment Blinding 
This is an open-label study.   
6.6 
Treating the Patient 
6.6.1 
Commencing Treatment 
At Visit 1 (Screening, Visit 1a) and Visit 2 (Baseline, Visit 1b), the investigator or his/her 
designee will verify that the patient fulfills all the inclusion/exclusion criteria to commence 
RAD001 treatment.  The Baseline Visit should be no sooner than 28 days and no later than  
35 days after the Screening Visit.  Study treatment can commence (Visit 2) immediately after 
the Baseline Visit. 
Patient stratification will be based on previous cytokine therapy. 
6.6.2 
Study Drug Administration 
The study drug will be self-administered (by the patients themselves).  The investigator will 
instruct the patient to take the study drug exactly as specified in the protocol. 


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Patients will be instructed to take RAD001 (two 5 mg tablets at once, ie., one tablet after 
another) orally daily with a glass of water, at the same time each day in a fasting state or with 
a light fat-free meal. 
If vomiting occurs, no attempt should be made to replace the vomited dose.  Any dietary 
habits around the time of RAD001 intake should be as consistent as possible throughout the 
study. 
RAD001 will be taken daily from Visit 2 (Day 1) until disease progression, unacceptable 
toxicity, death, or discontinuation from the study for any other reason. 
6.6.3 
Permitted Study Drug Adjustments 
Dose adjustments are permitted in those patients who are unable to tolerate the protocol-
specified dosing schedule.  If administration of RAD001 must be interrupted because of 
unacceptable toxicity, drug dosing will be interrupted or modified according to the rules 
described in Section 6.1.3. 
6.6.3.1 
Follow-Up for Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
abnormal laboratory value suspected to be related to RAD001 must be followed at least 
weekly until the AE or abnormal laboratory value resolves or returns to grade 1.  
If a patient requires a dose delay of >21 days from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study. 
6.6.4 
Concomitant Medications 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator.  
At each visit, the investigator will ask the patient about any new medications he/she is or has 
taken after the start of the study drug.  All medications taken ≤30 days prior to study entry 
should be recorded on the Concomitant Medications/Significant Non-Drug Therapies Prior to 
Start of Study Drug CRF page.  All medications (other than the study drug) and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
patient starts treatment with study drug must be listed on the Concomitant 
Medications/Significant Non-Drug Therapies CRF.  Prior and concomitant medications will 
be coded to indication-specific Anatomic Therapeutic Chemical classification (ATC) and 
preferred name using the World Health Organization (WHO) Drug Dictionary (latest version). 
Permitted treatments during the study include: 
 
Bisphosphonate therapy for treatment of bone metastases.  This therapy should be 
initiated before the patient is enrolled into the study; 
 
Pain medication to allow the patient to be as comfortable as possible; 
 
Localized radiotherapy, for the treatment of pre-existing, painful bone metastases is 
allowed during the study only if evidence of radiological progression is not present. 
Radiotherapy for brain metastases is not permitted during the course of the study (the 
need for CNS radiation will constitute disease progression); 


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 
Nutritional support as recommended by the investigator; 
 
Megesterol acetate may be prescribed during the course of the study as an appetite 
stimulant; 
 
Oxygen therapy and blood transfusions. 
The following restrictions apply during the entire duration of the study: 
 
No other investigational therapy should be given to patients; 
 
No anticancer agents other than the study drug (RAD001) should be given to patients.  
If such agents are required for a patient, then the patient must first be withdrawn from 
the study; 
 
Leukocyte growth factors (e.g., colony-stimulating factor and granulocyte-macrophage 
colony-stimulating factor) are not to be administered prophylactically, but may be 
prescribed by the investigator for severe neutropenia if this is thought to be 
appropriate; 
Drugs or substances known to be inhibitors or inducers or substrates of the isoenzyme 
CYP3A4 should be avoided in association with RAD001 because these can alter the 
metabolism of RAD001.  In addition, patients should refrain from grapefruit juice, which is a 
potent CYP3A4-inhibitor.  Complete details are provided in Table 8. 
 
Table 8 
Clinically Relevant Drug Interaction:  Substrates, Inducers, and 
Inhibitors of Isoenzyme CYP3A 
Substrates (competitive inhibition) 
 
Antibioticsa: 
clarithromycin* 
erythromycin 
telithromycin* 
Anti-arrhythmics: 
quinidine 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
Human immunodeficiency virus  protease 
inhibitors:  
indinavir* 
ritonavir* 
saquinavir* 
Prokinetic: 
cisapride 
Antihistamines: 
astemizole 
chlorpheniramine 
Calcium channel blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
HMG -CoA reductase inhibitorsb: 
cerivastatin 
lovastatin 
simvastin 
Miscellaneous: 
aprepitant 
buspirone 
haloperidol 
methadone 
pimozide 
quinine 
sildenafil 
tamoxifen 
trazodone 
vincristine 
Inducers 
 


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Carbamazepine 
Phenobarbitol 
Phenytoin* 
Rifabutin* 
Rifampin* 
St. John‟s wort 
Troglitazone 
Inhibitors 
 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
Base on:  Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes:  Properties and polymorphisms. 
Naunyn Schmiedebergs Arch Pharmacol 2004;369:89-104  (http://www.medicine.iupui.edu/flockhart/clinlist.htm). 
* Denotes strong inhibition/induction.  Please note: 
 Strong inhibitor implies that it can cause ≥5-fold increase in area under the concentration curve (AUC) or  
≥80% decrease in clearance of sensitive CYP substrates; 
 Moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50% to 80% decrease in clearance of 
sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary depending on conditions). 
a  Macrolide antibiotics:  Azithromycin is not a CYP3A substrate.  It may therefore be employed where antibiotic therapy 
with a macrolide is desirable in a patient being treated with RAD001.  
b  Statins:  Pravastatin may be taken with RAD001 since a pharmacokinetic interaction study has shown that there is no 
relevant pharmacokinetic interaction. 
6.6.5 
Interruption or Discontinuation of Study Drug 
The term “interruption” refers to a patient stopping all study drug during the course of the 
study, but then re-starting it at a later time in the study.  If treatment has to be interrupted for 
more than 14 days for any reason other than toxicities suspected to be related to RAD001, the 
patient will be discontinued from the study.  If treatment has to be interrupted for more than 
21 days due to suspected study drug-related toxicity, the patient will be discontinued from the 
study. 
Tumor evaluations will continue until the start of new anticancer therapies.  The term 
“discontinuation” refers to a patient‟s premature withdrawal from the study treatment.  In 
accordance with the current revision of the Declaration of Helsinki and current US Food and 
Drug law, a patient has the right to withdraw from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the institution. 
The reason for discontinuation from treatment will be recorded on the appropriate CRF page.  
The patient may discontinue participation in the study for any of the following reasons: 
1. Adverse event(s); 
2. Abnormal laboratory value(s); 
3. Abnormal test procedure result(s); 
4. Disease progression; 
5. Protocol violation; 


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6. Patient withdrew consent; 
7. Lost to follow-up; 
8. Administrative problems; 
9. Death. 
If a patient has discontinued the study due to an unacceptable adverse drug reaction or an 
abnormal laboratory value, he/she should not have withdrawal of consent recorded as the 
reason for discontinuation.  Instead, the reason for discontinuation must be recorded as due to 
adverse drug reaction or an abnormal laboratory value. 
6.6.6 
Patient Withdrawal 
6.6.6.1 
End of Treatment 
All cancer medications/therapies given to a patient ≤4 weeks after the last dose of study 
treatment must be recorded on the CRF. 
Patients who discontinue the study regardless of the reason must have end-of-study treatment 
evaluations (see Table 9) on the day of study drug discontinuation or within 2 weeks of study 
drug discontinuation.  The investigator or his/her designee will proceed as follows: 
 
Notify clinical team immediately of patient discontinuation; 
 
Complete the end of study assessments and complete the End-of-Treatment CRF page 
indicating the date and reason for stopping the study drug.  Additional details are 
provided in Table 9; 
 
All patients will have a follow-up visit 28 days after the last dose of the study drug. 
During this visit, AE and SAE information will be collected and recorded on the 
appropriate CRF pages.  If the patient is unable to return to the clinic, the investigator 
or his/her designee will contact the patient or caregiver to collect this information; 
 
All patients who are discontinued from the study drug for any reason (i.e., documented 
disease progression by the investigator, an AE or SAE, administrative reasons, etc.) 
will continue to have tumor assessments at 12-week intervals until the initiation of 
new anticancer therapy.  This information will be recorded on the appropriate CRF 
pages; 
 
If patients refuse to return to the clinic for follow-up assessments or are unable to do 
so, the investigator or his/her designee will make every effort to contact the patient, a 
close relative, or caretaker by telephone to collect survival information.  The 
investigator or his/her designee should show “due diligence” by documenting on the 
source documents steps taken to contact the patient, i.e., dates of telephone calls, 
registered letters, etc. 
6.6.7 
Emergency Unblinding of Treatment Assignment 
Not applicable to this open-label study. 


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7 
Visit Schedule and Assessments 
Table 9 lists all of the assessments and indicates the visits with an “X” and when they are to 
be performed.  All data obtained from these assessments must be supported in the patient‟s 
source documentation. 


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Table 9 
Visit Evaluation Schedule 
 
Screening -
35 
Baseline 
-7 to -1 
Cycle 1  
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
Subsequent 
Cycles  
(28 days) 
End-of-
Study 
Treatment 
Endpoint 
Follow-Upa 
Visit number 
1a 
1b 
2 
3 
4 
5 
6 
7 
8, 9 
Last visit 
 
Day of cycle 
 
 
1 
15 
1 
15 
1 
15 
1 
Last day 
 
Demography/informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Medical history/current medical conditions 
X 
 
X 
 
 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsa 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination/neurological assessmentb 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Karnofsky Performance Status 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Hematologyc 
X 
X 
X 
Xc 
X 
Xc 
X 
Xc 
X 
X 
 
Coagulationd 
X 
 
 
 
X 
 
 
 
 
 
 
Serum chemistrye 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Serum lipid profilef 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Urinalysisg 
X 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy testh 
X 
X 
 
 
 
 
 
 
 
 
 
HBV-DNA & serology, HCV RNA-PCR r 
X 
 
X 
 
X 
 
X 
X                     X 
 
X 
 
CT scan or MRI of chest, abdomen, and pelvisi 
If the CT Scan was performed during the 
screenig (in the range of 35 days) it does not 
need to be performed again at baseline 
X 
X 
 
 
 
 
X 
 
Every 12 
weeks after 
Visit 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI/brain CT scank 
X 
X 
As described in footnotek 
Bone scanl 
X 
X 
As described in footnotel 
Electrocardiogramm 
Electrocardiograms are to be performed at the investigator‟s discretion as clinically indicated 
Pulmonary function testsn 
X 
X 
Pulmonary function tests to be performed as described in footnoten 


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Table 9 
Visit Evaluation Schedule 
 
Screening -
35 
Baseline 
-7 to -1 
Cycle 1  
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
Subsequent 
Cycles  
(28 days) 
End-of-
Study 
Treatment 
Endpoint 
Follow-Upa 
Visit number 
1a 
1b 
2 
3 
4 
5 
6 
7 
8, 9 
Last visit 
 
Day of cycle 
 
 
1 
15 
1 
15 
1 
15 
1 
Last day 
 
Concomitant medications0 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse eventp 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Imaging for tumor evaluationq 
 
 
 
 
 
 
X 
 
Every 12 
weeks after 
Visit 6 
X 
 
RAD001 administrationr 
 
 
Daily administration 
 
 
Study completions 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-up and survivalt 
 
 
 
 
 
 
 
 
 
 
 
X 
Post-discontinuation antineoplastic therapiesu 
 
 
 
 
 
 
 
 
 
 
 
X 
a  Vital signs will be collected at screening and repeated on Day 1 of every treatment cycle and at the end of-the-study (within ≤2 weeks). 
b  A complete physical examination includes a neurological examination.  All significant findings will be noted on the Relevant Medical History pages or Adverse Event pages of the case report form (CRF).  If 
a skin lesion or lesions are selected as target lesions, they must be clearly photographed and measured with a measuring device (a caliper or ruler) in clear focus to allow the size of the lesion(s) to be 
determined from the photograph.  Serial photographs from the skin lesion(s) must be performed at every physical exam visit.  Copies of the serial photographs must be submitted with the radiological 
assessments for radiology review. 
 c  Hematology tests must include:  hemoglobin, hematocrit, platelets, total white blood count (WBC), and differential.  Hematological tests will be performed at screening and on Day 1 (prior to administration 
of the study drug) of each treatment cycle.  Hematological tests may also be performed on Day 15 of the first 3 treatment cycles at the investigator‟s discretion and according to local practice.  Subsequently, 
on Day 1 (of every treatment cycle) or as medically necessary and at discontinuation from the study drug (within ≤2 weeks).   
 d  The prothrombin time will be performed at screening and on Day 1 of Cycle 2.  Prothrombin time will be repeated as clinically indicated and will be reported as international normalized ratio (INR). 
e  Serum blood chemistry evaluations must include:  lactate dehydrogenase (LDH), fasting glucose, magnesium, sodium, potassium, chloride, creatinine, blood urea nitrogen, albumin, total protein, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, gamma-glutamyl-transferase (GGT), alkaline phosphatase, urea, uric acid, serum calcium, and serum corrected calcium (measured 
at screening only).  These assessments will be performed at screening and on Day 1 of every treatment cycle and at the time of discontinuation from the study drug (within ≤2 weeks).  
f  Serum lipid profile includes:  total cholesterol, trigycerides, low-density lipoprotein, and high-density lipoprotein.  These assessments will be performed at screening and on Day 1 of every treatment cycle and 
at the time of discontinuation from the study drug (within ≤2 weeks).  
g  Urine analysis assessments include:  gross or a microscopic urine exams.  A dipstick assessment includes:  specific gravity, pH, protein, glucose, bilirubin, ketones, blood cells, and leukocytes.  The urinalysis 
will be performed at screening and as clinically indicated.  Urine specimens will be sent to the local laboratory for analysis. 
h  Serum urine pregnancy test.  Females of childbearing potential must have a serum or urine pregnancy test performed within 7 days prior to the first dose of study drug. 
i  A computerized tomography (CT) scan or magnetic resonance image (MRI) of the chest/abdomen and pelvis will be performed at screening (≤35 days) prior to the first dose of study drug and at 8 weeks  
(±1 week).  Thereafter, a CT scan or MRI of the chest/abdomen and pelvis will be performed every 12 weeks (±1 week), and at the time of discontinuation of the study drug (within 2 weeks). 
j  A chest x-ray can  be performed at the investigator‟s discretion, if there is a suspicion of non-infectious pneumonitis.  
k  A brain MRI or brain CT scan will be obtained within 2 weeks of the first dose of study drug and as clinically indicated if the patient develops signs or symptoms of central nervous system (CNS) 
involvement.  If brain metastases are present at baseline, brain MRI/brain CT scan will be performed every 8 weeks during the study. 
l  A bone scan will be obtained at screening (within 3 weeks of the first dose of study drug) and as clinically indicated if the patient develops signs or symptoms of bone disease.  If bone metastases are present at 
baseline, the bone scans will be performed every 12 weeks (±1 week) during the study. 
m  Standard 12-lead electrocardiograms are to be performed at the investigator‟s discretion according to local practice, or if there are signs and symptoms of cardiotoxicity.  Any significant findings will be noted 
 


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Table 9 
Visit Evaluation Schedule 
 
Screening -
35 
Baseline 
-7 to -1 
Cycle 1  
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
Subsequent 
Cycles  
(28 days) 
End-of-
Study 
Treatment 
Endpoint 
Follow-Upa 
Visit number 
1a 
1b 
2 
3 
4 
5 
6 
7 
8, 9 
Last visit 
 
Day of cycle 
 
 
1 
15 
1 
15 
1 
15 
1 
Last day 
 
on the Relevant Medical History or Adverse Event pages of the CRF.  
n  Pulmonary function tests (including spirometry, diffusion capacity of carbon monoxide, and room air O2 saturation at rest) will be performed at screening per investigator discretion, and at the end of the study  
(≤2 weeks) and as medically necessary if there is evidence of non-infectious pneumonitis.  A bronchoscopy with a biopsy and/or brancheoalveolar lavage will be performed when medically necessary for 
decisions regarding patient care.  The results will be recorded on the appropriate CRF page.   
o  Record all medications given ≤30 days prior to study entry on the Concomitant Medications/Significant Non-Drug Therapies Prior to the Start of the Study CRF page.  After the start of the study, concomitant 
medications must be recorded on the Concomitant Medications/Significant Non-Drug Therapies CRF page. 
p  All adverse events (AEs) occurring after the start of the study, even if the event is not considered to be related to the study drug, must be documented on the Adverse Event CRF page. 
 
q  Information on all target tumor and non-target lesions will be collected at screening.  Subsequently, radiological assessments (to follow the target and non-target lesions identified at baseline) will be 
performed at 8 weeks (±1 week).  In the absence of progressive disease, assessments will continue every 12 weeks (±1 week) until the start of new anticancer therapy and at the End-of-Study Visit (within  
1 week of stopping treatment) or until death.  Observation of tumor response (partial or complete response) warrants a confirmation no sooner than 4 weeks.  The same type of scan (CT or MRI) used at 
screening must be used for all subsequent follow-up assessments. 
r  RAD001 10 mg daily dosing will begin on Day 1 of Cycle 1.  Treatment with the study drug will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, etc.  
s  Patients who discontinue the study drug will have end-of-study evaluations performed on that day or within 2 weeks of discontinuation of the study drug. 
t  All patients will have a follow-up visit 28 days after the last dose of RAD001.  During this visit, AE and serious adverse event information occurring since the last dose of study drug will be collected and 
recorded on the appropriate CRF pages.  All patients who are discontinued from the study drug for any reason will continue to have tumor assessments until the start of any new anticancer therapy. 
u  After discontinuation of the study drug, the investigator or his/her designee will collect information on the initiation of new anticancer therapies given after the last dose of study drug. 
r All patients will be screened for HBV-DNA, HBV serologic markers and HCV RNA-PCR. It is highly recommended that patients positive for HBV-DNA or HBsAg receive prophylactic antivirals for 1-2 
weeks prior to receiving study drug. The antiviral treatment should continue throughout the entire study period and for at least 4 weeks after the last dose of study drug. Monitoring for HBV reactivation, 
according to Table 6-5, will only require the measurement of HBV-DNA from Visit 2 onwards. Patients who are HBV-DNA / HBsAg positive at screening will be monitored every cycle. Patients who are 
HBV-DNA and HBsAg negative at screening (and not receiving prophylaxis) but HBsAb or HBcAb positive will be monitored every cycle. Follow-up testing for HCV RNA-PCR will be performed every cycle 
only if the patient has a history of HCV or is positive at baseline, or both. If there is no history of HCV and HCV RNA-PCR test is negative at baseline, no follow-up testing is required. 
 


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7.1 
Visit Windows 
For Cycles 1, 2, and 3, visits will be on the 1st and 15th day (±5 days) of each 28-day cycle.  
For each subsequent cycle, patients will return to the site on the 1st day (±5 days) of each  
28-day cycle.  
7.2 
Information to be Collected on Screening Failures 
Patients who are screened and do not meet all entry criteria will not receive the first dose of 
RAD001.  Such patients are considered to be screen failures.  The reason for not being started 
on RAD001 will be entered on the Screening Log CRFs.  Screen failures are not entered into 
the clinical data base. 
7.3 
Patient Demographics/Other Baseline Characteristics 
Data will be collected on patient characteristics, including demographic information (age, sex, 
race, weight) and other background or relevant medical history (cancer history and extent of 
cancer, prior anticancer therapies) and any other assessments that are done for the purpose of 
determining eligibility for inclusion in the study (i.e., Karnofsky Performance Status, 
complete physical examination including a neurological assessment, vital signs, hematology, 
blood chemistries including coagulation studies and a serum lipid profile, urinalysis, 
pregnancy test [only required for females of childbearing potential], a brain MRI or a brain 
CT scan, electrocardiogram [ECG]).  
Urinalysis and the pregnancy test are only performed at either screening or baseline for 
eligibility, but are not repeated after the patient has started the study drug or at discontinuation 
from the study. 
The patient population will be stratified by prior cytokine therapy. 
7.4 
Treatments 
RAD001 10 mg daily dosing will begin on Day 1 of Cycle 1.  This study does not have a 
fixed treatment duration.  Patients will receive study treatment until disease progression or 
until unacceptable toxicity is observed.  Information on drug exposure will be collected on the 
Dosage Administration Record CRF page.  Concomitant medications/significant non-drug 
therapies prior to start (≤30 days) and after the start of study treatment will be recorded on the 
appropriate CRF pages.  Patient screening and randomization data will be stored on the 
appropriate CRF pages. 
7.5 
Efficacy 
The primary efficacy endpoint is PFS as defined in Section 10.4.1. Secondary efficacy 
endpoints are OS, disease control rate (SD + PR + CR), the ORR (CR + PR) as defined in 
Section 10.5.1, as well as response duration. 
7.5.1 
Radiological Assessment of Tumor(s) 
Tumor response, stable disease, and progression, will be assessed using the RECIST criteria 
(see Post-Text Supplement 1 for complete details).  A CT scan or MRI of the chest/abdomen 


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and pelvis will be obtained at screening (≤35 days) prior to the first dose of RAD001 and 
periodically as indicated in Table 9.  Tumor response will be assessed at  
8 weeks (±1 week) and every 12 weeks (±1 week) thereafter until determination of disease 
progression (by the local radiologist) and at the end of the study. 
All patients who are discontinued from RAD001 for any reason (i.e., documented disease 
progression by the investigator, an AE or SAE, or administrative reasons, etc.) will continue 
to have tumor assessments until the start of new anticancer therapy. 
At screening (≤35 days prior to the first dose of RAD001), all patients must have a CT scan 
with contrast or MRI with contrast of the chest, abdominal, and pelvic area.  Patients who are 
allergic/sensitive to the radiographic contrast media used in CT scans and MRIs may have a 
CT scan of the chest without contrast and a MRI of the abdomen and pelvis without contrast. 
The same imaging modality used at screening must be used for all subsequent follow-up 
assessments.  
Ultrasound scans cannot be used to measure tumor lesions. 
All patients should have at least one measurable disease lesion by CT scan or MRI or by 
physical exam.  Physical examination findings, such as skin lesions, must be photographed 
(color photography) using a digital camera.  Subcutaneous nodules will be measured with a 
caliper or a ruler.  If skin lesions are used for assessment of disease, at least one skin lesion 
should be biopsied to establish the malignant nature of the lesions.  The site must document 
on the Tumor Assessment Comments CRF page that a biopsy of at least one skin lesion 
confirming the presence of metastatic disease has been obtained or was available for this 
purpose. 
Measurable disease lesions must be accurately measured in at least one dimension with the 
longest diameter ≥20 mm using conventional techniques, or ≥10 mm with spiral CT scan 
(with a minimum lesion size no less than double the slice thickness).  Conventional CT and 
MRI should be performed with contiguous cuts of 7.5 mm or less in slice thickness.  Spiral 
CT should be performed using a 5 mm or less contiguous reconstruction algorithm (this 
specification applies to tumors of the chest, abdomen, and pelvis). 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions.  The target lesions 
will be measured and recorded at baseline and during the course of the study.  The target 
lesions should be selected on the basis of their size (lesions with the longest diameters) and 
suitability for accurate repeated measurements.  A sum of the longest diameter for all target 
lesions will be calculated and reported as the baseline sum of the longest diameter. 
If a very small lesion cannot be reliably measured because of its size, it is recommended to 
enter the minimum lesion size (i.e., 5 mm for spiral CT).  In other cases where the lesion 
cannot be reliably measured for reasons other than its size (i.e., borders of the lesion are 
confounded by neighboring anatomical structures), no measurement should be entered and the 
lesion cannot be evaluated. 
A target lesion that resolves from baseline must be assigned a size of 0 mm when 
documenting on the patient‟s RECIST CRF page.  Refer to Supplement 1 for additional target 
and non-target lesion reporting guidelines. 


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Partial response requires at least a 30% decrease in the sum of the longest diameters of all 
target lesions, taking as reference the baseline sum of the longest diameters.  
Complete response requires a disappearance of all target and non-target lesions.  If an initial 
observation of partial or complete response is made, a confirmation scan is required no sooner 
than 4 weeks.  
In case of an unscheduled or delayed tumor assessment (i.e., to confirm a PR/CR or due to 
any other reason), subsequent tumor assessments must be performed according to the 
originally planned scheme from baseline, i.e., every 12 weeks from the time of the second 
assessment at 8 weeks.  
Disease progression is either 1) a 20% increase in the sum of the longest diameter of all target 
lesions, taking as reference the smallest sum of the longest diameters of all target lesions 
recorded at or after baseline, or 2) the appearance of a new lesion, or 3) the unequivocal 
progression of non-target lesions overall.  Patients who had suspected clinical symptoms of 
disease progression should be immediately evaluated with a physical examination and 
imaging (CT scan or MRI) assessment for objective evidence of disease progression. 
7.5.2 
Imaging Procedures 
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedure must be implemented at the study site: 
 
All lesions identified at baseline (target and non-target) will be reassessed using the 
same method (CT scan with contrast or MRI) throughout the course of the study; 
 
All CT scans, MRIs, bone scans, and chest x-rays obtained on all patients enrolled at 
the site should be reviewed by the local radiologist who, together with the investigator, 
will determine the local assessment of response and progression; 
 
If skin lesions are used for tumor assessment, the corresponding photos must also be 
transmitted/delivered to the local radiologists.  
7.6 
Safety 
Safety assessments will consist of monitoring and recording all AEs, including SAEs, the 
regular monitoring of hematology, serum chemistry, routine monitoring of vital signs (heart 
rate, blood pressure, and body temperature), and chest x- rays, ECGs, and physical condition. 
Toxicity will be assessed using the National Institutes of Health (NIH) NCI-CTCAE, version 
3.0 (CTCAE v3.0, [http://ctep.cancer.gov/forms/CTCAEv3.pdf]). 
7.6.1 
Adverse Events 
An AE, for the purposes of this protocol, is the appearance of (or worsening of any pre-
existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the 
informed consent, even if the event is not considered to be related to the study drug (study 
drug refers to the drug under evaluation [RAD001], and study treatment also refers to 
RAD001). 


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Adverse events will be assessed according to the CTCAE, version 3.0.  If CTCAE grading 
does not exist for a particular AE, the severity of mild, moderate, severe, and life-threatening, 
or grades 1 to 4, will be used.  The CTCAE grade 5 (death) will not be used in this study; 
rather, this information will be collected on the End of Treatment or Survival Information 
CRF page.  All AEs will be coded by System Organ Class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA), latest version. 
Adverse event monitoring should be continued for at least 4 weeks following the last dose of 
study treatment.  Adverse events (but not SAEs) occurring before starting study treatment, but 
after signing the informed consent form, are recorded on the Medical History/Current Medical 
Conditions CRF pages.  Abnormal laboratory values or test results constitute an AE only if 
they induce clinical signs or symptoms, are considered clinically significant, or require 
therapy (e.g., any hematological abnormality that requires transfusion or cytokine treatment); 
and should be recorded on the Adverse Events CRF page under the signs, symptoms, or 
diagnosis associated with them.  In addition, isolated abnormal laboratory values that are 
considered clinically significant (e.g., cause study discontinuation or constitutes in and of 
itself a SAE) should be recorded on the Adverse Events CRF page. Serious AEs occurring 
after signing the Informed Consent are recorded on the Adverse Event CRF page. 
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study.  Adverse events may also be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments.  
As far as possible, each AE should be evaluated to determine: 
1. The severity grade (CTCAE grades 1 to 4); 
2. Its relationship to study drug (suspected/not suspected); 
3. Its duration (start and end dates or if continuing at final exam); 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this AE; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization); 
5. Whether it is serious, where a SAE is defined as one which: 
 
Is fatal or life-threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Constitutes a congenital anomaly/birth defect; 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
a) 
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (specify what this includes); 
b) 
Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the informed 
consent; 


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c) 
Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission; 
d) 
Social reasons and respite care in the absence of any deterioration in the 
patient‟s general condition. 
 
Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1. 
All AEs should be treated appropriately.  Such treatment may include changes in the study 
drug treatment, including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention.  Once an AE is detected, it should be followed until 
its resolution, an assessment should be made of any changes in its severity at each visit (or 
more frequently, if necessary), its suspected relationship to the study drug, any of the 
interventions required to treat it, and its outcome. 
Information about common side effects already known about the study drug can be found in 
the IB or will be communicated between IB updates in the form of Investigator Notifications.  
This information will be included in the patient informed consent and should be discussed 
with the patient during the study as needed. 
7.6.2 
Physical Examination, Including a Neurological Examination 
A complete physical examination includes a major review of body systems (general 
appearance, skin, neck including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, and a neurological examination).  Significant findings must be 
recorded either as relevant medical history/current medical conditions, if present before the 
start of study treatment, or as an AE, if newly occurring or worsening since start of treatment. 
A physical examination must be performed at screening, on Day 1 of each study treatment 
cycle (≤1 week), and at completion/discontinuation from study treatment (≤2 weeks). 
7.6.3 
Vital Signs 
Body temperature, sitting pulse rate, and sitting blood pressure will be routinely measured. 
Blood pressure will be measured according to the NIH, National Heart, Lung, and Blood 
Institute Guidelines (NIH, 1997) with the following standardized techniques: 
 
Patients are seated in a chair; blood pressure measurement begins after at least  
5 minutes of rest; 
 
The appropriate cuff size is used to ensure accurate measurement. 
Vital signs will be performed at screening, on Day 1 of each cycle (≤1 week), and at the 
completion/discontinuation from the study drug (≤2 weeks).  Height and weight will be 
measured and recorded at screening only. 


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7.6.4 
Karnofsky Performance Status 
The baseline Karnofsky Performance Status will be assessed and recorded at baseline (within 
1 week of the first dose of the study drug), on Day 1 of every subsequent treatment cycle, and 
at discontinuation from the study drug (within 1 week).  The Karnofsky Performance Scale 
Index allows patients to be classified as to their functional impairment.  The definition of 
scores in relation to the performance status is given in Table 7. 
Table 7 
Karnofsky Performance Scale 
Score (%) 
Performance Status 
100 
Normal, no complaints; no evidence of disease  
90 
Able to carry out normal activity; minor symptoms 
80 
Normal activity with effort; some symptoms 
70 
Cares for self; unable to carry out normal activities 
60 
Requires occasional assistance; cares for most needs 
50 
Requires considerable assistance and frequent care 
40 
Disabled:  requires special care and assistance 
30 
Severely disabled:  Hospitalized, but death not imminent 
20 
Very sick:  active supportive care needed 
10 
Moribund:  fatal processes are progressing rapidly 
0 
Dead 
 
7.6.5 
Laboratory Evaluations 
All standard clinical laboratory analyses described below are performed by local laboratories.  
The frequency of the assessments is indicated in Table 9.  All laboratory procedures including 
collection of samples, shipment, reporting of results, alerting of extreme values, and notable 
values are provided in the Laboratory Manual.  The local laboratory will provide the sponsor 
with a copy of the laboratory certification and tabulation of the reference ranges. 
Abnormal laboratory values that are clinically relevant (i.e., require a dose modification, 
interruption, or indicate changes in previously abnormal values) must be recorded on the 
Adverse Events CRF page.  For clinically relevant values from local laboratories, record 
actual laboratory abnormality value and grade on the local laboratory CRF page only if the 
severity grade is different from the severity grade reported by the local laboratory.  
If a local laboratory value is recorded on the local laboratory CRF page, the site will provide 
the local laboratory reference range attached to the local laboratory CRF page. 
All laboratory results must be available at the time the patient sees his/her attending 
oncologist. 
7.6.5.1 
Hematology 
Hematological tests include a complete blood count, a total white blood cell (WBC), 
neutrophil count (including bands), lymphocyte, monocyte, eosinophil, basophil counts, Hb, 
hematocrit, and a platelet count. 


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Hematological tests will be performed at screening, on Day 1 (prior to administration of the 
study drug) of each treatment cycle.  Hematological tests may also be performed on  
Day 15 of the first 3 treatment cycles at the investigator‟s discretion and according to local 
practice.  Subsequently, these tests will be performed on Day 1 (of every treatment cycle), or 
as medically necessary, and at discontinuation from study treatment (≤2 weeks).  In the event 
of grade 2, grade 3, or grade 4 hematological toxicities that require study drug dose 
modifications or interruptions, hematological tests must be repeated until recovery to the 
baseline value or grade 1. 
7.6.5.2 
Coagulation 
The prothrombin time (PT) will be performed at screening and on Day 1, Cycle 2.  
Prothrombin time will be repeated as clinically indicated and will be reported as international 
normalized ratio (INR). 
7.6.5.3 
Biochemistry 
Serum chemistry tests include urea, blood urea nitrogen, creatinine, lactate dehydrogenase, 
total protein, fasting glucose, phosphorus, serum corrected calcium (calculated at baseline 
only), electrolytes (sodium, magnesium, chloride, and potassium), total bilirubin, gamma-
glutamyl-transferase, albumin, alkaline phosphatase, ALT, AST, and uric acid.  The patient 
must be in a fasting state (at least 12 hours) at the time of blood sampling for this evaluation. 
Serum chemistries must be performed at screening and on Day 1 of each treatment cycle and 
at discontinuation from study treatment (≤2 weeks).  In the event of grade 2, grade 3, or  
grade 4 non-hematological toxicities that require study drug dose modifications or 
interruptions, biochemistry tests must be repeated until recovery to the baseline value or  
grade 1. 
7.6.5.4 
Serum Lipid Profile 
A serum lipid profile includes: total cholesterol, triglycerides, low-density lipoprotein, and 
high-density lipoprotein.  This assessment will be performed at screening and on Day 1 of 
every treatment cycle and at the time of discontinuation from the study drug (within  
2 weeks).  The patient must be in a fasting state (at least 12 hours) at the time of blood 
sampling for this evaluation.  In the event of grade 2, grade 3, or grade 4 toxicities that require 
study drug dose modifications or interruptions, serum lipid tests must be repeated until 
recovery to the baseline value or grade 1. 
7.6.5.5 
Urinalysis 
Urine analysis includes gross or microscopic urine exams.  Gross (dipstick) urine examination 
includes: specific gravity, pH, protein, glucose, bilirubin, ketones, blood cells, and leukocytes. 
The microscopic examination includes: WBC/high-powered field, RBC/high-powered field, 
and casts.  A dipstick analysis will be done locally, if its results are abnormal, a urine 
specimen will be sent to the local laboratory for microscopy analysis.  The urinalysis test is 
required only at screening. 


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7.6.5.6 
Pregnancy Test 
Females of childbearing potential will have a serum or urine pregnancy test that must be 
performed within 7 days prior to the administration of study drug. 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence.  Any patient who becomes pregnant 
must be discontinued from study drug immediately.  The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Integrated Medical Safety (IMS) Department.  
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
drug in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
7.6.5.7 
Electrocardiogram 
Standard 12-lead ECGs are to be performed at the investigator‟s discretion according to local 
practice, or if there are signs and symptoms of cardiotoxicity.  Tracings must be dated and 
signed by the investigator or his/her designee and filed with the patient‟s source documents. 
Significant findings must be recorded as relevant medical/current medical conditions if 
present before treatment with study drug or as an AE (if newly occurring or worsening since 
start of treatment).  An ECG must be performed at screening and as clinically indicated. 
7.6.5.8 
Chest X-Ray/Chest Computed Tomography Scans/Pulmonary 
Function Tests 
A chest x-ray can  be performed at the investigator‟s discretion, if there is a suspicion of non-
infectious pneumonitis 
as indicated in Table 9.  Chest x-rays will be used in this study solely for the purpose of 
detecting non-infectious pneumonitis.  Chest x-rays will not be used to report tumor-related 
findings.  
Pulmonary function tests (spirometry, diffusion capacity of carbon monoxide, and room air O2 
saturation at rest) will be performed as medically necessary if there is evidence of non-
infectious pneumonitis per invistigator discretion..  
A bronchoscopy with biopsy and/or broncheoalveolar lavage will be performed when 
medically necessary for decisions regarding patient care.  The results will be recorded on the 
appropriate CRF page.  Additional details are provided in Table 4. 


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8 
Safety Monitoring 
8.1 
Serious Adverse Event Reporting 
The investigator must fax each SAE or pregnancy (see below) to Novartis within 24 hours of 
learning of its occurrence, even if it is not felt to be treatment-related.  Follow-up information 
about a previously reported SAE must also be faxed to Novartis within 24 hours of receipt.  If 
the SAE is not documented in the IB (i.e., unexpected), and it is thought to be related to the 
Novartis investigational drug(s), central IMS may need to contact the investigator urgently in 
order to obtain further information prior to the submission of the reported event to the health 
authorities.  If warranted, to fulfill the regulatory requirement, an Investigator Notification 
may be issued, to inform all investigators involved in any study with the same drug (or 
therapy) that this serious unexpected and suspected adverse reaction has been reported.  
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until the patient has stopped study participation 
must be reported to Novartis within 24 hours of learning of its occurrence.  Any SAEs 
experienced by the patient during the follow-up period beginning 4 weeks after study drug has 
been stopped should only be reported to Novartis if the investigator suspects a causal 
relationship to the study drug.  Recurrent episodes, complications, or progression of the initial 
SAE must be reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information.  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. 
The telephone and telefax number of the contact persons in the local department of Clinical 
Safety and Epidemiology, specific to the site, are listed in the investigator folder provided to 
each site.  
The investigator must complete the SAE Report Form in English, assess the relationship to 
the Novartis investigational drug(s) and send the completed, signed-off, form by fax within  
24 hours to the local Novartis safety office (for trials monitored by Novartis) or to the relevant 
Contract Research Organization (CRO).  The local Novartis safety office or CRO, after 
ensuring that the form is accurately and fully completed, must then fax it to the central 
Novartis IMS Department within 2 to 3 calendar days for deaths or life-threatening events and 
within 5 calendar days for other SAEs.  The original copy of the SAE Report Form and the 
fax confirmation sheet must be kept with the CRFs at the study site.  A copy of the SAE 
Report Form is forwarded to the monitor by the local Novartis safety office or CRO, to 
perform source data verification. 
Follow-up information is always forwarded to the same person to whom the original SAE 
Report Form was sent.  A new SAE Report Form should be sent stating that this is a follow-
up.  The follow-up should describe whether the event has resolved or continues, if and how it 
was treated, whether the blind was broken or not (in the case of a blinded study), and whether 
the patient continued or discontinued study participation.  Where a SAE is followed by reports 
of recurrent episodes, complications or progression of the initial event, all such reports will be 
treated as follow-up to the original episode.  If a new SAE occurring at a different time 
interval is considered completely non-associated to a previously reported one, a new SAE 


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Report Form should be submitted as an initial report.  All forms and fax confirmation sheets 
must be retained by the study site. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the Novartis study drug, a Clinical Safety and Epidemiology 
Department associate may urgently require further information from the investigator for 
Health Authority reporting.  Novartis may need to issue an Investigator Notification 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. 
8.2 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence.  Any patient who becomes pregnant 
must be discontinued from study drug immediately.  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.  An abortion is to be regarded always as a SAE and assessed as 
“other medically significant event” even if no other seriousness criterion is fulfilled.   
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety and Epidemiology Department.  Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome.  Any SAE 
experienced during pregnancy must be reported as instructed for SAEs, using the SAE report 
form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
drug in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
8.3 
Data Monitoring Board 
Since this study has a single open-label treatment arm, a Data Monitoring Committee is not 
required. 
9 
Data Review and Data Management 
9.1 
Site Monitoring 
Before study initiation, at a site initiation visit or at an investigator‟s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff.  During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications.  Key study 
personnel must be available to assist the field monitor during these visits. 


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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 on CRFs must be traceable to these source documents in the 
patient‟s file.  The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries.  Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables.  Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan.  No information in source 
documents about the identity of the patients will be disclosed. 
9.2 
Data Collection 
For studies using paper CRFs, designated investigator staff must enter the information 
required by the protocol onto the Novartis CRFs that are printed on 3-part, non-carbon-
required paper.  Field monitors will review the CRFs for completeness and accuracy and 
instruct site personnel to make any required corrections or additions.  The CRFs are 
forwarded to the Medical Documents Reception Center of Novartis and the designated CRO 
by field monitors or by the investigational site, with one copy being retained at the 
investigational site. 
9.3 
Auditing Procedures 
The Quality Assurance unit in Novartis (sponsor of this study) conducts audits of clinical 
research activities in accordance with internal Standard operating Procedures to evaluate 
compliance with the principles of Good Clinical Practice.  A regulatory authority may also 
wish to conduct and inspection (during the study or even after its completion).  If an 
inspection is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 
9.4 
Database Management and Quality Control 
Data will be entered into the study database by Novartis Data Management personnel (or 
designated CRO) for paper studies. 
For studies using paper CRFs, the entered data are systematically checked by Novartis Data 
Management personnel (or designated CRO) using error messages printed from validation 
programs and database listings.  Obvious errors are corrected by Novartis Data Management 
personnel (or designated CRO).  Other errors or omissions are entered on Data Query Forms, 
which are returned to the investigational site for resolution.  The signed original and resolved 
Data Query Forms are kept with the CRFs at the investigator site, and a copy is sent to 
Novartis so the resolutions can be entered into the database.  Quality control audits of all key 
safety and efficacy data in the database are made prior to locking the database. 


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Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.  
Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) latest version terminology. 
This is an open-label study; therefore, no Interactive Voice Randomization System (IVRS) 
will be used. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Global Head 
of Biostatistics and Statistical Reporting and the Global Therapeutic Area Head. 
10 
Statistical Methods and Data Analysis 
This is an open-label, multi-center, single arm Phase 2 study to evaluate the safety and 
efficacy of RAD001 as monotherapy in patients with any MSKCC prognosis metastatic 
recurrent and/or unresectable clear cell or non-clear cell carcinoma of the kidney, with or 
without prior cytokine therapy. 
The data will be analyzed by Novartis and/or designated CRO.  Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. It is planned that the data from participating centers in this protocol will be 
combined, so that an adequate number of patients will be available for analysis.  The data will 
be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, and safety observations and measurements.  Categorical data 
will be presented as absolute frequencies and percentages.  For continuous data, number (N), 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.  Time to event variables, Kaplan-Meier product-limit estimates will also be 
presented. 
The final safety and efficacy analyses will be conducted at the time when approximately  
110 patients have completed the study.  There will be no interim analysis. 
10.1 
Populations for Analysis 
The Full Analysis Set (FAS)  consists of all patients treated with RAD001.  Following the 
ITT principle, patients are analyzed according to the treatment and stratum they were in at the 
start of the study. 
The Safety population consists of all patients who received at least one dose of the study 
drug and who have at least one post-baseline safety assessment.  Patients are analyzed 
according to the treatment received. 
Please note: the statement that a patient had no AEs (on the Adverse Event CRF page) 
constitutes a safety assessment.  Patients who have received at least one dose of study 
drug, but who have no post-treatment safety data of any kind, would be excluded from the 
Safety population. 


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10.2 
Patient Demographics/Other Baseline Characteristics 
Demographic and background information will be summarized for the Safety population and 
the FAS, using frequency distributions for categorical variables and descriptive statistics for 
continuous variables.  Background information includes prior medication, past/current 
medical conditions, diagnosis and extent of cancer, Karnofsky Performance Status and tumor 
history at baseline.  Medical history will be coded using MedDRA and will be presented by 
System Organ Class and MedDRA preferred term.  Separate tables will be provided for past 
medical condition and current medical condition.  Prior medication will be coded according to 
WHO Drug Dictionary (latest version). 
10.3 
Treatments (Study Drug, Concomitant Therapies, Compliance) 
10.3.1 
Study Drug 
The study drug administration will be summarized.  The number of treated patients and the 
duration of treatment will be presented. 
10.3.2 
Concomitant Therapies 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug will be listed and summarized by ATC class preferred term for the safety population by 
frequency tables.  These summaries will include medications starting on or after the start of 
study treatment or medications starting prior to the start of study treatment and continuing 
after the start of study treatment. 
10.4 
Primary Objective 
The primary objective of this study is to estimate the PFS over time in patients who receive 
RAD001 as monotherapy. 
10.4.1 
Variable:  Progression-Free Survival 
The primary endpoint of this study, PFS, is defined as the time from the date of the start of 
RAD001 treatment to the date of the first documented disease progression or death due to any 
cause.  
A patient who has not progressed or died at the date of the analysis cut-off, or when he/she 
receives any further anticancer therapy, would have his/her PFS censored at the time of the 
last tumor assessment, before the first of the cut-off date or the anticancer therapy date.  
For the primary analysis, PFS will be based on the review by the local radiologist who, 
together with the investigator, will determine the local assessment of response and 
progression according to the RECIST criteria. 
 
 
 
 


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10.4.2 
Statistical Hypothesis, Model, and Method of Analysis 
No statistical test of hypotheses will be performed in this study.   
The primary analysis for this study is to estimate the PFS rate over time and its  
95% CI by the method of Kaplan-Meier for:  
1. All patients;  
2. First-line patients (receiving RAD001 as their first treatment);  
3. Second-line patients (patients who received cytokine therapy as first-line therapy). 
Progression-free survival curves (graphing the PFS rate over time) will be displayed, overall 
and by strata, according to the Kaplan-Meier product-limit method.  The PFS rate over time 
will also be tabulated.  The resulting median PFS time will be given with 95% CIs. 
The primary analysis will be performed on the Full Analysis Set (FAS).  Consolidated 
summary results obtained from the local radiological review will be used for this analysis. 
10.4.3 
Handling of Missing Values/Censoring/Discontinuations 
By default, if disease progression or death is documented after one single missing tumor 
assessment, the actual event date of disease progression/death will be used for the PFS event 
date.  If disease progression is documented after two or more missing tumor assessments, the 
PFS time of these patients will be censored at the date of the last tumor assessment, with 
overall lesion response of CR, PR, or SD. 
Additionally, sensitivity analyses will be performed where: 
1. The actual event date of disease progression/death will be used for the PFS event date, 
irrespective of whether it is preceded by missing tumor assessments; 
2. In case of a documented progression/death after one or more missing tumor 
assessments, disease progression is considered to have occurred at the next scheduled 
tumor assessment after the date of the last tumor assessment with overall lesion 
response of CR, PR, or SD. 
10.4.4 
Supportive Analyses 
The primary analysis will also be performed on all available events (progressions) as per local 
radiological review, as a supportive, secondary analysis. 
All analyses will be fully described and document in the statistical analysis plan (SAP).   
10.5 
Secondary Objectives 
10.5.1 
Secondary Efficacy Evaluation 
The analyses of all secondary efficacy endpoints will be performed on the FAS. 
10.5.1.1 Disease Control Rate (SD + PR + CR) 
The disease control rate will be based on the data as per local radiological review, following 
the RECIST criteria.  The disease control rate is defined as the proportion of patients with CR, 


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PR, or SD.  The disease control rate (CR + PR + SD) will be summarized in terms of 
percentage with 95% CIs. 
10.5.1.2 Objective Response Rate and Duration 
The overall tumor response will be based on the data as per local radiological review, 
following RECIST criteria.  The ORR is defined as the proportion of patients with CR or PR.  
The ORR (CR + PR) will be summarized in terms of percentage with 95% CIs. 
The duration of overall response (CR or PR) will also be calculated, and is defined as the time 
from the first occurrence of PR or CR (as per local radiological review) until the date of the 
first documented disease progression or death due to underlying cancer.  If a patient has not 
had an event, or when he/she receives any further anticancer therapy, duration of overall 
response is censored at the date of the last adequate tumor assessment.  In case of missing 
data, the same rules will be applied as for PFS (see Section 10.4.3). 
Duration-of-response curves (graphing the proportion of patients remaining free from 
progression and death due to cancer) will be displayed, overall and by strata, according to the 
Kaplan-Meier product-limit method, for those patients who had an overall response.  This 
proportion over time will also be tabulated.  The resulting median duration of response will be 
given with 95% CIs. 
10.5.1.3 Overall Survival  
Overall survival is defined as the time from date of start of treatment to date of death due to 
any cause. If a patient is not known to have died, survival will be censored at the date of last 
contact. Overall survival will be analyzed for the FAS. The Kaplan Meier curve will be 
displayed. Median, 25th and 75th percentile of the Kaplan Meier estimator along with their 
95% confidence intervals will be reported. 
10.5.2 
Safety Evaluation 
For all safety analyses, the Safety population will be used.  The assessment of safety will be 
based mainly on the frequency of AEs and on the number of laboratory values that fall outside 
of pre-determined ranges.  Other safety data (i.e., ECG, vital signs) will be considered as 
appropriate. 
For all safety analyses, the safety population will be used.  The assessment of safety will be 
based mainly on the frequency of AEs and on the number of laboratory values that fall outside 
of pre-determined ranges.  Other safety data (i.e., electrocardiogram, vital signs) will be 
considered as appropriate. 
Adverse events will be summarized by presenting the number and percentage of patients 
having any AE, having an AE in each body system and having each individual AE. Any other 
information collected (e.g., CTC grades or relatedness to study drug) will be listed as 
appropriate.  In addition, the incidence of pneumonitis AEs will be summarized by preferred 
term. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by the 
type of AE. 


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Laboratory data will be summarized by presenting shift tables using CTC grades (screening to 
most extreme post-screening value), by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations) and by the flagging of CTC 
grades in data listings. 
Data from other tests (e.g., electrocardiogram or vital signs) will be listed and any other 
information collected will be listed as appropriate. 
10.5.3 
Tolerability 
Frequency and severity of all treatment-emergent AEs will be listed. 
10.5.4 
Resource Utilization 
No resource utilization will be specifically collected in this study. 
10.5.5 
Patient-Reported Outcomes 
No patient-reported outcomes are planned. 
10.5.6 
Pharmacokinetics 
Not applicable. 
10.5.7 
Biomarkers 
Not applicable.  
10.6 
Interim Analysis  
No interim analysis is planned for this study. 
10.7 
Sample Size Calculation 
By way of background, Hudes et al. (2006), for first-line poor-prognosis metastatic RCC 
patients, estimated at 3.8 months a PFS rate of 50% for temsirolimus treatment.  Amato, et al. 
2008 (draft manuscript), for mostly second-line RCC patients, observed at 11.2 months a PFS 
rate of 50% for everolimus (RAD001) treatment.  How patients are selected (i.e., whether the 
selected patients are poor-prognosis patients or patients are selected irrespective of prognosis) 
may have a large impact on the observed median PFS. 
The sample size for this study will be determined with reference to estimating a CI for the 
PFS rate at 10 months, assuming (for simplicity) the use of the normal approximation to the 
binomial distribution and assuming that a CI for a proportion is based on this normal 
approximation.  To be able to estimate a 95% CI for the PFS rate, centered at 0.50, and having 
an expected total interval width of approximately 0.27, requires a sample size of 55 patients in 
each cohort (first- and second-line). With 95% confidence, the expected total interval width is 
approximately 0.19 for all 110 patients (both cohorts combined).  
Some alternative sample size calculations, using different assumptions about the desired 
expected CI width, are as shown in Table 8. 
Table 8 
Number of Patients Required per Cohort Depending on Desired Width of 


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Confidence Interval (CI) for the 10-Month Progression-Free Survival 
Proportion 
Expected CI Width for 
One Cohort 
Number of Patients 
Required Per Cohort 
Total Required Number 
of Patients 
Expected CI Width for 
all Patients Combined 
0.2 
97 
194 
0.14 
0.25 
62 
124 
0.18 
0.3 
43 
86 
0.21 
0.35 
32 
64 
0.24 
0.4 
25 
50 
0.28 
 
10.8 
Power for Analysis of Critical Secondary Variables 
Not applicable. 


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11 
Administrative Procedures 
11.1 
Administrative Structure 
Novartis, the sponsor for this study, is responsible for overseeing all activities conducted 
during the course of the study.   
The study administrative structure is described in Table 9. 
Table 9 
Study Administrative Structure 
Steering Committee: 
Chair: 
Co-Chair: 
Country Representative: 
Drug Safety Reporting: 
 
Clinical Study Supply Management: 
 
Data Management: 
 
Study Monitoring: 
 
Biostatistics: 
 
Medical Monitoring: 
 
Study Report Preparation: 
 
Clinical Laboratory: 
 
 
 
 
11.2 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the protocol, the International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guidelines for Good Clinical Practice (GCP), 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. 
11.3 
Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) before study initiation.  A signed and dated statement 
that the protocol and informed consent have been approved by the IRB/IEC/REB must be 
given to Novartis before study initiation.  Prior to study start, the investigator is required to 
sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs, and regulatory authorities as required. 


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11.4 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient.  In cases where the patient‟s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding.  If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form.  Informed consent must be obtained 
before conducting any study-specific procedures (i.e., all of the procedures described in the 
protocol).  The process of obtaining informed consent should be documented in the patient 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is 
considered appropriate for this study.  Any changes to the proposed consent form 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. 
Females of childbearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study.  If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
11.5 
Exploratory Biomarker Consent Form 
Not applicable. 
11.6 
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 within 10 working days. 
11.7 
Discontinuation of the Study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. 


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11.8 
Study Drug Supply and Resupply, Storage, and Tracking/Drug 
Accountability 
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access.  Upon receipt, the study drug should be stored according to 
the instructions specified on the drug labels.  Clinical supplies are to be dispensed only in 
accordance with the protocol. 
Study drug labels will be in the local language and comply with the legal requirements of each 
country.  They will include storage conditions for the drug and the medication number, but no 
information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of the study 
drug in a drug accountability ledger.  Drug accountability will be noted by the field monitor 
during site visits and at the completion of the study.  Patients will be asked to return all 
unused study drug and packaging at the end of the study or at the time of study drug 
discontinuation. 
At the conclusion of the study, and, as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
11.9 
Study Duration/Timelines 
The enrollment period for this study is expected to last approximately 18 months. 
Table 10 
Study Milestones 
First patient, first visit: 
31 July 2009 
Last patient, last visit: 
30 January 2012 
Total number of patients: 
110 
Number of study sites: 
25 
Number of patients per study site: 
4 
Location of study sites: 
Algeria, Morocco, Tunisia, Egypt, Saudi Arabia, Thailand, 
Jordan, Lebanon, India, Russia, and South Africa. 
 
11.10 
Publication 
Novartis has sole ownership of all data, results, reports, and any other information collected 
and full rights of publication based on data from this trial and will maintain full access to the 
database. 
Interim data cuts are planned and any formal presentation or publication of data from this trial 
will be considered as a joint publication by the physician(s) and appropriate Novartis 
personnel.  Publications will be based on data from all centers, analyzed as stipulated in the 
protocol.  Investigators agree not to present data gathered from one center or a small group of 
centers before the global publication, unless formally agreed to by all other investigators and 


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Novartis. Authorship will be determined by agreement with Novartis and the Scientific 
Steering Committee. 
Regional and local publications are permitted once the global publication for each interim 
data summary or aggregate thereof has been published.  Novartis and the Scientific Steering 
Committee must receive copies of any intended communication in advance of publication (at 
least 15 working days for an oral presentation and 45 working days for any other proposed 
publication). Novartis shall have the right to require amendments to any such proposed 
presentation or publication on reasonable grounds including without limitation: 
a)  To ensure the accuracy of the presentation or publication; 
b)  To ensure that proprietary information is not inadvertently divulged; 
c)  To enable intellectual property rights to be secured; 
d)  To enable relevant supplementary information to be provided. 
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. 
 


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12.1 
Signature Pages 
 
 
 
 
Clinical Development & Medical Affairs 
  
RAD001, Everolimus 
Clinical Trial Protocol CRAD001LIC01 
 An Open-Label, Multi-Center Phase 2 Study to Evaluate 
Everolimus as Monotherapy Treatment for Patients with 
Metastatic Recurrent and/or Unresectable Renal Cell 
Carcinoma (EVERMORE) 
 
 
 


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Protocol  Signature Page 
 
 
 
 
 
 
 
 
 
Novartis approval signature for: 
 
Clinical Study Protocol:  CRAD001LIC01 
 
 
 
 
 
 
 
  
Sr. Clinical Trial Head 
 
Signature 
 Date 
 
 
 
 
 
 
 
Study Statistician 
 
Signature 
 Date 
 
 
 
 
 
 
 
Medical Brand Leader 
 
Signature 
 Date 
 
 
 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title:  An Open-Label, Multi-Center Phase 2 Study to Evaluate Everolimus as 
Monotherapy Treatment for Patients with Metastatic Recurrent and/or Unresectable Renal 
Cell Carcinoma (EVERMORE) 
IMP:  RAD001 
 
 
 
  
Protocol Number:  CRAD001LIC01  
  
Version Date:  
 
  
Amendment Number: 01 
I have read and understood the protocol and agree to implement the study in accordance with 
the procedures set forth in the protocol and in accordance with the sponsor‟s guidelines and 
all applicable government regulations and the International Conference on Harmonisation 
Good Clinical Practice Guidelines E6 (ICH-GCP), Good Clinical Practices (GCP) as 
described in the United States Code of Federal Regulations (CFR) – 21 CFR parts 50, 56, and 
312, and the International Conference on Harmonisation (ICH) document “Guidance for 
Industry – E6 Good Clinical Practice:  Consolidated Guidance” dated April 1996. 
I will provide adequate protocol training to my associates, colleagues, and employees 
assisting in the conduct of the study. 
I will obtain Institutional Biosafety Review Committee (or equivalent) and Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) approval of the Protocol and 
Patient Informed Consent Form prior to enrollment of patients in the study.  I understand that 
any modifications to the protocol made during the course of the study must first be approved 
by the Institutional Review Committee (or equivalent) and IRB/IEC except when such 
modification is made to remove an immediate hazard to the patient. 
I will ensure that a fully executed Patient Informed Consent is obtained from each patient 
prior to initiation of any study procedures. 
I will report (within 24 hours) any serious adverse event that occurs during the course of the 
study in accordance with the procedures described in Section 8.1 of the protocol. 
I will allow the sponsor, Novartis and its agents, as well as the United States of America 
(USA) Food and Drug Administration (FDA) and other regulatory agencies, to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, ensuring 
patient confidentiality. 
 
 
 
 
 
  
Investigator‟s Name 
 
Signature 
 Date 
 


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STEERING COMMITTEE 
 
 
 
 
 
Name and Affiliation 
 
 
 
Name and Affiliation 
 
 
 
Name and Affiliation 


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13 
References (available upon request) 
Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. A phase 2 Study with a Daily Regimen of 
the Oral mTOR RAD001 (everolimus) Inhibitor in patients with metastatic clear cell renal 
cancer. Cancer 2009;115:2438-2446. 
Amato RJ, Misellati A, Khan M, Chiang S. A Phase II trial of RAD001 in patients (Pts) with 
metastatic renal cell carcinoma (MRCC). J Clin Oncol 2006;24 (ASCO Annual Meeting 
Proceedings Part I):4530.  
Amato RJ. Chemotherapy for renal cell carcinoma. Semin Oncol 2000;27:177-186. 
American Cancer Society (2005) Cancer Facts & Figures 2005. Atlanta: American Cancer 
Society. 
Atkins MB, Hildalgo M, Stadler WM, et al. Randomized Phase II study of multiple dose 
levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with 
advanced refactory renal cell carcinoma. J Clin Oncol 2004;22(5):909-918. 
Awada A, Hendlisz A, Gil T, et al. Phase 1 safety and pharmacokinetics of BAY 43-9006 
administered for 21 days on/7 days off in patients with advanced, refractory solid tumors. Br J 
Cancer 2005;92:1855-1861. 
Beck SD, Patel MI, Snyder ME, et al. Effect of papillary and chromophobe cell type on 
disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol. 
2004;11:71-77. 
Bjormnsti MA, Houghton PJ. The TOR pathway. A target for cancer chemotherapy. Nature 
Rev Cancer 2004;4:335-338. 
Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477-2490. 
Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and 
immunohistochemical study of 105 tumors. Mod Pathol 1997;10:537-544. 
Dutcher JP, Szczylik C, Tannir N, et al. Correlation of survival with tumor histology, age, and 
prognostic risk group for previously untreated patients with advanced renal cell carcinoma 
(adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN). J Clin Oncol 2007;25 
(ASCO Annual Meeting Proceedings):5033. 
Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. 
Lancet 2007;370:2103-2111. 
Ferlay J, Bray F, Pisani P, Parkin DM. Cancer Incidence, Mortality and Prevalence 
Worldwide GLOBOCAN 2000, Version 1.0. IARC Cancer Base No. 5. Lyon, IARCPress, 
2001. 
Figlin RA. Renal cell carcinoma: Management of advanced disease. J Urol 1999;161:381- 
387. 
George DJ, Kaelin WG. The Von Hippel-Lindau protein, vascular endothelial growth factor, 
and kidney cancer. N Engl J Med 2003;349:419-421. 


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Gnarra JR, Dressler GR. Expression of Pax-2 in human renal cell carcinoma and growth 
inhibition by antisense oligonucleotides. Cancer Res 1995;18:4092-4098. 
Hudes G, Carducci M, Tomczak P, et al. A Phase 3, randomized, three arm study of 
temsirolimus (TEMSR) or interferon-alpha (IFN), or the combination of TEMSR + IFN in the 
treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). J 
Clin Oncol 2006;24 (ASCO Annual Meeting Proceedings, No 18S Part II of II): LBA4. 
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 2007;356:2271-2281. 
Iliopoulus O, Levy AP, Jiang C, et al.  Tumour suppression by the human Von Hippel-Lindau 
protein. Proc Natl Acad Sci USA 1996;93:10595-10599. 
Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes: properties and 
polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 2004;369(1):89-104. 
Kay A, Motzer R, Figlin R, et al. Updated data from a phase III randomized trial of 
everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). Genitourinary 
Cancers Symposium 2009, American Society of Clinical Oncology.  Abstract 278. 
Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 
2004;22:4991-5004. 
Kovacs G, Brusa P, De Riese W. Tissue-specific expression of a constitutional  
3;6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer 
1989;43:422-427. 
Lane H, Tanaka C, Kovarik J, et al. Preclinical and clinical pharmacokinetic/ 
pharmacodynamic (PK/PD) modeling to help define an optimal biological dose for the oral 
mTOR inhibitor RAD001 in oncology. J Clin Oncol 2003;22:237A. 
Linehan WM, Zbar B, Bates SE, Zelesky MJ, Yang JC. Cancer of the kidney and ureter. 
Cancer: Principles and Practice of Oncology, 6th edition, 2001;1362-1383. 
Loomba R, Rowley A, Wesley R et al (2008). Systematic review: the effect of preventive 
lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7): 519-28. 
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-
cell carcinoma. N Engl J Med 2007;356:115-124. 
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everloimus in advanced renal cell 
carcinoma:  A double-blind, randomized, placebo-controlled Phase III trial.  Lancet 
2008;372:449-456. 
Pignot G, Elie C, Conquy S, et al. Survival analysis of 130 patients with papillary renal cell 
carcinoma: prognostic utility of type 1 and type 2 subclassification. Urology 2007;69(2):230-
235. Epub 2007 Jan 31. 
Porter LL, Burris HA, Jones SF, et al. Summary of results in patients with metastatic renal 
cell cancer (RCC) from Phase 1 studies of RAD001 (everolimus) [abstract]. 2006;ASCO 
Annual Meeting Proceedings:06-AB-33581-ASCO. 


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Sorrell M, Belongia E, Costa J et al (2009). National Institutes of Health Consensus 
Development Conference Statement: Management of Hepatitis B. Ann Intern Med 150: 104-
110. 
 
Storkel S, and van den Berg E. Morphological classification of renal cancer.  World J Urol 
1995;13(3):153-158. 
Thomas GV, Tran C, Millinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to 
inhibitors of mTOR in kidney cancer. Nature Med 2006;12(1):122-127. 
Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an antivascular 
endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 
2003;349(5):427-434. 


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14 
Post-Text Supplements 
 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference: 
Eligibility 
 Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
Measurable disease – the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
Measurable lesions – lesions that can be accurately measured in at least one dimension 
with longest diameter  20 mm using conventional techniques or 10 mm with spiral CT 
scan. 
Non-measurable lesions – all other lesions, including small lesions (longest diameter  
<20 mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 
 All measurements should be taken and recorded in metric notation, using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.  
 The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
 Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
Methods of Measurement  
 CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen, and pelvis.  Head and neck tumors and those of extremities usually require specific 
protocols. 
 Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung; however, CT is preferable.  
 When the primary endpoint of the study is objective response evaluation, ultrasound should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules.  Ultrasound might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 


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 The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been 
fully and widely validated. Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may only be available in some sites. Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in specialized sites. However, such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
 Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
 Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and  recorded and 
measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
 A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the presence 
or absence of each should be noted throughout follow-up.  
Response Criteria 
Evaluation of target lesions 
 Complete Response (CR): 
Disappearance of all target lesions. 
 Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
 Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions. 
 Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
 
 
 
 
 


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Evaluation of non-target lesions 
 Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. 
 Incomplete Response/         
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.*  
* Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient‟s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
 In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR status. 
Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed.  In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. 
 To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.  


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 In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol.  
Duration of overall response 
 The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 
Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
 The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD. This time interval should take 
into account the expected clinical benefit that such a status may bring to the population under 
study.  
Response review 
 For studies where the response rate is the primary endpoint it is strongly recommended that 
all responses be reviewed by an expert(s) independent of the study at the study‟s completion.  
Simultaneous review of the patients‟ files and radiological images is the best approach.  
Reporting of results 
 All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned 
one of the following categories: 1) CR, 2)PR, 3) SD, 4) PD, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown 
(not assessable, insufficient data). 
 All of the patients who met the eligibility criteria should be included in the main analysis of 
the response rate.  Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific. 
 All conclusions should be based on all eligible patients. 
 Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly reported.   
 The 95% confidence intervals should be provided. 
 

SAP_000.pdf: 
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Clinical Development & Medical Affairs 
RAD001, Everolimus
CRAD001LIC01 / NCT01206764
An Open-Label, Multi-Center Phase 2 Study to Evaluate Everolimus as 
Monotherapy Treatment for Patients with Metastatic Recurrent and/or 
Unresectable Renal Cell Carcinoma (EVERMORE) 
Trial: Phase II 
RAP Module and appendix deliverables 
Author (s) 
 
Document type: 
RAP  
Document status: 
Final 
Release date: 
22SEP2017 
Number of pages: 
101 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 


 
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List of abbreviations used in the text  
 
ATC 
Anatomical Therapeutic Chemical 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ECG 
Electrocardiogram 
GGT 
Gamma-Glutamyl-Transferase 
HDL 
High Density Lipoprotein 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic Resonance Imaging 
QC 
Quality Control 
ORR 
Objective Response Rate 
PFS 
Progression Free Survival 
PT 
Preferred Term 
RAP 
Reporting Analysis Plan 
RCC 
Renal Cell Carcinoma 
SAE 
Serious Adverse Event 
SBR 
Senior Biostatistical Review 
SI 
Standard International 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


 
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Table of contents 
1. 
Introduction .......................................................................................................................... 6 
1.1 
Background and rationale ........................................................................................................ 6 
1.2 
Study Description .................................................................................................................... 6 
2. 
Study Objectives .................................................................................................................. 6 
2.1 
Primary .................................................................................................................................... 6 
2.2 
Secondary ................................................................................................................................ 6 
3. 
Study Design ........................................................................................................................ 6 
3.1 
Assessments ............................................................................................................................ 7 
3.2 
Study Medication .................................................................................................................... 7 
3.3 
Treatment Arms....................................................................................................................... 7 
3.4 
Randomization and Blinding Procedure .................................................................................. 7 
3.5 
Sample size calculation ........................................................................................................... 8 
4. 
Endpoints .............................................................................................................................. 8 
4.1 
Primary Endpoint .................................................................................................................... 8 
4.1.1 Progression Free Survival Rate ............................................................................................... 8 
4.2 
Secondary Endpoints ............................................................................................................... 8 
4.2.1 Disease Control Rate (SD + PR + CR) .................................................................................... 8 
4.2.2 Objective Response Rate and Duration ................................................................................... 8 
4.2.3 Overall Survival ...................................................................................................................... 8 
4.2.4 Safety Endpoints ..................................................................................................................... 8 
5. 
Analysis Populations ............................................................................................................ 8 
6. 
Interim Analysis ................................................................................................................... 9 
7. 
Statistical Analysis Methods ................................................................................................ 9 
7.1 
General Principles ................................................................................................................... 9 
7.2 
Data handling .......................................................................................................................... 9 
7.2.1 Calculation of time-to-event .................................................................................................... 9 
7.2.2 RECIST Criteria .................................................................................................................... 10 
7.2.3 Handling of Missing and Incomplete Data ............................................................................ 10 
7.3 
Patient Disposition ................................................................................................................ 13 
7.4 
Protocol Deviation................................................................................................................. 13 
7.5 
Demographic and Baseline Characteristics ........................................................................... 13 
7.6 
Time to Event Analysis ......................................................................................................... 14 
7.7 
Other Efficacy Analysis ........................................................................................................ 15 
8. 
Safety Analyses .................................................................................................................. 15 


 
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8.1 
Adverse Events ...................................................................................................................... 15 
8.2 
Cardiac assessments .............................................................................................................. 16 
8.3 
Laboratory Tests .................................................................................................................... 16 
8.4 
Vital Signs ............................................................................................................................. 17 
8.5 
Other Safety Assessments ..................................................................................................... 17 
8.6 
Dosage Administration and Compliance ............................................................................... 17 
9. 
Programming/QC Plan and Software/System .................................................................... 18 
10. 
Technical programming specifications .............................................................................. 18 
10.1 
General notes .................................................................................................................... 18 
10.2 
Decimal places.................................................................................................................. 18 
10.3 
Font size ........................................................................................................................... 19 
11. 
Table and Listings shells .................................................................................................... 19 
 
 
 


 
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1. INTRODUCTION 
1.1 Background and rationale 
The reporting analysis plan (RAP) is based upon section 10 'Statistical Methods and Data Analysis' of the 
study protocol. The RAP has been prepared in compliance with ICH E9.  
Statistical analyses will be carried out using all available case report form (CRF) data. 
1.2 Study Description 
This is an open-label, multi-center Phase II study to evaluate RAD001 (everolimus) as monotherapy 
treatment for patients with metastatic recurrent and/or unresectable renal cell carcinoma (RCC). 
The purpose of this study is to demonstrate the safety and efficacy of RAD001, an mTOR inhibitor, as 
monotherapy in patients with metastatic carcinoma of the kidney who have not received prior systemic 
treatment, other than cytokine therapy. The proposed dose and schedule (10 mg/day) is based on various 
Phase 1 and Phase 2 studies (monotherapy and combination therapy) in advanced cancers, including RCC, 
and a large controlled Phase 3 study (RECORD-1).  
Current standard therapies (chemotherapies and cytokine-based therapies) have produced few and short-
lived tumor responses, and are associated with severe toxicities. The efficacy of RAD001 as monotherapy 
in patients who were previously treated with cytokine therapy (Amato et al., 2009), and whose disease had 
progressed on VEGF-tyrosine kinase inhibitor therapy (Motzer et al., 2008) were recently reported.  
2. STUDY OBJECTIVES 
2.1 Primary 
The primary objective of the study is to evaluate Progression Free Survival (PFS) rate over time. 
2.2 Secondary 
1. To evaluate the disease control rate (stable disease [SD] + partial response [PR] + complete response 
[CR]) (SD + PR + CR); 
2. To evaluate the objective response rate (ORR; where ORR = CR + PR); 
3. To evaluate duration of response; 
4. To evaluate OS; 
5. To describe the safety profile of RAD001. 
3. STUDY DESIGN 
This is an open-label, multi-center, single arm Phase II study. 
It is anticipated that approximately 142 patients will be enrolled in the study. 
The target population is patients with any Memorial Sloan-Kettering Cancer Center prognosis metastatic 
recurrent and/or unresectable clear cell or non-clear cell carcinoma of the kidney. Patients who have 
received prior cytokine therapy are permitted to participate in the study. 
 


 
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3.1 Assessments 
Upon provision of written, informed consent patients will be given a unique 9 digit patient number.  This 
will be a combination of their 4 digit center number and 5 digit subject number. 
The patient will be assessed for their eligibility to take part in the study (i.e. receive study medication) 
using the inclusion and exclusion criteria stated in the protocol (Sections 5.1 and 5.2).  If the patient fails 
to start on treatment for any reason, this reason will be entered on the Screening Log.  No data for screen 
failures will be entered into the clinical database. 
Patients who are eligible for treatment will be dispensed their study medication on completion of their 
baseline visit.  Patients should present to the clinic on Day 1 and Day 15 of treatment Cycles 1, 2, and 3 
and Day 1 of each subsequent treatment cycle to complete the assessments detailed in Table 6 of the 
protocol, until completion of treatment which will occur when the patient experiences disease progression, 
unacceptable toxicity, death or discontinues from the study for any other reason.  An end of study 
treatment assessment should then be performed.  All patients will have a follow-up visit 28 days after the 
last dose of the study drug to follow for adverse events (AEs) and serious adverse events (SAEs) that may 
have occurred after discontinuation from the study. 
Tumor response will be assessed at 8 weeks (+/- 1 week), and every 12 weeks (+/- 1 week) thereafter until 
determination of disease progression and at the end of the study. 
Patients who discontinue treatment, or are withdrawn from treatment by the investigator, for any reason, 
should complete an early discontinuation assessment. All patients who discontinue treatment will continue 
to have tumor assessments at 12-week intervals until the initiation of new cancer therapy.   
The efficacy assessments for this study will be the assessment of tumor response/progression and survival 
status. Tumor response/progression assessments should be performed by a Computerized Tomography 
(CT) or Magnetic Resonance Imaging (MRI) scan.  The same imaging modality used at screening must be 
used for all subsequent follow-up assessments. 
Safety assessments will consist of evaluating AEs and SAEs, laboratory parameters including hematology, 
chemistry, vital signs and documentation of all concomitant medications and/or therapies.  The Karnofsky 
Performance Status score will also be recorded.    
3.2 Study Medication 
Eligible patients will receive RAD001 (10 mg/day) continuously from Visit 2 (Cycle 1, Day 1) until 
disease progression, unacceptable toxicity, or death or discontinuation from the study for any other reason. 
Patients will be instructed to take two 5 mg RAD001 tablets (one tablet after another) orally, with a glass 
of water at the same time each day, in a fasting state or with a light fat-free meal. 
Dose adjustments are permitted in those patients who are unable to tolerate the protocol-specified dosing 
schedule. Rules for the interruption or modification of dosing are described in Table 2, Table 3 and Table 
4 of the protocol. 
3.3 Treatment Arms 
This is a single arm study with all patients receiving RAD001 (10mg/day). There is no control group for 
this study. 
3.4 Randomization and Blinding Procedure 
Since this study is an open-label, single arm study no randomization or blinding procedures are required. 


 
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3.5 Sample size calculation 
The sample size for this study was determined with reference to estimating a CI for the PFS rate at 10 
months, assuming (for simplicity) the use of the normal approximation to the binomial distribution and 
assuming that a CI for a proportion is based on this normal approximation. To be able to estimate a 95% 
CI for the PFS rate, centered at 0.50, and having an expected total interval width of approximately 0.27, 
requires a sample size of 55 patients in each of the 2 cohorts (first- and second-line). With 95% 
confidence, the expected total interval width is approximately 0.19 for all 110 patients (both cohorts 
combined).   
4. ENDPOINTS 
4.1 Primary Endpoint 
4.1.1 Progression Free Survival Rate 
The primary endpoint for this study is progression free survival (PFS). The derivation for this is given in 
Section 7.2.1.   
4.2 Secondary Endpoints 
 
 
 
 
4.2.1 Disease Control Rate (SD + PR + CR) 
Disease control rate is defined in Section 7.2.2.   
4.2.2 Objective Response Rate and Duration  
Objective response rate and duration are defined in Section 7.2.2.   
4.2.3 Overall Survival 
Overall survival is defined in Section 7.2.1.   
4.2.4 Safety Endpoints 
The safety endpoints defined for this study are frequency of adverse events and laboratory values. 
5. ANALYSIS POPULATIONS 
A full description of the patient populations is given below: 
Intent-to-treat (ITT) population: Consists of all patients treated with RAD001.  
Safety population: Consists of all patients who received at least one dose of the study drug and who have 
at least one post-baseline safety assessment. Please note that the statement that a patient had no adverse 
events (on the Adverse Event CRF) constitutes a safety assessment. Patients who have received at least 
one dose of study drug but who have no post-treatment safety data of any kind would be excluded from 
the safety population. 
The ITT population will be the primary population of interest for the efficacy analyses. The safety 
population will be used when presenting safety data. 
It should also be noted that patients who give informed consent and record any baseline data but are found 
not to meet the inclusion/exclusion criteria and are not given study medication will be classed as screening 
failures.  No data for these subjects will be recorded in the clinical database.  Should a patient receive 


 
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study medication and it is subsequently found that they fail to meet inclusion/exclusion criteria then the 
patient will be included in the ITT population (and safety if they have at least one post-baseline 
assessment).  
6. INTERIM ANALYSIS 
There is no interim analysis planned for this study. 
7. STATISTICAL ANALYSIS METHODS 
7.1 General Principles 
The number of patients in the population of interest will be presented on each table, shown as N=XXX.  
For data summarized by visit, the N will be the number of patients in the population of interest still 
present in the study at that visit.  See Section 7.3 on Patient Disposition for a full definition. 
Data from unscheduled visits will be listed only, except for the End of Treatment row in safety tables if 
the unscheduled visit is the patient's last on-treatment record.   
No visit windowing will be applied for this study.  However, it will be checked when summarizing any 
data that are collected by visit that on-treatment assessments did actually take place prior to the end of 
treatment date.  Should an on-treatment assessment be performed later than the date of last treatment, the 
data will be listed but will not be included in the summary tables.  The timing of off-treatment data will be 
checked again prior to database lock as data collected within 30 days of end of treatment may be 
considered valid for use in summary tables in which case this definition will be updated to allow for these 
cases. 
It should be noted this rule does not cover adverse event data which have a separate definition of 
on-treatment. 
7.2 Data handling 
7.2.1 Calculation of time-to-event  
In the following definitions the time of study entry has been defined as date of first dose of study 
medication (taken from the dosage administration record on the CRF).  
The date of last contact (used in the censoring rules below) is collected on the End of Study/Survival 
Information page of the CRF.  However, it should be noted that it is only planned for contact with patients 
to take place at the clinic visits and so the date of last contact captured on the CRF should always be equal 
to the date of last visit attended. 
Progression Free Survival: 
PFS is defined as the time from date of first dose of study medication until the date of the first 
documented disease progression or death due to any cause. Date of progression and date of death will be 
captured on the CRF. 
For the purpose of calculating the PFS Rate if a patient has not progressed or died at the date of analysis 
cut-off, or when he/she received further anticancer therapy, then their time to progression or death will be 
censored at the time of last tumor assessment, before the first cut-off date or the anticancer therapy date.   
Progression Free Survival Rate: 


 
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The PFS rate is defined as the survival function at the end of the time point based on a Kaplan-Meier 
analysis of the time to either progression (as per the local radiological review) or death (see next section 
for handling of censored data).  
The time points at which PFS rate will be summarized are: 8 weeks, 20 weeks, 32 weeks, 44 weeks, 56 
weeks and every 12 weeks thereafter as appropriate. 
Overall Survival: 
Overall survival is defined as the time fromdate of first dose of study medication until death due to any 
cause.  The date of death will be captured on the CRF. 
If a patient is still alive and not lost to follow-up at the end of the study then their time to death will be 
censored at the date of last contact date, as recorded on the CRF. 
If the patient has been lost to follow-up by the end of the study then their time to death will be censored at 
the date of last   contact as recorded on the CRF.  
In the event that a date of last contact has not been recorded on the CRF, then the date of the last 
assessment recorded should be used instead. 
Duration of Response: 
The duration of response (CR or PR) is defined as the time from from the first occurrence  of PR or CR 
(as per the local radiological review) until the date of the first documented disease progression or death 
due to underlying cancer. If a patient has not had an event, duration of response is censored at the date of 
last adequate tumor assessment prior to starting new anticancer therapy. 
7.2.2 RECIST Criteria 
Disease Control Rate: 
The disease control rate is based on the data as per local radiological review following the RECIST V1.0  
criteria. The disease control rate is defined as the proportion of patients with CR, PR, or SD. 
 
Objective Response Rate: 
The overall tumor response will be based on the data as per local radiological review, following RECIST 
criteria. The ORR is defined as the proportion of patients with CR or PR. 
7.2.3 Handling of Missing and Incomplete Data  
Prior Antineoplastic Therapy: 
Missing or partial dates of antineoplastic therapy will be imputed in order to determine the duration of 
treatment with each therapy.  If the end date of antineoplastic therapy is missing or partial the latest 
possible date will be imputed up until the day prior to start of study medication (since antineoplastic 
therapy use is pre-study).  Partial start dates of antineoplastic therapy will be imputed as the earliest 
possible date.  It should be noted that use of antineoplastic therapy during the study would be considered a 
protocol deviation.  Imputed dates will be for the purpose of calculating duration only and the listing 
should display only the partial date information recorded on the CRF.  
Adverse Events (AEs): 
In the event of a missing severity for a patient’s adverse event, no imputation will be made but this should 
be raised with Data Management for further discussion since no missing data would be expected for this 
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Partial start dates for adverse events will be imputed in order to determine if the event is treatment 
emergent. The imputation of partial start dates of adverse events will follow the following rules:  
Adverse Event Start Date Imputation 
Available Data (YYYY-MM-DD) 
Imputation Rule 
YYYY 
If the year part is the same as the year of first dose 
of study medication, impute with the date of first 
dose of study medication. 
Otherwise, impute with the 1st of January of the 
known year. 
YYYY-MM 
If the known part is same as the date of first dose of 
study medication then impute with date of first dose 
of study medication. 
Otherwise, impute with the 1st of the known month. 
All missing 
If the known end date is after date of first dose of 
study medication then impute with the date of first 
dose of study medication. 
Otherwise, impute with the date of informed 
consent.  
 
Concomitant Medications/Significant Non-Drug Therapies: 
Patial start and end dates of medications will be imputed to determine if a medication is concomitant. The 
imputation of partial start and/or end dates of medcations will follow the following rules: 


 
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Medication Start Date 
Medication End Date 
Available Data  
(YYYY-MM-DD) 
Imputation Rule  
Available Data  
(YYYY-MM-DD) 
Imputation Rule  
YYYY 
If the year part is the 
same as the year of first 
dose of study 
medication, impute with 
the date of first dose of 
study medication. 
Otherwise, impute with 
the 1st of January of the 
known year. 
YYYY 
Impute as 31'st 
December of the known 
year. 
YYYY-MM 
If the known part is 
same as the date of first 
dose of study 
medication then impute 
with date of first dose of 
study medication. 
Otherwise, impute with 
the 1st of the known 
month. 
YYYY-MM 
Impute as the last day of 
the known month. 
All missing 
If the known end date is 
after date of first dose of 
study medication then 
impute with the date of 
first dose of study 
medication. 
Otherwise, impute with 
the date of informed 
consent.  
All missing 
Impute as date of last 
contact 
 
Disease Progression: 
If disease progression or death is documented after one single missing tumor assessment, the 
actual event date of disease progression/death will be used for the PFS event date. If disease 
progression is documented after two or more missing tumor assessments, the PFS time of the 
patient will be censored at the date of the last tumor assessment with overall lesion response of 
CR, PR or SD.  
Additional sensitivity analyses will be performed where: 


 
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1. The actual event date of disease progression/death will be used for the PFS event date, 
irrespective of whether it is preceded by missing tumor assessments;  
2. In case of a documented progression/death after one or more missing tumor assessments, 
disease progression is considered to have occurred at the next scheduled tumor assessment after 
the date of the last tumor assessment with overall lesion response of CR, PR, or SD.  
Duration of Response: 
The same rules for missing data for calculation of duration of response will be applied as for PFS 
described above. 
7.3 Patient Disposition 
Patients will be defined as enrolled if they gave written, informed consent to enter the study.  Disposition 
will be assessed at the end of the time of data cut-off for analysis (or at end of treatment if the patient 
withdraws from the study before then).  A patient will be defined as completing treatment if they have not 
been recorded as discontinuing treatment on the End of Study page of the CRF.  If they record any reason 
for discontinuing treatment on the End of Study page they will be considered as an early withdrawal from 
treatment.  Their primary reason for early discontinuation of treatment will be summarized. 
The disposition table will also show the number and percentage of patients in each of the analysis 
populations and in each stratum (first-line patients and second-line patients).  The summaries of safety 
data that are collected by visit (i.e. laboratory tests and vital signs etc but not adverse events or 
concomitant medications) will present data relative to the number of patients still present in the study at 
that visit.  A patient will be defined as being still present in the study at Visit X if they have data at Visit X 
or they have data at a later visit, noting that it cannot be assumed a patient was still in the study at an on-
treatment visit if the only later data are from a follow-up visit.  A patient with at least one on-treatment 
visit will be included in the End of Treatment row, even if that one visit is an unscheduled visit.   
7.4 Protocol Deviation 
Protocol deviations will be identified prior to database lock.   
Major protocol deviations will be summarized and tabulated. Other protocol deviations will also be 
identified, summarized and listed. 
 
7.5 Demographic and Baseline Characteristics  
Demographic data including date of birth, sex, race and ethnicity will be collected at Screening Visit 1a.  
Age will be derived as the age in years at Screening Visit 1a.  Age, sex, race, ethnicity, height, weight, 
BMI and Karnofsky Performance Status will be summarized for the ITT population.  In the event of a 
difference between the safety and ITT populations, this summary of demographic data will be repeated for 
the safety population. 
The date of informed consent, any failed inclusion or exclusion criteria and the source of subject referral 
will be listed only.   
Relevant medical history and current medical conditions are collected at Screening Visit 1a.    The number 
of patients with at least one relevant medical history or current medical condition and at least one active 
problem will be presented and a summary will also be provided of the medical history by body system and 
preferred term.  These summaries will be performed on the ITT population. 


 
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A pregnancy test is performed at Screening Visit 1a and Baseline Visit 1b and the data collected will be 
listed only.  If any unscheduled pregnancy tests are performed during the treatment or follow-up periods 
of the study these data will also be listed.  
Each patient's prior antineoplastic therapy is recorded at Screening Visit 1a.  The number of patients 
taking each therapy type overall and by setting will be presented along with the total number of separate 
courses of therapy.  Each separate record entered on the CRF will be counted as a separate course of 
therapy.  For each therapy type/setting combination the overall best response per patient will be 
determined as either Complete Response (best), Partial Response, Stable Disease, Complete Response 
(unconfirmed), Unknown, Not Applicable or Progressive Disease (worst).  The total duration of time per 
therapy type/setting will be calculated for each patient based on the CRF data.  It is expected the duration 
will be calculated in months and should take into account any overlap in dates recorded on the CRF.  See 
Section 7.2.2 regarding the handling of partial dates.  Summaries of prior antineoplastic therapy will be 
performed on the ITT population, and in the event of a difference between the safety and ITT populations 
will be repeated for the safety population. 
A chest x-ray will be performed at Screening Visit 1a.  These data will be summarized presenting the 
investigator's assessment of abnormality for the safety population.   
Data for all chest x-ray assessments throughout the study (including unscheduled) will be listed. 
Medications (other than study medication) and significant non-drug therapies used throughout the 
treatment period are captured on the CRF.  These will be coded using the Novartis Drug and Therapy 
Dictionary (Version Sep 2009).  Those that start on or after the first day of dosing with study medication 
and no later than 30 days after the last dose of study medication, and those that end after the start of study 
medication (even if started prior to study medication) will be defined as concomitant and will be 
summarized.  Summaries will be presented by Anatomical Therapeutic Classification (ATC) class and 
preferred term for the safety population.  If a patient takes multiple medications/therapies within an ATC 
class or within an ATC class and preferred term, the patient will be counted once.   
7.6 Time to Event Analysis 
At each visit where tumor assessment is performed the CRF will capture the RECIST assessment of tumor 
response according to local radiological review.  If disease progression occurs then the End of Treatment 
pages of the CRF should be completed. 
The patient's status at the end of study will be summarized with patients being classed as either alive, dead 
or lost to follow-up and either having had a relapse/recurrence or not.  Further, if the patient has died it 
will be summarized whether death was due to study indication or not.  These summaries will be performed 
on the ITT population.   
The time to event variables are defined in Section 7.2.1. 
No statistical test of hypotheses will be performed in this study. PFS rate and 95% confidence intervals 
will be presented graphically and tabulated, overall and by strata, using the Kaplan-Meier product-limit 
method.  The resulting median PFS will be presented along with 95% CIs.  These analyses will be 
performed on the ITT population. 
The analysis of PFS will be repeated for the sensitivity analyses described in Section 7.2.3 and also for 
Duration of Response. 
For Overall Survival the Kaplan-Meier curve will be displayed and the median, 25th and 75th percentile of 
the Kaplan-Meier estimate will be reported for the ITT population. 


 
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7.7 Other Efficacy Analysis 
Disease control rate and ORR (as defined in Section 7.2.2) will be summarized by percentage of 
subjects along with 95% CIs for the ITT population. 
8. SAFETY ANALYSES 
All Summaries of safety data will be conducted on the safety population. 
8.1 Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) Version 12.1 
to provide the system organ class (SOC) and preferred term for each AE. 
An adverse event will be defined as treatment emergent if it begins on or after the first day of dosing with 
study medication and no later than 30 days after the last dose of study medication.  It is expected that 
adverse event monitoring will continue for at least 4 weeks after the last dose of study medication but new 
events occurring after the end of the treatment period will not be recorded on the CRF (unless they are 
serious or lead to death).   
Since adverse events occurring prior to start of study or between signing informed consent and start of 
study medication should be considered as medical history, it is anticipated that all adverse events will be 
treatment emergent adverse events.  However, in the event of any non-treatment emergent adverse events 
occurring, these will be indicated on the adverse event listings.  Non-treatment emergent adverse events 
are defined as events that begin prior to the first day of dosing. If these events are Serious Adverse Events 
(SAEs) then they will also be summarized. 
The number of patients experiencing each of the following will be summarized: 
 
At least one treatment emergent adverse event (TEAE) 
 
At least one SAE 
 
At least one SAE with a suspected relationship to study medication 
 
At least one adverse TEAE event leading to death 
 
At least one TEAE leading to modification of study medication 
 
At least one TEAE leading to permanent discontinuation of study medication 
 
At least one severe TEAE 
 
At least one TEAE with a suspected relationship to study medication 
 
Serious adverse events will be indicated on the CRF, as will adverse events leading to modification or 
permanent discontinuation of study medication.  The addition of non-drug therapy will not be classed as a 
modification of study medication.   
Adverse events resulting in death are not indicated on the CRF so will be defined as adverse events 
experienced by a patient who died, with a severity of life-threatening and an end date either missing or 
equal to the patient's date of death.  If a patient has more than one adverse event identified as leading to 
death then a review by the Novartis medical contact should be performed to determine if each event led to 
death or whether one supersedes the other (e.g. underlying life threatening condition but patient actually 
died in an unrelated fatal accident). 
All treatment emergent adverse events will be summarized by SOC and preferred term.  If a patient 
experiences multiple events within a SOC the patient will only be counted once within that SOC. If a 


 
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patient experiences multiple preferred terms with in a SOC the patient will be counted for each preferred 
term but only only once for each unique preferred term. Deaths reportable as SAEs and non-fatal SAEs 
will each be summarized by SOC and preferred term and also listed. 
Deaths as reported on the Survival Information and Study Evaluation Completion CRF will be listed.  
The handling of missing or partial start and end dates of adverse events, and missing assessments of 
severity and relationship is covered in Section 7.2.2.        
All adverse events captured on the CRF will be listed, regardless of severity, relationship or treatment 
emergence. 
8.2 Cardiac assessments 
Standard 12 lead ECG assessments will be performed at the investigator’s discretion according to local 
practice, or if there are signs and symptoms of cardiotoxicity. These data will be listed. 
8.3 Laboratory Tests   
Each hematology, blood chemistry and serum lipid parameter will be summarized at the Baseline visit 
(Visit 1a), each cycle, the End of Treatment visit (last assessment up to and including 30 days after last 
dose date, including unscheduled assessments).  The change from baseline will be presented at all post-
baseline visits where this can be calculated.   
Each coagulation parameter is collected at Screening Visit 1a and Day 1of Cycle 2.  These data will be 
listed. 
Each urinalysis parameter will be collected at Screening Visit 1a and subsequently as clinically required.  
These data will be listed. 
The hematology parameters collected are: 
 
White blood cells (WBC), hemoglobin, hematocrit, platelets 
 
Either: absolute neutrophils, absolute lymphocytes, absolute eosinophils, absolute basophils and 
 
absolute monocytes 
 
Or: percentage neutrophils, percentage lymphocytes, percentage eosinophils, percentage 
 
basophils and percentage monocytes 
 
The CRF allows for "other" differential counts to be recorded.  These results will be listed only. 
 
The blood chemistry parameters collected are: 
Urea, blood urea nitrogen, creatinine, lactate dehydrogenase (LDH), total protein, fasting glucose, 
phosphorus, serum calcium, serum corrected calcium (calculated at baseline only), electrolytes 
(sodium, magnesium, chloride, and potassium), total bilirubin, gamma-glutamyl-transferase 
(GGT), albumin, alkaline phosphatase, alanine aminotransferase (ALT) (or SGPT), aspartate 
aminotransferase (AST) (or SGOT), uric acid 
The serum lipid parameters collected are: 
 
Total cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL) 
The coagulation parameters collected are: 
 
Prothrombin time (PT), International normalized ratio (INR) 


 
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All laboratory test results will be converted into Standard International (SI) Units by Data Management.  
Summary tables will present the results in SI Units.   
The normal ranges for each parameter will also be included on the database so results can be calculated as 
being below, within or above the normal range. 
Laboratory results will be graded using the Common Toxicity Criteria for Adverse Events (CTCAE) v3.0 
document for each parameter where a CTC grade is defined.  The parameters with grades defined are: 
Hematology: WBC, hemoglobin, platelets and absolute neutrophils 
Blood Chemistry: Creatinine, fasting glucose, sodium, magnesium, potassium, albumin, bilirubin, GGT, 
SGOT (AST), SGPT (ALT) and alkaline phosphatase 
Serum Lipid Profile: total cholesterol, triglycerides 
A shift table will be presented showing the change from screening to most extreme post-screening value 
(including the End of Treatment visit and any unscheduled assessments) in CTC grading. 
In the event that an unscheduled laboratory test is performed the data from this test will be listed.  
Unscheduled visit results will only be summarized if the unscheduled visit supersedes the schedules visit’s 
results.  I.e. if a scheduled visit is missed, or the laboratory sample is not taken, or there are no results 
from the laboratory sample, but there is an unscheduled visit occurring prior to the next scheduled visit 
then the results from the unscheduled visit should be used instead. 
8.4 Vital Signs  
Body temperature, pulse rate, systolic and diastolic blood pressure will be collected at Screening Visit 1a, 
Baseline Visit 1b, day1 of each cycle and the End of Treatment visit.  Height and weight will be collected 
at Screening Visit 1a only.  The vital signs data, including any unscheduled assessments, will be listed. 
8.5 Other Safety Assessments 
The Karnofsky Performance Status will be assessed at Screening Visit 1a, Baseline Visit 1b, at day 1 of 
each subsequent cycle and at End of Treatment.  The baseline data will be summarized as well as change 
from baseline for post-baseline visits. All data, including unscheduled assessments, will be listed. 
Pulmonary function test (including spirometry, diffusion capacity of carbon monoxide and room air O2 
saturation at rest) will be performed at screening, as medically necessary if there is evidence of 
non-infectious pneumonitis, and at the end of the study.  These data will be listed.  
8.6 Dosage Administration and Compliance 
Study medication, RAD001, is given as a 10mg oral dose to be taken daily until the end of treatment.  The 
dose administered throughout the entire treatment period should be captured on the CRF, including any 
changes in dosing initiated by the investigator for patients unable to tolerate the planned dosage, and any 
changes as a result of lack of compliance with the planned dosing regimen by the patient. 
The total duration of treatment will be calculated as the number of days from the first to the last dose of 
study medication inclusive (regardless of any breaks in treatment).  The total duration of treatment will 
also be categorized as up to 4 months, >4 to 8 months, >8 to 12 months, >12 to 16 months, >16 to 20 
months, >20 to 24 months and >24 months.  This will be calculated by dividing the duration of treatment 
in days by 365.25/12.  The duration in days will be summarized and the number of patients in each 4-
month treatment category will also be presented. 
All dosage administration data will also be listed. 


 
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9. PROGRAMMING/QC PLAN AND SOFTWARE/SYSTEM 
All statistical programs will be written in SAS® 9.2 or higher. Programming will be done as per 
 
Standard Operating Procedures and Work Instructions. All outputs produced will undergo an independent 
quality control (QC) and Senior Biostatistical Review (SBR).  A QC and SBR Plan will be produced to 
detail the checks to be performed. 
10. TECHNICAL PROGRAMMING SPECIFICATIONS 
10.1 General notes 
 
All data listings should be sorted by country, investigator site, by patient, and by time point within 
patient, where appropriate. 
 
Table specific footnotes should be printed below the table, separated from the end of the table by 
one blank line and left aligned. Avoid numeric references, which can be confused with data; rather 
use asterisks and other non-numeric symbols to refer to footnotes.  Patient-specific footnotes 
should be avoided. 
 
For tables that summarize categorical (discrete) data, an Unknown or Missing category should be 
added to any parameter for which information is not available for any patient.  The table should 
make clear, whether the denominator for percentages includes the Missing category or not. 
 
Data in columns of a table should be formatted as follows: 
 
alphanumeric values are left-justified  
 
whole numbers (e.g., counts) are right-justified 
 
numbers containing fractional portions are decimal aligned 
 
All fractional numeric values should be printed with a zero to the left of the decimal point (e.g., 
0.12, 0.3). If -0.0 value occurs due to rounding off it should be printed as 0.0. 
 
Unless otherwise specified, percentage values should be printed with one digit to the right of the 
decimal point (e.g., 12.8%, 5.4%).   
 
Less-than-signs “0.1%” should be printed when values are 0.0 and 0.1%  
 
If  >100% occurs due to rounding off errors then present as 100% 
 
Missing data should be represented as blank in listings, unless a missing category was explicitly 
defined.  
 
Dates should be printed in SAS format DATE9. (e.g. 01Jul1994). Missing portions of dates 
should be represented on patient listings as dashes (e.g. --Jul1994).   
 
10.2 Decimal places 
Unless otherwise specified, the estimated mean and median for a set of values should be printed out to one 
more decimal place than the raw (observed) data and rounded appropriately.  Standard errors (or standard 
deviations) should be printed out to two additional decimal places than the raw (observed) data and 
rounded appropriately. 


 
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Decimal places for summary tables and listings will be as follows: 
 
3 decimal places (p-values; if p-value is less than 0.001, display <0.001). 
 
data precision + 2 decimal places (standard errors and standard deviations) 
 
data precision + 1 decimal place (means, medians) 
 
same as data precision (minimums, maximums) 
 
1 decimal place (percentages)  
 
if percentage =100, no decimal is required. 
 
For example, for age (with raw data in whole years): 
 
                      N     
 
xx 
                      Mean         
xx.x 
                      S.D.            
 x.xx 
                      Min   
             xx 
                      Median      
xx.x 
                      Max   
             xx 
 
10.3 Font size 
Font size should be Courier 9 points. Line size is 120 characters. Page size is 30 lines per page. 
Column headings should be in initial upper-case characters. 
For numeric variables, include “unit” in column heading when appropriate. 
11. TABLE AND LISTINGS SHELLS 
Each table should be identified by a numeral, and the table designation (e.g., Table 1) should be centered 
above the title.  A decimal system (x.y-c.d) should be used to identify tables and listings with related 
contents.  Tables/listings should be internally paginated in relation to total length (i.e., page number 
should appear sequentially as page X of N, where N is the total number of pages within a table or listing). 
The title is in mixed-case characters.  The title and table designation are single-spaced, but are separated 
from the table by at least a double space. The study population or subgroup (e.g., Intent-to-Treat 
Population) should be identified on the line immediately following the title. 
 
Table 14.x-c.d (page n of y) 
Title1 
Title2 
...  
TitleN 
Population / Subgroup 
 
The tables are numbered starting from 14 (as per ICH guidelines), Figures start with 15 and Listings start 
with 16.  Numbering then follows the pattern given below:  
x takes the values   
1 – Baseline  (section 11.1)  


 
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2 – Visit (section 11.2)  
                                  
3 – Lab  (section 11.3)  
 
 
 
4 – Conmed (section 11.4)  
 
 
 
5 – AE/SAE  
 
 
 
6 – Time-to-event  analysis 
c takes the values according to the topics under the respective section x. 
d is the unique table number under a topic 
Examples: 
The first table under Patient Disposition will be numbered as: Table 14.1-1.1 and Listing 16.1-1.1.  
Table 14.2-5.3 refers to the third table under Patient Outcome topic in Visit section.  See Sections 11.1 to 
11.6 for full details of output grouping. 
The output should contain information about the program name and the date when output was generated. 
This information should be given in a footnote (in the bottom row of a page) in the following format: 
 
E:\EMD\EMR62202\abc.sas, (01Jun2003 10:15) 
All output should have the four-line header (the 4th line is left blank) indicating the study protocol and the 
purpose of the analysis at the upper left margin: 
 
       Novartis 
Protocol No.: CRAD001LIC01 
------------------------------------------------------------------------------------------------------ 
 
Section 11.1– Demographic data 
This section should include tables and listings for the following data: 
1. Patient disposition 
2. Demographic and other baseline characteristics (including medical history) 
3. Diagnosis and extent of cancer 
4. Prior antineoplastic therapy 
5. Chest x-ray 
Section 11.2– Visit data 
This section should include tables and listings for the following data: 
1. Vital signs 
2. Karnofsky Performance status 
3. Dose administration 
4. ECG Assessments 
5. Pulmonary Function Test 
Section 11.3– Lab data 


 
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This section should include tables and listings for the following data: 
1. Hematology 
2. Blood Chemistry 
3. Serum Lipid Parameters 
4. Coagulation 
5. Urinalysis 
Section 11.4– Conmed and concomitant diseases data 
This section should include tables and listings for the following data: 
1. All concomitant medication 
Section 11.5– AE/SAE data 
This section should include tables and listings for the following data: 
1. Summary of all adverse events  
2. Adverse events by system organ class and preferred term 
Section 11.6– Time-to-event data 
This section should include tables and listings for the following data: 
1. Summary of time to event data 
2. Survival analysis  


 
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Table of contents for Table, Listing and Figures templates: 
Outputs marked with an asterisk will only be produced if the Safety population differs from the 
ITT population. 
 
Table Number 
Title 
Population 
 
 
 
Table 14.1-1.1 
Patient Disposition and Analysis 
Populations 
 
Table 14.1-1.2 
Number (%) of Patients with Major 
Protocol Deviations Post Inclusion 
ITT 
Table 14.1-2.1 
Patient Demographic Characteristics  
ITT 
Table 14.1-2.2* 
Patient Demographic Characteristics  
Safety 
Table 14.1-2.3 
Diagnosis and Extent of Cancer 
ITT 
Table 14.1-2.4* 
Diagnosis and Extent of Cancer 
Safety 
Table 14.1-2.5 
Medical History by System Organ class and 
Preferred Term 
Safety 
Table 14.1-2.6 
Summary Statistics of Change from 
Baseline in  Karnofsky Performance Status 
Safety 
Table 14.1-3.1 
Summary of Prior Antineoplastic Therapy 
ITT 
Table 14.1-3.2* 
Summary of Prior Antineoplastic Therapy 
Safety 
Table 14.1-3.3 
Duration of Prior Antineoplastic Therapy 
(months) 
ITT 
Table 14.1-3.4* 
Duration of Prior Antineoplastic Therapy 
(months) 
Safety 
Table 14.1-5.1 
Summary of Chest X-ray Evaluation at 
Screening 
Safety 
Table 14.2-3.1 
Summary of Duration of Treatment with 
Study Medication 
Safety 
Table 14.3-1.1 
Normal ranges for Hematology and Blood 
Chemistry Parameters 
 
Table 14.3-2.1 
Summary Statistics of Hematology by Visit 
Safety 
Table 14.3-2.2 
Summary Statistics of Change from 
Baseline in Hematology by Visit 
Safety 
Table 14.3-2.3 
Shift Table for CTC Grade for Hematology 
Parameters 
Safety 
Table 14.3-3.1 
Summary Statistics of Blood Chemistry by 
Visit 
Safety 
Table 14.3-3.2 
Summary Statistics of Change from 
Baseline in Blood Chemistry by Visit 
 
Safety 
Table 14.3-3.3 
Shift Table for CTC Grade for Blood 
Chemistry Parameters 
Safety 
Table 14.3-4.1 
Summary Statistics of Serum Lipid Profile 
by Visit 
Safety 
Table 14.3-4.2 
Summary Statistics of Change from 
Safety 


 
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Baseline in Serum Lipid Profile by Visit 
 
Table 14.3-4.3 
Shift Table for CTC Grade for Serum Lipid 
Profile Parameters 
Safety 
Table 14.4-1.1 
Concomitant Medications and Non-Drug 
Therapies by ATC class and Preferred 
Term 
Safety 
Table 14.5-1.1 
Summary of Adverse Events 
Safety 
Table 14.5-2.1 
Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety 
Table 14.5-2.2 
Deaths Reportable as Serious Adverse 
Events by System Organ Class and 
Preferred Term 
Safety 
Table 14.5-2.3 
Serious Adverse Events by System Organ 
Class and Preferred Term 
Safety 
Table 14.6-1.1 
Summary of Survival and End of Study 
Status 
 
ITT 
Table 14.6-2.1 
Analysis of Progression Free Survival 
Rate 
ITT 
Table 14.6-2.2 
Analysis of Progression Free Survival 
Rate – Sensitivity Analysis 
ITT 
Table 14.6-2.3 
Progression Free Survival Descriptive 
Statistics 
ITT 
Table 14.6-2.4 
Progression Free Survival Descriptive 
Statistics – Sensitivity Analysis 
ITT 
Table 14.6-2.5 
Duration of Response Descriptive 
Statistics 
ITT 
Table 14.6-2.6 
Objective Response Rate and Disease 
Control Rate 
ITT 
Table 14.6-2.7 
Overall Survival Descriptive Statistics 
ITT 
 


 
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Figure Number 
Title 
Population 
 
 
 
Figure 15.6-2.1 
Kaplan Meier Plot for Progression Free 
Survival 
ITT 
Figure 15.6-2.2 
Kaplan Meier Plot for Progression Free 
Survival – Sensitivity Analysis 1 
ITT 
Figure 15.6-2.3 
Kaplan Meier Plot for Progression Free 
Survival – Sensitivity Analysis 2 
ITT 
Figure 15.6-2.4 
Kaplan Meier Plot for Duration of 
Response 
ITT 
Figure 15.6-2.5 
Kaplan Meier Plot for Overall Survival 
ITT 
 
 
 
 


 
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Listing Number 
Title 
Population 
 
 
 
Listing 16.1-1.1 
End of Treatment Status 
All Treated Patients 
Listing 16.1-1.2 
Analysis Populations and Strata 
All Patients 
Listing 16.1-1.3 
Failed Inclusion/Exclusion 
Criteria and Major Protocol 
Deviations 
All Patients 
Listing 16.1-1.4 
All Protocol Deviations 
All Patients 
Listing 16.1-2.1 
Patient Demographic 
Characteristics 
All Patients 
Listing 16.1-2.2 
Relevant Medical History/Current 
Medical Conditions 
All Patients 
Listing 16.1-3.1 
Diagnosis and Extent of Cancer 
All Patients 
Listing 16.1-3.2 
Diagnosis and Extent of Cancer – 
Lesions 
All Patients 
Listing 16.1-4.1 
Prior Antineoplastic Therapy – 
Medication Details 
All Patients 
Listing 16.1-4.2 
Prior Antineoplastic Therapy – 
Response 
All Patients 
Listing 16.1-5.1 
Baseline Chest X-Ray Evaluation 
All Patients 
Listing 16.2-1.1 
Vital Signs by Visit 
All Treated Patients 
Listing 16.2-2.1 
Karnofsky Performance Status by 
Visit 
All Treated Patients 
Listing 16.2-3.1 
Study Drug Administration 
All Treated Patients 
Listing 16.2-3.2 
Dosage Administration Details 
All Treated Patients 
Listing 16.2-4.1 
ECG Assessments  
All Treated Patients 
Listing 16.2-5.1 
Pregnancy Test Results 
All Patients 
Listing 16.2-6.1 
Pulmonary Function Test – 
Spirometry 
All Patients 
Listing 16.2-6.2 
Pulmonary Function Test – 
Diffusion Capacity for Carbon 
Monoxide 
All Patients 
Listing 16.2-6.3 
Pulmonary Function Test – Pulse 
Oximetry 
All Patients 
Listing 16.2-7.1 
Post-Baseline Chest X-Ray 
Evaluation 
All Patients 
Listing 16.2-7.2 
Imaging 
All Patients 
Listing 16.3-1.1 
Hematology by Visit 
All Treated Patients 
Listing 16.3-2.1 
Blood Chemistry by Visit 
All Treated Patients 
Listing 16.3-3.1 
Serum Lipid Profile by Visit 
All Treated Patients 
Listing 16.3-4.1 
Coagulation by Visit 
All Treated Patients 
Listing 16.3-5.1 
Urinalysis Dipstick Analysis by 
Visit 
All Treated Patients 
Listing 16.3-5.2 
Urinalysis Microscopic Analysis 
by Visit 
All Treated Patients 
Listing 16.4-1.1 
Concomitant Medications and 
All Treated Patients 


 
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Non-Drug Therapies 
Listing 16.4-2.1 
Antineoplastic Therapy Since 
Discontinuation of Study Drug 
All Treated Patients 
Listing 16.5-1.1 
All Adverse Events 
All Treated Patients 
Listing 16.5-2.1 
Deaths Reportable as SAEs 
All Patients 
Listing 16.5-2.2 
Non-Fatal SAEs 
All Patients 
Listing 16.6-1.1 
RECIST Solid Tumor Response 
Assessment – Target Lesions 
All Treated Patients 
Listing 16.6-1.2 
RECIST Solid Tumor Response 
Assessment – Non-Target Lesions 
All Treated Patients 
Listing 16.6-1.3 
RECIST Solid Tumor Response 
Assessment – Overall Response 
All Treated Patients 
Listing 16.6-1.4 
Survival Status at End of Study 
All Treated Patients 
Listing 16.6-1.5 
Progression and Survival Details 
All Treated Patients 
Listing 16.7-1.1 
Comments Listing 
All Patients 


 
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Table 14.1-1.1 (page 1 of 2) 
Patient Disposition and Analysis Populations 
 
 
 
Disposition 
     Reason 
Total 
n (%) 
 
 
Enrolled 
xx     
Completed  
 
xx (xx.x%) 
Withdrawn 
xx (xx.x%) 
 
 
Primary reason for early discontinuation of treatment 
 
     Adverse event(s) 
xx (xx.x%) 
     Abnormal laboratory value(s) 
xx (xx.x%) 
     Abnormal test procedure result(s) 
xx (xx.x%) 
     Patient withdrew consent 
xx (xx.x%) 
     Lost to follow-up 
xx (xx.x%) 
     Administrative problems 
xx (xx.x%) 
     Death 
xx (xx.x%) 
       Death due to study indication                           
xx (xx.x%) 
       Death due to other reason 
xx (xx.x%) 
     New cancer therapy 
xx (xx.x%) 
     Disease progression 
xx (xx.x%) 
     Protocol deviation 
xx (xx.x%) 
 
 
 
 
Percentages are based on the number enrolled in the study. Enrolled is defined as patients 
who gave informed consent. 
Disposition is assessed at the cut off date for analysis therefore completed patients are 
those remaining on study treatment at this time. 
Source: Listings 16.1-1.1 and 16.1-1.2 
 
Programming Note: See Section 7.3 of text for definitions of enrolled, completed and withdrawn.
 


 
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Table 14.1-1.1 (page 2 of 2) 
Patient Disposition and Analysis Populations 
 
 
 
Disposition 
     Reason 
Total 
n (%) 
 
 
Intent-to-treat population 
xx (xx.x%) 
Safety population 
xx (xx.x%) 
 
 
First-line Patients 
xx (xx.x%) 
Second-line Patients 
xx (xx.x%) 
 
 
Still present in study at each visit (safety population) 
 
  Baseline Visit  
xx 
  Cycle 1 Visit 2 
xx 
  Cycle 1 Visit 3 
xx 
  Cycle 2 Visit 4 
xx 
  Cycle 2 Visit 5 
xx 
  Cycle 3 Visit 6 
xx 
  Cycle 3 Visit 7 
xx 
  Cycle 4 Visit 8 
xx 
  Cycle 5 Visit 9 
xx 
  Cycle 6 Visit 10 
xx 
  Cycle 7 Visit 11 
xx 
  Cycle 8 Visit 12 
xx 
…repeat for all treatment cycles 
xx 
  End of Treatment 
xx 
 
 
 
 
Percentages are based on the number enrolled in the study. 
A patient is defined as being in the population at a visit if they have data at that visit 
or a subsequent visit.  The population at the End of Treatment visit will be anyone who 
had data for at least one on-treatment visit. 
Source: Listings 16.1-1.1 and 16.1-1.2 
 
 


 
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Table 14.1-1.2 (page 1 of n) 
Number (%) of Patients with Major Protocol Deviations Post-Inclusion 
Population ITT 
 
 
Protocol Deviation Description 
         Total 
         N=xxxx 
         n (%) 
 
 
Xxxxxxxx 
         xx (xx.x%) 
Xxxx xxxxx 
         xx (xx.x%) 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
         xx (xx.x%) 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
         xx (xx.x%) 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
         xx (xx.x%) 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
         xx (xx.x%) 
Etc. 
 
 
 
 
Percentages are based on the ITT population. 
Source: Listing 16.1-1.3 


 
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Patient Demographic Characteristics  
Population ITT 
 
Demographic variable 
Total 
N=xxxx 
 
 
Age (years)  
 
  N 
xx 
  Mean 
xx.x 
  SD 
xx.xx 
  Min 
xx 
  Median 
xx.x 
  Max 
xx 
  Missing 
xx 
 
 
  < 65 years 
xx (xx.x%) 
  >= 65 years 
xx (xx.x%) 
 
 
Sex 
 
  Male 
xx (xx.x%) 
  Female 
xx (xx.x%) 
  
 
Race 
 
  Caucasian  
xx (xx.x%) 
  Black 
xx (xx.x%) 
  Oriental 
xx (xx.x%) 
  Native American 
xx (xx.x%) 
  Pacific Islander 
xx (xx.x%) 
  Other 
xx (xx.x%) 
  Missing 
xx 
 
 
Ethnicity 
 
  Hispanic/latino 
xx (xx.x%) 
  Chinese 
xx (xx.x%) 
  Indian (Indian subcontinent)  
xx (xx.x%) 
  Japanese 
xx (xx.x%) 
  Mixed ethnicity 
xx (xx.x%) 
  Other 
xx (xx.x%) 
  Missing 
xx 
 
 
 
Demography information is collected at the baseline visit (Visit 1). 
Percentages are based on the number of patients in the ITT population with non-missing  
data for that parameter. 
Source: Listing 16.1-2.1, 16.2-1.1 and 16.2-2.1 
 
     Table 14.1-2.1 (page 1 of 3) 


 
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Patient Demographic Characteristics  
Population ITT 
 
Demographic variable 
Total 
N=xxxx 
 
 
Height (cm) 
 
  N 
xx 
  Mean 
xx.xx 
  SD 
xx.xxx 
  Min 
xx.x 
  Median 
xx.xx 
  Max 
xx.x 
  Missing 
xx 
 
 
Weight (kg) 
 
  N 
xx 
  Mean 
xx.xx 
  SD 
xx.xxx 
  Min 
xx.x 
  Median 
xx.xx 
  Max 
xx.x 
  Missing 
xx 
 
 
BMI (kg/m2) 
 
  N 
xx 
  Mean 
xx.xx 
  SD 
xx.xxx 
  Min 
xx.x 
  Median 
xx.xx 
  Max 
xx.x 
  Missing 
xx 
 
 
 
Demography information is collected at the screening visit (Visit 1a). 
Percentages are based on the number of patients in the ITT population with non-missing  
data for that parameter. 
Source: Listing 16.1-2.1, 16.2-1.1 and 16.2-2.1 
 
Programming Note: This table will be repeated for the Safety population if this differs from the ITT population (Table 
14.1-2.2). 
 
 
       Table 14.1-2.1 (page 2 of 3) 


 
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Patient Demographic Characteristics  
Population ITT 
 
Demographic variable 
Total 
N=xxxx 
 
 
Karnofsky Performance Status 
 
  100% 
xx (xx.x%) 
  90% 
xx (xx.x%) 
  80% 
xx (xx.x%) 
  70% 
xx (xx.x%) 
  60% 
xx (xx.x%) 
  50% 
xx (xx.x%) 
  40% 
xx (xx.x%) 
  30% 
xx (xx.x%) 
  20% 
xx (xx.x%) 
  10% 
xx (xx.x%) 
  Missing 
xx 
 
 
 
Demography information is collected at the screening visit (Visit 1a) for all patients. 
Percentages are based on the number of patients in the ITT population with non-missing  
data for that parameter. 
Source: Listing 16.1-2.1, 16.2-1.1 and 16.2-2.1 
 
Programming Note: This table will be repeated for the Safety population if this differs from the ITT population (Table 
14.1-2.2). 
 
 
 
 
       Table 14.1-2.1 (page 3 of 3) 


 
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Diagnosis and Extent of Cancer 
Population ITT 
 
Diagnosis variable 
Total 
N=xxxx 
 
 
Primary Site of Cancer 
 
  Site 1 
xx (xx.x%) 
  Site 2 
xx (xx.x%) 
  Site 3 
xx (xx.x%) 
  … 
xx (xx.x%) 
  Missing 
xx 
 
 
Details of Tumor Histology/Cytology 
 
  Histology/Cytology 1 
xx (xx.x%) 
  Histology/Cytology 2 
xx (xx.x%) 
  Histology/Cytology 3 
xx (xx.x%) 
  … 
xx (xx.x%) 
  Missing 
xx 
 
 
Histologic Grade 
 
  Well differentiated 
xx (xx.x%) 
  Moderately differentiated 
xx (xx.x%) 
  Poorly differentiated 
xx (xx.x%) 
  Undifferentiated 
xx (xx.x%) 
  Unknown 
xx (xx.x%) 
  Missing 
xx 
 
 
 
Diagnosis and extent of cancer information is collected at the screening visit (Visit 1a). 
Percentages are based on the number of patients in the ITT population with non-missing  
data for that parameter. 
Source: Listing 16.1-3.1 and 16.1-3.2 
 
Programming Note: This table will be repeated for the Safety population if this differs from the ITT population (Table 
14.1-2.4). 
 
       Table 14.1-2.3 (page 1 of 2) 


 
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Diagnosis and Extent of Cancer 
Population ITT 
 
Diagnosis variable 
Total 
N=xxxx 
 
 
Stage at Initial Diagnosis 
 
  Stage 0 
xx (xx.x%) 
  Stage I 
xx (xx.x%) 
  Stage Ia 
xx (xx.x%) 
  … 
xx (xx.x%) 
  Missing 
xx 
 
 
Dosing Phase 
 
  Dose escalation phase 
xx (xx.x%) 
  Dose expansion phase 
xx (xx.x%) 
  Missing 
xx 
 
 
Any Target Lesions 
 
  Yes 
xx (xx.x%) 
  No 
xx (xx.x%) 
  Missing 
xx 
 
 
Any Non-Target Lesions 
 
  Yes 
xx (xx.x%) 
  No 
xx (xx.x%) 
  Missing 
xx 
 
 
Any Sites of Metastasis to be Reported 
 
  Yes 
xx (xx.x%) 
  No 
xx (xx.x%) 
  Missing 
xx 
 
 
 
Diagnosis and extent of cancer information is collected at the screening visit (Visit 1a). 
Percentages are based on the number of patients in the ITT population with non-missing  
data for that parameter. 
Source: Listing 16.1-3.1 and 16.1-3.2 
 
Programming Note: This table will be repeated for the Safety population if this differs from the ITT population (Table 
14.1-2.4). 
 
 
       Table 14.1-2.3 (page 2 of 2) 


 
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Table 14.1-2.5 
Medical History by System Organ Class and Preferred Term 
Population Safety 
 
System Organ Class 
   Preferred Term 
Total 
N = xxxx 
n (%) 
 
 
Any relevant medical history/current medical conditions? 
 
   Yes 
xx (xx.x%) 
   No 
xx (xx.x%) 
 
 
Any active problems? 
 
   Yes 
xx (xx.x%) 
   No 
xx (xx.x%) 
 
 
System Organ Class 1 
xx (xx.x%) 
   Preferred Term 1 
xx (xx.x%) 
   Preferred Term 2 
xx (xx.x%) 
   Preferred Term 3 
xx (xx.x%) 
 
 
System Organ Class 2 
xx (xx.x%) 
   Preferred Term 4 
xx (xx.x%) 
   Preferred Term 5 
xx (xx.x%) 
 
 
 
 
Patients experiencing more than one medical history within a system organ class or within 
          a system organ class and preferred term are only counted once. 
 
Percentages are based on the number of patients in the Safety population. 
 
Source: Listing 16.1-2.2 
 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: Table continues for remaining Cycles then presents and End of Treatment summary which will be the 
last on-treatment assessment.
Table 14.1-2.6 (page 1 of n) 
Summary Statistics of Change from Baseline in  Karnofsky Performance Status 


 
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Table 14.1-3.1 (page 1 of n) 
Summary of Prior Antineoplastic Therapy 
Population ITT 
 
 
 
 
Therapy Type 
  Setting 
Best Response Achieved 
   Total 
   N=xxxx 
   n (%)  
 
 
 
Chemotherapy 
 
   xx (xx.x%) xxx 
 
 
 
   Adjuvant 
Overall 
   xx (xx.x%)  
 
Complete Response 
   xx (xx.x%)  
 
Partial Response 
   xx (xx.x%)  
 
Stable Disease 
   xx (xx.x%)  
 
Complete Response (unconfirmed) 
   xx (xx.x%) 
 
Unknown 
   xx (xx.x%) 
 
Not Applicable 
   xx (xx.x%) 
 
Progressive Disease 
   xx (xx.x%)  
 
 
 
   Neoadjuvant 
Overall 
   xx (xx.x%)  
 
Complete Response 
   xx (xx.x%)  
 
Partial Response 
   xx (xx.x%)  
 
Stable Disease 
   xx (xx.x%)  
 
Complete Response (unconfirmed) 
   xx (xx.x%) 
 
Unknown 
   xx (xx.x%) 
 
Not Applicable 
   xx (xx.x%) 
 
Progressive Disease 
   xx (xx.x%)  
 
 
 
Etc. 
 
 
 
 
 
 
Percentages of patients on each therapy type/setting combination are based on the ITT population. 
Patients are counted once under the best response level achieved within that therapy type/setting  
combination and percentages are based on the number of patients receiving that therapy type/setting 
combination. 
Source: Listing 16.1-4.1 
 
Programming Note: Table continues for the Chemotherapy/Therapeutic, Chemotherapy/Prevention and then  
for the therapy types Hormonal Therapy, Immunotherapy, Targeted Therapy and Other Therapy. 
This table will be repeated for the Safety population if this differs from the ITT population (Table 14.1-3.2). 


 
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Table 14.1-3.3 (page 1 of n) 
Duration of Prior Antineoplastic Therapy (months) 
Population ITT 
 
 
 
 
Therapy Type 
  Setting 
 
   Total 
   N=xxxx 
   n (%) 
 
 
 
Chemotherapy 
 
xx (xx.x%)  
 
 
 
  Adjuvant 
 
xx (xx.x%)  
    N 
 
xx 
    Min 
 
xx.x 
    Median 
 
xx.xx 
    Max 
 
xx.x 
    Missing 
 
xx 
 
 
 
  Neoadjuvant 
 
xx (xx.x%)  
    N 
 
xx 
    Min 
 
xx.x 
    Median 
 
xx.xx 
    Max 
 
xx.x 
    Missing 
 
xx 
 
 
 
Etc. 
 
 
 
 
 
 
Percentages of patients on each therapy type/setting combination are based on the ITT population. 
Source: Listing 16.1-4.1 
 
Programming Note: Table continues for the Chemotherapy/Therapeutic, Chemotherapy/Prevention and then  
for the therapy types Hormonal Therapy, Immunotherapy, Targeted Therapy and Other Therapy. 
This table will be repeated for the Safety population if this differs from the ITT population (Table 14.1-3.4). 


 
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Table 14.1-5.1 
Summary of Chest X-ray Evaluation at Screening 
Population Safety 
 
Description 
Total 
N = xxxx 
n (%) 
 
 
X-ray interpretation 
 
   Number with assessment 
xx  
     Normal 
xx (xx.x%) 
     Clinically insignificant abnormality 
xx (xx.x%) 
     Clinically significant abnormality 
xx (xx.x%) 
   Missing 
xx  
 
 
 
 
Percentages are based on the number of patients in the Safety population who had 
          the relevant assessment performed. 
 
Source: Listings 16.1-5.1 
 


 
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Population Safety 
 
 
Total  
N = xxxx 
 
 
Overall (days) 
 
    N 
                   xx 
    Min 
                   xx 
    Median 
                   xx.x 
    Max 
                   xx 
    Missing 
                   xx 
 
 
>0 to 4 months 
                   xx (xx.x%) 
>4 to 8 months 
                   xx (xx.x%) 
>8 to 12 months 
                   xx (xx.x%) 
>12 to 16 months 
                   xx (xx.x%) 
>16 to 20 months 
                   xx (xx.x%) 
>20 to 24 months 
                   xx (xx.x%) 
>24 months 
                   xx (xx.x%) 
 
 
 
                 Percentages are based on the number of patients in the Safety Population. 
                 Source: Listing 16.2-3.1 
Table 14.2-3.1 (page 1 of 1) 
Summary of Duration of Treatment with Study Medication 


 
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Parameter 
Unit 
Lab Number 
Gender 
Age Range 
Lower Limit 
Upper Limit 
 
 
 
 
 
 
 
xxxxxxxxxxxx 
xx 
xxxxx 
Male 
xx-xx 
xx 
xx 
 
 
 
 
xx-xx 
xx 
xx 
 
 
 
Female 
xx-xx 
xx 
xx 
 
 
 
 
xx-xx 
xx 
xx 
 
 
xxxxx 
Male 
 
xx 
xx 
 
 
 
Female 
 
xx 
xx 
 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxx 
xx 
xxxxx 
Male 
 
xx 
xx 
 
 
 
Female 
 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. . . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Will need to confirm once ranges are available – if ranges are in SI units and hence do not vary 
across lab then the “lab number” column can be dropped.
Table 14.3-1.1 (page 1 of n) 
Normal Ranges for Hematology and Blood Chemistry Parameters 
 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: WBC (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Baseline  (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  End of Treatment (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-1.1 
 
Programming note: Table continues for all Cycles. Repeat for each hematology parameter in turn noting that absolute 
and percentage differentials need to be summarized separately.  Results should be shown in SI units.   
Table 14.3-2.1 (page 1 of n) 
Summary Statistics of Hematology by Visit 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: WBC (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-1.1 
 
Programming note: Table continues for all Cycles, then presents an End of Treatment summary which will be the last on-
treatment assessment. Repeat for each hematology parameter in turn noting that absolute and percentage differentials 
need to be summarized separately.  Results should be shown in SI units.   
Table 14.3-2.2 (page 1 of n) 
Summary Statistics of Change from Baseline in Hematology by Visit 


 
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CTC grades are calculated from V3.0 of the CTCAE manual.   
Percentages are based on the number of patients in the Safety Population with data at Screening and the visit of 
interest. 
Source: Listing 16.3-1.1 
 
Programming Note: Repeat for each hematology parameter for those parameters that have a CTC grade defined (see SAP 
text). 
Table 14.3-2.3 (page 1 of n) 
 
Shift Table for CTC Grade for Hematology Parameters 
 
Population Safety 
 
 
 
 
 
Screening Visit 1a (N=xxxx) 
 
 
 
Grade 1 
n (%) 
Grade 2 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Total 
n (%) 
Missing 
n 
 
 
 
 
 
 
 
 
Parameter: WBC (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
Xx 
 
Missing 
Xx 
Xx 
Xx 
Xx 
xx 
Xx 
 
 
 
 
 
 
 
 
Parameter: Hemoglobin 
(units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
Xx 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: Urea (units)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Baseline (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-2.1 
 
Programming note: Table continues for remaining Cycles then presents and End of Treatment summary which will be the 
last on-treatment assessment. Repeat for each blood chemistry parameter in turn. Results should be shown in SI units. 
 
Table 14.3-3.1 (page 1 of n) 
Summary Statistics of Blood Chemistry by Visit 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: Urea (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-2.1 
 
Programming note: Table continues for remaining Cycles then presents and End of Treatment summary which will be the 
last on-treatment assessment. Repeat for each blood chemistry parameter in turn. Results should be shown in SI units. 
 
Table 14.3-3.2 (page 1 of n) 
Summary Statistics of Change from Baseline in Blood Chemistry by Visit 


 
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CTC grades are calculated from V3.0 of the CTCAE manual.   
Percentages are based on the number of patients in the Safety Population with data at Screening and the visit of 
interest. 
Source: Listing 16.3-2.1 
 
Programming Note: Repeat for each blood chemistry parameter that has a CTC grade defined (see SAP text). 
Table 14.3-3.3 (page 1 of n) 
 
Shift Table for CTC Grade for Blood Chemistry Parameters 
 
Population Safety 
 
 
 
 
 
Screening Visit 1a (N=xxxx) 
 
 
 
Grade 1 
n (%) 
Grade 2 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Total 
n (%) 
Missing 
n 
 
 
 
 
 
 
 
 
Parameter: Creatinine (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
xx 
 
Missing 
xx 
Xx 
Xx 
Xx 
xx 
xx 
 
 
 
 
 
 
 
 
Parameter: Fasting Glucose (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
xx 
 
Missing 
xx 
Xx 
Xx 
Xx 
xx 
xx 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: Total Cholesterol (units)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Baseline (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-3.1 
 
Programming note: Table continues for remaining Cycles then presents and End of Treatment summary which will be the 
last on-treatment assessment. Repeat for each blood chemistry parameter in turn. Results should be shown in SI units. 
 
Table 14.3-4.1 (page 1 of n) 
Summary Statistics of Serum Lipid Profile by Visit 


 
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Population Safety 
 
 
Statistic 
Visit 
n 
Missing 
Mean 
SD 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
Parameter: Total Cholesterol (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 2 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 1 Visit 3 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 4 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 2 Visit 5 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 6 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 3 Visit 7 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 4 Visit 8 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 5 Visit 9 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 6 Visit 10 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Cycle 7 Visit 11 (N=xxxx) 
  xx 
   xx 
   xx.xx 
   xx.xxx 
    xx.x 
  xx.xx 
   xx.x 
 
 
 
 
 
 
 
 
  Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.3-3.1 
 
Programming note: Table continues for remaining Cycles then presents and End of Treatment summary which will be the 
last on-treatment assessment. Repeat for each serum lipid profile parameter in turn. Results should be shown in SI 
units. 
 
Table 14.3-4.2 (page 1 of n) 
Summary Statistics of Change from Baseline in Serum Lipid Profile by Visit 


 
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CTC grades are calculated from V3.0 of the CTCAE manual.   
Percentages are based on the number of patients in the Safety Population with data at Screening and the visit of 
interest. 
Source: Listing 16.3-3.1 
 
Table 14.3-4.3 (page 1 of 1) 
 
Shift Table for CTC Grade for Serum Lipid Profile Parameters 
 
Population Safety 
 
 
 
 
 
Screening Visit 1a (N=xxxx) 
 
 
 
Grade 1 
n (%) 
Grade 2 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Total 
n (%) 
Missing 
n 
 
 
 
 
 
 
 
 
Parameter: Total Cholesterol (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
xx 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Parameter: Triglycerides (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most Extreme Post-
Screening Visit 1a Value 
(N=xxxx) 
Grade 0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (100%) 
xx 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 


 
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Table 14.4-1.1 (page 1 of n) 
Concomitant Medications and Non-Drug Therapies by ATC class and Preferred Term 
Population Safety 
 
ATC Class 
   Preferred Term 
Total 
N = xxxx 
n (%) 
 
 
ATC Class 1 
xx (xx.x%) 
   Preferred Term 1 
xx (xx.x%) 
   Preferred Term 2 
xx (xx.x%) 
   Preferred Term 3 
xx (xx.x%) 
 
 
ATC Class 2 
xx (xx.x%) 
   Preferred Term 4 
xx (xx.x%) 
   Preferred Term 5 
xx (xx.x%) 
 
 
 
 
Patients receiving more than one medication/therapy within an ATC Class or within 
          an ATC Class and preferred term are only counted once. 
 
Percentages are based on the number of patients in the Safety population. 
 
Source: Listing 16.4-1.1 


 
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Percentages are based on the number of patients in safety population. 
Source: Listings 16.5-1.1 
 
Table 14.5-1.1 (page 1 of 1) 
Summary of Adverse Events 
Population Safety 
 
Events 
Total 
N = xxxx 
n (%)  
 
 
At least one treatment emergent adverse event 
xx (xx.x%)  
 
 
At least one serious adverse event 
xx (xx.x%) 
At least one adverse event leading to death 
xx (xx.x%) 
 
 
At least one adverse event leading to discontinuation of study medication 
xx (xx.x%) 
At least one adverse event leading to modification of study medication 
xx (xx.x%) 
 
 
At least one severe adverse event 
xx (xx.x%) 
At least one adverse event with suspected relationship to study medication 
xx (xx.x%) 
 
 


 
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Patients are counted once within each System Organ Class and Preferred Term or once within each 
System Organ Class for the summary row. 
Percentages are based on the number of patients in safety population. 
The table is sorted by system organ class then preferred term within system organ class alphabetically. 
Source: Listing 16.5-1.1 
 
Programming Note: Use same template for the following tables (but with different source listings). 
- Table 14.5-2.2 Deaths Reportable as Serious Adverse Events by System Organ Class and Preferred Term 
- Table 14.5-2.3 Serious Adverse Events by System Organ Class and Preferred Term 
 
 
Table 14.5-2.1 (page 1 of n) 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Population Safety 
 
System Organ Class 
   Preferred Term 
Total 
N = xxxx 
n (%)  
 
 
All treatment emergent adverse events 
xx (xx.x%)  
 
 
SOC 1 
xx (xx.x%)  
   Preferred Term 1 
xx (xx.x%)  
   Preferred Term 2 
xx (xx.x%)  
   Preferred Term 3 
xx (xx.x%)  
 
 
SOC 2 
xx (xx.x%)  
   Preferred Term 4 
xx (xx.x%)  
   Preferred Term 5 
xx (xx.x%)  
 
 
Etc. 
 
 
 


 
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Percentages are based on the number of patients in ITT population. 
With recurrence refers to subjects that had disease progression prior to death. 
Source: Listings 16.6-1.2 and 16.6-1.4 
 
Table 14.6-1.1 (page 1 of 1) 
Summary of Survival and End of Study Status 
Population ITT 
 
 
 
Total 
N = xxxx 
n (%) 
 
 
 
Alive at end of study 
Overall 
xx (xx.x%) 
 
With recurrence 
xx (xx.x%) 
 
Without recurrence 
xx (xx.x%) 
 
 
 
Died 
Overall 
xx (xx.x%) 
 
Due to study indication 
xx (xx.x%) 
 
Due to other reason  
xx (xx.x%) 
 
 
 
Died due to study indication 
Already experienced recurrence 
xx (xx.x%) 
 
No recurrence 
xx (xx.x%) 
 
 
 
Died due to other reason 
Already experienced recurrence 
xx (xx.x%) 
 
No recurrence 
xx (xx.x%) 
 
 
 
Lost to follow-up 
Overall 
xx (xx.x%) 
 
Already experienced recurrence 
xx (xx.x%) 
 
No recurrence 
xx (xx.x%) 
 
 
 


 
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Number of patients achieving PFS = number of subject that experienced progression or died prior to the time of data 
analysis cut-off.  
PFS Rate = survival function at the time of data analysis cut-off based on a Kaplan-Meier analysis of time to  
either progression or death.  
The 95% CI also comes from the Kaplan-Meier analysis. 
 
Source: Listings 16.6-1.5 
 
 
Table 14.6-2.1 (page 1 of 1) 
Analysis of Progression Free Survival Rate 
Population ITT 
 
 
 
First-line Patients 
N = xxxx 
Second-line Patients 
N = xxxx 
Total 
N = xxxx 
 
 
 
 
 
 PFS  Events  
 
          xxx 
         xxx 
         xxx 
PFS Rate 
         xx.xx 
        xx.xx 
        xx.xx 
95% CI for PFS Rate 
    (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
 
 
 
 


 
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Number of patients achieving PFS = number of subject that experienced progression or died prior to the time of data 
analysis cut-off.  
PFS Rate = survival function at the time of data analysis cut-off based on a Kaplan-Meier analysis of time to  
either progression or death.  
The 95% CI also comes from the Kaplan-Meier analysis. 
Sensitivity Analysis 1 = Actual event date of disease progression/death used for the PFS event date, regardless of 
whether is it proceeded by missing tumor assessments. 
Sensitivity Analysis 2 = In case of a documented progression/death after one of more missing tumor assessments, 
disease progression is considered to have occurred at the next scheduled tumor assessment after the date of last tumor 
assessment with overall lesion response of CR, PR, or SD. 
 
Source: Listings 16.6-1.5 
 
Table 14.6-2.2 (page 1 of 1) 
Analysis of Progression Free Survival Rate – Sensitivity Analysis 
Population ITT 
 
 
 
First-line Patients 
N = xxxx 
Second-line Patients 
N = xxxx 
Total 
N = xxxx 
 
 
 
 
 
Sensitivity Analysis 1: 
 
 
 
 
 
 
 
PFS Events 
          xxx 
         xxx 
         xxx 
PFS Rate 
         xx.xx 
        xx.xx 
        xx.xx 
95% CI for PFS Rate 
    (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
 
 
 
 
Sensitivity Analysis 2: 
 
 
 
 
 
 
 
PFS Events 
          xxx 
         xxx 
         xxx 
PFS Rate 
         xx.xx 
        xx.xx 
        xx.xx 
95% CI for PFS Rate 
    (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
   (xx.xxx, xx.xxx) 
 
 
 
 


 
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* Censored is defined as the number of patients who have discontinued from the study for any reason other than 
progression/death within the time period. 
# Event is progression/death within the time period. 
 
Source: Listings 16.6-1.5 
 
Programming Note: Table continues for every 12 week assessment as appropriate until analysis data cut-off. 
 
Table 14.6-2.3 (page 1 of 2) 
Progression Free Survival Descriptive Statistics 
Population ITT 
 
 
 
Product Limit Estimates 
Time to Event 
Censored * 
Event # 
Survival 
Rate 
95% CI of 
Survival Rate 
Failure 
Rate 
Survival 
Standard Error 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<= Week 8 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 20 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 32 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 44 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 56 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Source: Listings 16.6-1.5 
 
Programming Note: Use previous template for the following tables. 
- Table 14.6-2.5 Duration of Response Descriptive Statistics – Population ITT 
 
Table 14.6-2.3 (page 2 of 2) 
Progression Free Survival Descriptive Statistics 
Population ITT 
 
 
Total 
N = xxxx 
 
 
Median (95% CI) 
                  xx.xx (xx.xxx) 
Number Assessed 
                  xx 
Number Censored 
                  xx 
Number Uncensored 
                  xx 
 
 
 
 


 
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* Censored is defined as the number of patients who have discontinued from the study for any reason other than 
progression/death within the time period. 
# Event is progression/death within the time period. 
Sensitivity Analysis 1 = Actual event date of disease progression/death used for the PFS event date, regardless of whether is 
it proceeded by missing tumor assessments. 
Sensitivity Analysis 2 = In case of a documented progression/death after one of more missing tumor assessments, disease 
progression is considered to have occurred at the next scheduled tumor assessment after the date of last tumor assessment with 
overall lesion response of CR, PR, or SD. 
 
Source: Listings 16.6-1.5 
 
Programming Note: Table continues for every 12 week assessment as appropriate until analysis data cut-off. 
 
Table 14.6-2.4 (page 1 of 4) 
Progression Free Survival Descriptive Statistics – Sensitivity Analysis 
Population ITT 
 
 
 
Product Limit Estimates 
Time to Event 
Censored * 
Event # 
Survival 
Rate 
95% CI of 
Survival Rate 
Failure 
Rate 
Survival 
Standard Error 
 
 
 
 
 
 
 
Sensitivity Analysis 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
<= Week 8 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 20 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 32 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 44 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
<=Week 56 
xx 
xx 
x.xxxx 
(x.xxxx-x.xxxx) 
x.xxxx 
x.xxxx 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Sensitivity Analysis 1 = Actual event date of disease progression/death used for the PFS event date, regardless of 
whether is it proceeded by missing tumor assessments. 
Sensitivity Analysis 2 = In case of a documented progression/death after one of more missing tumor assessments, 
disease progression is considered to have occurred at the next scheduled tumor assessment after the date of last tumor 
assessment with overall lesion response of CR, PR, or SD. 
 
Source: Listings 16.6-1.5 
 
Programming Note: Repeat for Sensitivity Analysis 2 
 
Table 14.6-2.4 (page 2 of 4) 
Progression Free Survival Descriptive Statistics – Sensitivity Analysis 
Population ITT 
 
 
Total 
N = xxxx 
 
 
Sensitivity 1: 
 
 
 
Median (95% CI) 
                  xx.xx (xx.xxx) 
Number Assessed 
                  xx 
Number Censored 
                  xx 
Number Uncensored 
                  xx 
 
 
 
 


 
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Source: Listings 16.6-1.5 
Table 14.6-2.6 (page 1 of 1) 
Objective Response Rate and Disease Control Rate 
Population ITT 
 
 
Total 
N = xxxx 
 
 
Objective Response 
 
  Patients with CR, n (%) 
                xx (xx.x%) 
  Patients with PR, n (%) 
                xx (xx.x%) 
  Objective Response Rate, n (%)  
                xx (xx.x%) 
  95% CI for Objective Response Rate 
               xx.x – xx.x 
 
 
Disease Control 
 
  Patients with CR, n (%) 
                xx (xx.x%) 
  Patients with PR, n (%) 
                xx (xx.x%) 
  Patients with SD, n (%) 
                xx (xx.x%) 
  Disease Control Rate, n (%) 
                xx (xx.x%) 
  95% CI for Disease Control Rate 
               xx.x – xx.x 
 
 


 
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Source: Listings 16.6-1.5 
 
Table 14.6-2.7 (page 1 of 1) 
Overall Survival Descriptive Statistics 
Population ITT 
 
 
Total 
N = xxxx 
 
 
25th Percentile (95% CI) 
                  xx.xx (xx.xxx, xx.xxx) 
Median (95% CI) 
                  xx.xx (xx.xxx, xx.xxx) 
75th Percentile (95% CI) 
                  xx.xx (xx.xxx, xx.xxx) 
 
 
Number Assessed 
                  xx 
Number Censored 
                  xx 
Number Uncensored 
                  xx 
 
 
 
 


 
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Figure 15.6-2.1 (page 1 of 1) 
Kaplan Meier Plot for Progression Free Survival 
Population ITT 


 
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Programming Note: Use same template for the following figures. 
- Figure 15.6-2.2 Kaplan Meier Plot for Progression Free Survival – Sensitivity Analysis 1, Population ITT 
- Figure 15.6-2.3 Kaplan Meier Plot for Progression Free Survival – Sensitivity Analysis 2, Population ITT 
- Figure 15.6-2.4 Kaplan Meier Plot for Duration of Response, Population ITT 
- Figure 15.6-2.5 Kaplan Meier Plot for Overall Survival, Population ITT 
 


 
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Listing 16.1-1.1 (page 1 of n) 
End of Treatment Status 
All Treated Patients 
 
Country/ 
Centre/ 
Patient 
Date/Day of 
Last Dose 
Status at 
Time of 
Analysis 
Reason for Not Completing Treatment 
Period 
Follow-Up for  
Post-
Treatment 
Evaluations? 
Follow-Up 
for 
Survival? 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy/ 
Xx 
Completed 
 
Yes 
No 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy/ 
Xx 
Discontinued 
New cancer therapy 
Yes 
Yes 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy/ 
xx  
Discontinued 
Protocol deviation - 
xxxxxxxxxxxxxxxxxxxxx 
Yes 
Yes 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
These data are collected at the end of the treatment period. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. 


 
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Listing 16.1-1.2 (page 1 of n) 
Analysis Populations and Strata 
All Patients 
 
Country/ 
Centre/ 
Patient 
Date of 
Informed 
Consent 
Intent-to-Treat 
Population? 
Safety Population? 
Strata 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy 
Yes/No 
Yes/No 
First-line 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy 
Yes/No 
Yes/No 
Second-line 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy 
Yes/No 
Yes/No 
First-line 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. 


 
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Listing 16.1-1.3 (page 1 of n) 
Failed Inclusion/Exclusion Criteria and Major Protocol Deviations 
All Patients 
 
Country/ 
Centre/ 
Patient 
Inclusion/Exclusion Criteria Not Met 
Major Protocol Deviations Post-Inclusion 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Only list patients who 
have either failed an inclusion/exclusion criteria and/or had a major protocol deviation post-inclusion. 
 


 
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Listing 16.1-1.4 (page 1 of n) 
All Protocol Deviations 
All Patients 
 
Country/ 
Centre/ 
Patient 
Deviation Code 
Date of Deviation 
(Day) 
Deviation Description 
Comment 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
XXX 
ddmmmyyyy (xx)/ 
Xxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
 
 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.   


 
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Listing 16.1-2.1 (page 1 of n) 
Patient Demographic Characteristics 
All Patients 
 
Country/ 
Centre/ 
Patient 
Date of 
Birth /  
Age (years) 
Sex 
Race 
Ethnicity 
Child Bearing 
Potential? 
Source of Referral 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy / 
xx 
Male 
Caucasian 
 
 
ER or hospital 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy / 
xx 
Female 
Black 
 
Able to bear children 
Radio advertisement 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy / 
xx 
Female 
Oriental 
Japanese 
Post-menopausal 
Friend/family member 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. 
 
 


 
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Listing 16.1-2.2 (page 1 of n) 
Relevant Medical History/Current Medical Conditions 
All Patients 
 
Country/ 
Centre/ 
Patient 
System Organ Class/  
Preferred Term/  
History/Condition 
Date of Diagnosis/ 
Surgery 
Active Problem? 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
ddmmmyyyy 
Yes/No 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
ddmmmyyyy 
Yes/No 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxx 
ddmmmyyyy 
Yes/No 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Conditions should be 
ordered by date of diagnosis/surgery with oldest condition shown first. 
 


 
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Listing 16.1-3.1 (page 1 of n) 
Diagnosis and Extent of Cancer 
All Patients 
 
Country/ 
Centre/ 
Patient 
Primary Site 
of Cancer 
Tumor 
Histology/ 
Cytology 
Histologic 
Grade 
Date of 
Initial 
Diagnosis 
Stage at 
Initial 
Diagnosis 
Date of 
First 
Recurrence/ 
Relapse 
Date of 
Most Recent 
Recurrence/ 
Relapse 
Dosing 
Phase 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxxx 
 
Xxxxxxxxxxxx 
 
Xxxxxxxxxxxx 
ddmmmyyyy 
Xxxxxx 
ddmmmyyyy 
ddmmmyyyy 
Xxxxxxx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx 
 
Xxxxxxxxxx 
 
Xxxxxxxxxxxx 
ddmmmyyyy 
Xxxxxx 
ddmmmyyyy 
ddmmmyyyy 
Xxxxxxxxx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx 
 
Xxxxxxxxx 
 
Xxxxxxxxxxxx 
ddmmmyyyy 
Xxxxxx 
ddmmmyyyy 
ddmmmyyyy 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  


 
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Listing 16.1-3.2 (page 1 of n) 
Diagnosis and Extent of Cancer – Lesions 
All Patients 
 
Country/ 
Centre/ 
Patient 
Any Target 
Lesions? 
Any Non-
Target 
Lesions? 
Any Sites of 
Metastasis? 
Metastatic 
Site(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Yes 
Yes 
Yes 
Xxxxxxxxxx 
 
 
 
 
 
 
 
 
Xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Yes 
Yes 
No 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
No 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. Metastatic sites should be 
ordered by the order they appear in the CRF. 


 
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Listing 16.1-4.1 (page 1 of n) 
Prior Antineoplastic Therapy – Medication Details 
All Patients 
 
Country/ 
Centre/ 
Patient 
 
 
 
 
Regimen 
Number 
Therapy Type 
(Number of 
Cycles) 
Medicatio
n 
First Dose 
Date (Day) 
/Last Dose 
Date (Day) 
Duration 
of 
Therapy 
(months) 
Cumulative 
Dose (Unit) 
Planned 
Dose 
(Unit) 
 
 
 
 
Route 
Setting 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Chemotherapy 
(xx) 
xxxxxxxxx
x 
ddmmmyyyy 
(xx)/ 
ddmmmyyyy 
(xx)  
xxx 
xx (Unit) 
xx 
(Unit) 
xx 
Therapeutic 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Immunotherapy 
(xx) 
xxxxxxxxx
x 
ddmmmyyyy 
(xx)/ 
ddmmmyyyy 
(xx)  
xxx 
xx (Unit) 
xx 
(Unit) 
xx 
Adjuvant 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Other: 
xxxxxxxx (xx) 
xxxxxxxxx 
ddmmmyyyy 
(xx)/ 
ddmmmyyyy 
(xx)  
xxx 
xx (Unit) 
xx 
(Unit) 
xx 
Prevention 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Therapy should be ordered 
by Regimen Number. 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
74 of 101 
 
 
Listing 16.1-4.2 (page 1 of n) 
Prior Antineoplastic Therapy – Response 
All Patients 
 
Country/ 
Centre/ Patient 
 
 
 
Regimen 
Number 
Therapy Type 
Medication 
Best 
Response 
Date of 
Best 
Response 
Duration 
of 
Response 
(Months) 
Reason for 
Discontinuation 
of Therapy 
Date of 
Progression 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Chemotherapy 
xxxxxxxxxx 
Complete 
Response 
ddmmmyyyy 
xx 
Adverse event(s) 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Immunotherapy 
xxxxxxxxxx 
Partial 
Response 
ddmmmyyyy 
xx 
Disease 
Progression 
ddmmmyyyy 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Other: 
xxxxxxxx 
xxxxxxxxx 
Unknown 
ddmmmyyyy 
xx 
Other: xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Therapy should be ordered 
by Regimen Number.  If necessary the Best Response column should use abbreviations as follows: CR=complete response, 
PR=partial response, SD=stable disease, PD=progressive disease, CRU=complete response, unconfirmed, UNK=unknown, 
NA=not applicable and these abbreviations should be footnoted. 


 
Novartis 
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Date 
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IMP : Everolimus 
Version   : 
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Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
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Listing 16.1-5.1 (page 1 of n) 
Baseline Chest X-Ray Evaluation 
All Patients 
 
Country/ 
Centre/ 
Patient 
Chest X-Ray 
Performed? 
Chest X-Ray 
Date/  
Day 
Interpretation 
Clinically Significant 
Abnormalities 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Yes/No 
ddmmmyyyy/  
xx 
Normal 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Yes/No 
ddmmmyyyy/  
xx 
Clinically insignificant abnormality 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Yes/No 
ddmmmyyyy/  
xx 
Clinically significant abnormality 
Xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
 
 
 
 
xxxxxxxxxxxxxxxxxx 
 
 
 
 
xxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. Multiple clinically 
significant abnormality details should be listed in the order they appear on the CRF.  


 
Novartis 
Confidential 
Date 
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22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
76 of 101 
 
 
Listing 16.2-1.1 (page 1 of n) 
Vital Signs by Visit 
All Treated Patients 
 
Country/ 
Centre/  
 
Assessment  Height  BMI 
Weight  
Body 
Temperature 
Sitting 
Pulse  
Sitting Blood 
Pressure (bpm) 
Patient 
Visit 
Date/Day 
(cm) 
(kg/m2) 
(kg) 
(oC) 
(bpm) 
Systolic 
Diastolic 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening 
Visit 1a 
ddmmmyyyy/ 
xx 
xxx 
xxx 
xxx 
xx.x 
xxx 
xxx 
xxx 
 
Baseline 
Visit 1b 
ddmmmyyyy/ 
xx 
 
 
 
xx.x 
xxx 
xxx 
xxx 
 
Cycle 1 
Visit 2 
ddmmmyyyy/ 
xx 
 
 
 
xx.x 
xxx 
xxx 
xxx 
 
Cycle 2 
Visit 4 
ddmmmyyyy/ 
xx 
 
 
 
xx.x 
xxx 
xxx 
Xxx 
 
Cycle 3 
Visit 6 
ddmmmyyyy/ 
xx 
 
 
 
xx.x 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”. 


 
Novartis 
Confidential 
Date 
: 
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IMP : Everolimus 
Version   : 
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Protocol No.: CRAD001LIC01 
Status 
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Page 
: 
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Listing 16.2-2.1 (page 1 of n) 
Karnofsky Performance Status by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Assessment  
Date/Day 
Performance Status 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 1a 
ddmmmyyyy/ 
xx 
100%: Normal, no complaints 
 
Baseline Visit 1b 
ddmmmyyyy/ 
xx 
90%: Able to carry on normal activity, minor signs or 
symptoms of disease 
 
Cycle 1 Visit 2 
ddmmmyyyy/ 
xx 
90%: Able to carry on normal activity, minor signs or 
symptoms of disease 
 
Cycle 2 Visit 4 
ddmmmyyyy/ 
xx 
80%: Normal activity with effort; some signs or 
symptoms of disease 
 
Cycle 3 Visit 6 
ddmmmyyyy/ 
xx 
90%: Able to carry on normal activity, minor signs or 
symptoms of disease 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  There 
is no date of assessment on the CRF page where unscheduled assessments are captured so these assessments cannot be 
slotted into the correct date order.  Therefore unscheduled assessments for a patient will appear at the end of the 
listing and a footnote will be added regarding this. 
 


 
Novartis 
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Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
78 of 101 
 
 
Listing 16.2-3.1 (page 1 of n) 
Study Drug Administration 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Start Date of 
Study Drug 
Planned Dose 
Total Daily Dose 
Administered 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  


 
Novartis 
Confidential 
Date 
: 
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IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
79 of 101 
 
 
Listing 16.2-3.2 (page 1 of n) 
Dosage Administration Details 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Regimen 
Number 
Planned 
Dose (mg) 
Actual 
Dose (mg) 
Regimen 
Dose 
Change? 
Reason for 
Change 
Start 
Date/Day 
End 
Date/Day 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
01 
10 
10 
o.d/q.d. No 
Lab Test 
Abnormality 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
02 
10 
5 
o.d/q.d. Yes 
 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
03 
10 
10 
o.d/q.d. No 
 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  It may 
be necessary to present Reason For Change using the following abbreviations: AE=adverse event, DOS=dosing error, 
LAB=lab test abnormality, SCH=scheduling conflict, DIS=dispensing error.  If so, these abbreviations will be 
footnoted.    


 
Novartis 
Confidential 
Date 
: 
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IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
80 of 101 
 
 
 
Listing 16.2-4.1 (page 1 of n) 
ECG Assessments 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Assessment  
Date/Day 
Result 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 1a 
ddmmmyyyy/ 
xx 
Normal 
 
Baseline Visit 1b 
ddmmmyyyy/ 
xx 
Clinically Significant Abnormality: 
xxxxxxxxxxx 
 
Cycle 1 Visit 2 
ddmmmyyyy/ 
xx 
Normal 
 
Cycle 2 Visit 4 
ddmmmyyyy/ 
xx 
Normal 
 
Cycle 3 Visit 6 
ddmmmyyyy/ 
xx 
Clinically Insignificant Abnormality 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Any unscheduled 
assessments should be included and labeled “Unscheduled Visit”.  ECG assessments are only performed at the 
investigator’s discretion, only records where the ECG was performed will be presented.    
 
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
81 of 101 
 
 
Listing 16.2-5.1 (page 1 of n) 
Pregnancy Test Results 
All Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample Date/Day 
Result 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Baseline Visit 1b 
ddmmmyyyy/ xx 
Negative/Positive 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Baseline Visit 1b 
ddmmmyyyy/ xx 
Negative/Positive 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Baseline Visit 1b 
ddmmmyyyy/ xx 
Negative/Positive 
 
Unscheduled Visit 
ddmmmyyyy/ xx 
Negative/Positive 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Only female patients need 
to be included on the listing.     


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
82 of 101 
 
 
Listing 16.2-6.1 (page 1 of n) 
Pulmonary Function Test  - Spirometry 
All Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Test 
Date/Day 
Total Lung 
Capacity (L) 
Forced Vital 
Capacity (L) 
Forced 
Expiratory  
Volume in One 
Second (L) 
Functional 
Residual 
Capacity (L) 
Residual 
Capacity (L) 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening 
Visit 1a 
ddmmmyyyy/ 
xx 
x.x 
x.x 
x.x 
x.x 
x.x 
 
End of 
Treatment 
ddmmmyyyy/ 
xx 
x.x 
x.x 
x.x 
x.x 
x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
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Listing 16.2-6.2 (page 1 of n) 
Pulmonary Function Test  - Diffusion Capacity for Carbon Monoxide 
All Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Was DLCO 
Done? 
Test 
Date/Day 
Diffusion 
Capacity for CO 
Unit 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening 
Visit 1a 
Yes 
ddmmmyyyy/ 
xx 
xx.xx 
xxxxxxxxxxx 
 
End of 
Treatment 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
84 of 101 
 
 
Listing 16.2-6.3 (page 1 of n) 
Pulmonary Function Test  - Pulse Oximetry 
All Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Was Pulse 
Oximetry 
Done? 
Test 
Date/Day 
Functional 
Residual 
Capacity (%) 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening 
Visit 1a 
Yes 
ddmmmyyyy/ 
xx 
xxx 
 
End of 
Treatment 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier. 
 
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
85 of 101 
 
 
Listing 16.2-7.1 (page 1 of n) 
Post-Baseline Chest X-Ray Evaluation 
All Patients 
 
Country/ 
Centre/ 
Patient 
 
 
Visit 
Chest X-Ray 
Performed? 
Chest X-
Ray Date/  
Day 
Interpretation 
Clinically 
Significant 
Abnormalities 
Abnormality 
Compared to 
Baseline 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 4 
Visit 8 
Yes/No 
ddmmmyyyy/  
xx 
Normal 
 
 
 
 
Yes/No 
ddmmmyyyy/  
xx 
Clinically insignificant 
abnormality 
 
 
 
 
Yes/No 
ddmmmyyyy/  
xx 
Clinically significant 
abnormality 
Xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
New or worsened 
 
 
 
 
 
xxxxxxxxxxxxxxxxxx 
Not compared 
 
 
 
 
 
xxxxxxxxxxxxxxxxxx 
Unchanged 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier and visit date. Multiple 
clinically significant abnormality details should be listed in the order they appear on the CRF.  
 
 
 
 
 
 
 
 
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
86 of 101 
 
 
Listing 16.2-7.2 (page 1 of n) 
Imaging 
All Patients 
 
Country/ 
Centre/ 
Patient 
 
 
Visit 
Date of 
Scan/Day 
Scan Category 
Location/ Site 
Scan Type 
Findings 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening 
Visit 1a 
ddmmmyyyy/  
xx 
Chest, Abdomen 
and Pelvis 
Other: xxxxxxx 
CT scan (with 
contrasts) 
xxxxxxx 
 
 
ddmmmyyyy/  
xx 
Brain 
Other: xxxxxxxx 
CT scan (with 
contrasts) 
xxxxxxx 
 
 
ddmmmyyyy/  
xx 
Bone 
Bone 
 
xxxxxxx 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier and visit date. 
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
87 of 101 
 
 
Listing 16.3-1.1 (page 1 of n) 
Hematology by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Laboratory 
Number / Name 
Parameter 
Result 
(units) 
CTC Grade 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a 
ddmmmyyyy/ 
xx 
Xxxxxxxxxxxxx/  
xxxxxxx 
WBC 
xx (unit) 
Xx 
 
 
 
 
Hemoglobin 
xx (unit) 
Xx 
 
 
 
 
Platelets 
xx (unit) 
Xx 
 
 
 
 
Hematocrit 
xx (unit) 
 
 
 
 
 
Neutrophils 
xx (unit) 
Xx 
 
 
 
 
Lymphocytes 
xx (unit) L  
 
 
 
 
Eosinophils 
xx (unit) 
 
 
 
 
 
Basophils 
xx (unit) 
 
 
 
 
 
Monocytes 
xx (unit) H  
 
 
 
 
Other: xxxxx 
xx (unit) 
 
 
 
 
 
 
 
 
 
Baseline Visit 1b 
ddmmmyyyy/ 
xx 
Xxxxxxxxxxxxx/  
xxxxxxx 
WBC 
xx (unit) 
Xx 
 
 
 
 
Hemoglobin 
xx (unit) 
Xx 
 
 
 
 
 
 
 
 
L=Low and H=High relative to normal ranges. 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”.


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
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Listing 16.3-2.1 (page 1 of n) 
Blood Chemistry by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Laboratory 
Number / Name 
Parameter 
Result (units) 
CTC Grade 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Urea 
xx (unit) 
 
 
 
 
 
BUN 
xx (unit) 
 
 
 
 
 
Creatinine 
xx (unit) L 
Xx 
 
 
 
 
LDH 
xx (unit) L 
 
 
 
 
 
Total Protein 
xx (unit) L 
 
 
 
 
 
Albumin 
xx (unit) 
Xx 
 
 
 
 
Total Bilirubin 
xx (unit) 
Xx 
 
 
 
 
SGOT(AST) 
xx (unit) 
Xx 
 
 
 
 
SGPT(ALT) 
xx (unit) 
Xx 
 
 
 
 
Alkaline 
Phosphatase 
xx (unit) 
Xx 
 
 
 
 
 
 
 
 
Baseline Visit 1b 
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Urea 
xx (unit) 
 
 
 
 
 
BUN 
xx (unit) 
 
 
 
 
 
 
 
 
 
L=Low and H=High relative to normal ranges. 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”. 


 
Novartis 
Confidential 
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: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
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Listing 16.3-3.1 (page 1 of n) 
Serum Lipid Profile by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Laboratory 
Number / Name 
Parameter 
Result 
(units) 
CTC 
Grade 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Total 
Cholesterol 
xx (unit) 
Xx 
 
 
 
 
Triglycerides 
xx (unit) 
Xx 
 
 
 
 
LDL 
xx (unit) L 
 
 
 
 
 
HDL 
xx (unit) L 
 
 
 
 
 
 
xx (unit) L 
 
 
 
 
 
 
 
 
 
Baseline Visit 1b 
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Total 
Cholesterol 
xx (unit) 
xx 
 
 
 
 
Triglycerides 
xx (unit) 
xx 
 
 
 
 
 
 
 
 
L=Low and H=High relative to normal ranges. 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”. 


 
Novartis 
Confidential 
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: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
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Listing 16.3-4.1 (page 1 of n) 
Coagulation by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Laboratory 
Number / Name 
Parameter 
Result 
(units) 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
PT 
xx (unit) 
 
 
 
 
INR 
xx (unit) L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Visit 4 
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
PT 
xx (unit) L 
 
 
 
 
INR 
xx 
 
 
 
 
 
 
 
L=Low and H=High relative to normal ranges. 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”. 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
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Page 
: 
91 of 101 
 
 
Listing 16.3-5.1 (page 1 of n) 
Urinalysis Dipstick Analysis by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Laboratory 
Number / Name 
Parameter 
Result 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Specific 
Gravity 
Xx 
 
 
 
 
pH 
Xx L 
 
 
 
 
Protein 
Xx 
 
 
 
 
Glucose 
Xx 
 
 
 
 
Bilirubin 
Xx 
 
 
 
 
Ketones 
Xx 
 
 
 
 
Blood Cells 
Xx 
 
 
 
 
Leukocytes 
Xx 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Xxxxxxxxxxx/ 
xxxxxxxxxxx 
Specific 
Gravity 
Xx L 
 
 
 
 
pH 
Xx 
 
 
 
 
Protein 
Xx 
 
 
 
 
Glucose 
Xx 
 
 
 
 
Bilirubin 
Xx 
 
 
 
 
Ketones 
Xx 
 
 
 
 
Blood Cells 
Xx 
 
 
 
 
Leukocytes 
Xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
L=Low and H=High relative to normal ranges. 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
unscheduled assessments should be included and labeled “Unscheduled Visit”. 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
92 of 101 
 
 
Listing 16.3-5.2 (page 1 of n) 
Urinalysis Microscopic Analysis by Visit 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
Visit 
Sample 
Date/ Day 
Any Abnormal 
Results 
Sample Name 
Result 
Value 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
No 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
No 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Screening Visit 
1a  
ddmmmyyyy/ 
xx 
Yes 
UWBC/HPF 
Present 
Not Present  
 
 
 
 
Casts/LPF 
Present 
Present 
xxxx 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by visit date.  Any 
abnormal results will be sorted by the order they appear on the CRF.


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
93 of 101 
 
 
Listing 16.4-1.1 (page 1 of n) 
Concomitant Medications and Non-Drug Therapies 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
ATC Class/  
Preferred Term/  
Medication or Non-Drug Therapy 
Dose 
Frequency 
Route 
Reason 
Start Date/ 
Day 
End Date/ 
Day 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx ^ 
Xx mg 
2x daily 
PO 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx  
Xx mg 
Xxxxxxx 
Nasal 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx 
Xx 
patch 
On demand 
Other 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx 
Xx mg 
1x weekly 
Oral 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
Ongoing 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx ^ 
Xx mg 
2x daily 
PO 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
Ongoing 
 
Xxxxxxxxxxxx/  
xxxxxxxxxxxxxxx 
Xx mg 
Xxxxxxx 
Nasal 
xxxxxxxxxxxx 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
^ Prior Medication 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by 
medications/therapies in order of start date (oldest first).  Where unit or frequency have been recorded as “other” 
and then specified, it is only necessary to show the text in the specification (rather than Other: xxxxx).  For route 
it appears from the CRF design that there is no further specification if “Other” is recorded so in this case the 
listing should just present “Other”. 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
94 of 101 
 
 
Listing 16.4-2.1 (page 1 of n) 
Antineoplastic Therapy Since Discontinuation of Study Drug 
All Treated Patients 
 
Country/ 
Centre/ Patient 
 
 
 
Regimen 
Number 
Therapy Type 
Medication/ 
Non-Drug 
Therapy 
Start Date/ 
Day 
Stop Date/ 
Day 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Chemotherapy 
xxxxxxxxxx 
ddmmmyyyy/ xx 
Ongoing 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Immunotherapy 
xxxxxxxxxx 
ddmmmyyyy/ xx 
ddmmmyyyy/ xx 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
1 
Other: 
xxxxxxxx 
xxxxxxxxx 
ddmmmyyyy/ xx 
ddmmmyyyy/ xx 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.  Therapy should be ordered 
by Regimen Number.   


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
95 of 101 
 
 
Listing 16.5-1.1 (page 1 of n) 
All Adverse Events 
All Treated Patients 
 
Country/ 
Centre/  
Patient 
System Organ Class/  
Preferred Term/  
Verbatim 
Serious 
Adverse 
Event 
Grade 
Relationship 
Suspected? /  
Action Taken 
Resulted 
in 
Death? 
Start Date/ 
Day 
End Date/ 
Day 
Treatment 
Emergent 
Event 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx/ 
Xxxxxxxxx 
Yes 
4 
No/  
No Action Taken 
No 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
No 
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxxxx 
No 
2 
No/  
Conmed Given 
No 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
Yes  
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx/ 
xxxxxxxxxxx 
No 
1 
Yes/  
Temporarily stopped 
study drug 
No 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
Yes 
 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx/ 
xxxxxxxxxx 
No 
1 
No/  
No action taken 
No 
ddmmmyyyy/ 
xx 
Ongoing 
Yes  
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Xxxxxxxxxxxx/  
Xxxxxxxxxxxxxxx/ 
xxxxx 
No 
2 
No/  
Permanently stopped 
study drug 
Yes 
ddmmmyyyy/ 
xx 
ddmmmyyyy/ 
xx 
No 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
Adverse events are flagged as resulting in death if the patient dies and the AE end date is the day of death or is 
missing. 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by adverse event in 
order of start date (oldest first).   
 
The following listings will follow this format: 
Listing 16.5-2.1 Deaths Reportable as SAEs – All Patients 
Listing 16.5-2.2 Non-Fatal SAEs – All Patients 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
96 of 101 
 
 
Listing 16.6-1.1 (page 1 of n) 
RECIST Solid Tumor Response Assessment – Target Lesions 
All Treated Patients 
 
Country/  
Centre/  
Patient 
Visit 
Visit Date/  
Day 
 
Lesion 
Number 
Location 
Evaluation 
Method 
Date of 
Baseline 
Evaluation 
Baseline 
Evaluation 
Method 
Date of 
Evaluation 
1 
Evaluation 
1 (mm) 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 3 
Visit 7 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
Cycle 6 
Visit 10 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
Cycle 9 
Visit 13 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
Cycle 12 
Visit 16 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
Cycle 15 
Visit 19 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
ddmmmyyyy 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then visit.  Lesions should 
be sorted by Lesion Number.  Any unscheduled assessments should be included and labeled “Unscheduled Visit”.   


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
97 of 101 
 
 
Listing 16.6-1.2 (page 1 of n) 
RECIST Solid Tumor Response Assessment – Non-Target Lesions 
All Treated Patients 
 
Country/  
Centre/  
Patient 
Visit 
Visit Date/  
Day 
 
Lesion 
Number 
Location 
Evaluation 
Method 
Date of 
Baseline 
Evaluation 
Baseline 
Evaluation 
Method 
Date of 
Evaluation 
1 
Evaluation 
1 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 3 
Visit 7 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
Cycle 6 
Visit 10 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
Cycle 9 
Visit 13 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
Cycle 12 
Visit 16 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
Cycle 15 
Visit 19 
ddmmmyyyy/  
xx 
1 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
2 
xxxxxxxx 
4 
ddmmmyyyy 
4 
4 
Xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then visit.  Lesions should 
be sorted by Lesion Number.  Any unscheduled assessments should be included and labeled “Unscheduled Visit”.   


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
98 of 101 
 
 
Listing 16.6-1.3 (page 1 of n) 
RECIST Solid Tumor Response Assessment – Overall Response 
All Treated Patients 
 
Country/  
Centre/  
Patient 
Visit 
Visit Date/  
Day 
 
Evaluation 
Number 
Date of 
Response 
Overall 
Lesion 
Response 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 3 
Visit 7 
ddmmmyyyy/  
xx 
1 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
2 
ddmmmyyyy 
Xxxxxxxx 
 
Cycle 6 
Visit 10 
ddmmmyyyy/  
xx 
1 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
2 
ddmmmyyyy 
Xxxxxxxx 
 
Cycle 9 
Visit 13 
ddmmmyyyy/  
xx 
1 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
2 
ddmmmyyyy 
Xxxxxxxx 
 
Cycle 12 
Visit 16 
ddmmmyyyy/  
xx 
1 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
2 
ddmmmyyyy 
Xxxxxxxx 
 
Cycle 15 
Visit 19 
ddmmmyyyy/  
xx 
1 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
2 
ddmmmyyyy 
Xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then visit.  Evaluations 
should be sorted by Evaluation Number.  Any unscheduled assessments should be included and labeled “Unscheduled 
Visit”.   
 
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
99 of 101 
 
 
Listing 16.6-1.4 (page 1 of n) 
Survival Status at End of Study 
All Treated Patients 
 
Country/  
Centre/  
Patient 
Current 
Status 
Death Date/ 
Day 
Principal Cause of Death 
Last Contact 
Date/  
Day 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Alive 
 
 
ddmmmyyyy/  
xx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Lost to 
Follow-up 
 
 
ddmmmyyyy/  
xx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Dead 
ddmmmyyyy/ 
xx 
Other: xxxxxxxxxxxxxxxxxxxxxxxx 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Alive 
 
 
ddmmmyyyy/  
xx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Dead 
ddmmmyyyy/ 
xx 
Study Indication 
 
 
 
 
 
 
 
Day is calculated relative to the day of first dose of study medication. 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.   
 


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
100 of 101 
 
 
Listing 16.6-1.5 (page 1 of n) 
Progression and Survival Details 
All Treated Patients 
 
Country/  
Centre/  
Patient 
Progression 
Status 
Date of 
First 
Progression 
Event 
Days from 
Start of 
Treatment to 
Progression 
Survival 
Status 
Date of 
Death/ 
Last 
Contact 
Days from 
Start of 
Treatment 
to Death 
Disease 
Control 
Objectiv
e 
Response 
Duration 
of 
Response 
(Days) 
 
 
 
 
 
 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Progression 
ddmmmyyyy 
xx 
Dead 
ddmmmyyyy 
xx 
No 
No 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
No 
Progression 
ddmmmyyyy 
xx^ 
Alive 
ddmmmyyyy 
xx^ 
Yes 
Yes 
xx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Progression 
ddmmmyyyy 
xx 
Alive 
ddmmmyyyy 
xx^ 
No 
No 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
No 
Progression 
ddmmmyyyy 
xx^ 
Alive 
ddmmmyyyy 
xx^ 
Yes 
Yes 
xx^ 
 
 
 
 
 
 
 
 
 
 
 
^Censored 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier.   


 
Novartis 
Confidential 
Date 
: 
22SEP2017 
IMP : Everolimus 
Version   : 
2 
Protocol No.: CRAD001LIC01 
Status 
: 
Final 
 
Page 
: 
101 of 101 
 
 
Listing 16.7-1.1 (page 1 of n) 
Comments Listing 
All Patients 
 
Country/  
Centre/  
Patient 
 
 
Cycle 
Page Number 
Comments 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 1 
Xxx 
Xxxxxxxx xxxxxxx xxxxx xxxxxxxxxxxx xxxxxxx 
Xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxx 
 
Cycle 4 
Xxx 
Xxxxxxxxxx xxxxxxxxxxx xxxxxxxxxxxxxxx xxxxxxxxxxxx xxxxxx 
 
 
 
 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
Cycle 2 
Xxx 
Xxxxxxxxxx xxxxxxxxxxx xxxxxxxxx xxxxxxxxx 
Xxxxxxxxxxx/ 
Xxxx-xxxxx 
End of 
Treatment 
Xx 
Xxxxxxxxxx xxxxxxxxxxx xxxxxxxxx xxxxxxxxx 
 
 
 
 
 
 
 
Programming note: Data ordered by country (alphabetically) then centre/patient identifier then by cycle and page 
number.