Conditions: Pancreatic Neuroendocrine Tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 61
Healthy volunteers: no

Brief summary:
To evaluate safety and efficacy of everolimus (Afinitor®) in Chinese adult patients with local advanced or metastatic, well differentiated progressive pancreatic neuroendocrine tumors.

Detailed description:
This was an open-label, multicenter, single-arm clinical study to evaluate the safety and efficacy of everolimus in Chinese adult patients with locally advanced, unresectable or metastatic, well differentiated progressive pancreatic neuroendocrine tumors. The inclusion and exclusion criteria, as well as the dosing and dose modification criteria are designed according to the approved Chinese Package Insert. The planned sample size of the study was approximately 60 subjects.

Subjects who were eligible received the treatment with everolimus provided by sponsor to treat pNET and followed the visit schedule in the protocol to collect safety and efficacy data until progression of disease, unacceptable toxicity, death, protocol deviation or other reason that may lead to discontinuation before the end of study. All subjects were followed-up for survival status every 6 months by the investigator until death, lost to follow-up, withdrawal of consent for survival or end of study.

The "End of study" is defined as either at least 75% of subjects have completed survival follow up or all subjects discontinued study treatment or the last subject finished 5-year survival follow up, whichever comes first. Final analysis was conducted at the end of the study.

Arms:
arm 1: Participants were instructed to take everolimus at a starting dose of 10 mg orally once daily. However, dose adjustments were permitted in order to allow the participant to continue the study treatment.

Interventions: intervention 1: everolimus
Intervention descriptions: intervention 1: Participants were instructed to take everolimus at a starting dose of 10 mg orally once daily. However, dose adjustments were permitted in order to allow the participant to continue the study treatment.

Protocol document:
Prot_000.pdf: 
Official Title: 
Phase IV, open-label, multi-center, single-arm study of the safety and 
efficacy of everolimus (Afinitor) in adult patients with locally 
advanced, unresectable or metastatic, well differentiated progressive 
pancreatic neuroendocrine tumors (pNET) in China. 
NCT Number: 
NCT02842749 
Document Date: Clinical Study Protocol Final Version 01: 31-May-2017 


Clinical Development 
Everolimus/ Afinitor 
Oncology Clinical Protocol CRAD001PCN31 
Phase IV, open-label, multi-center, single-arm study of the 
safety and efficacy of everolimus (Afinitor) in adult patients 
with locally advanced, unresectable or metastatic, well 
differentiated progressive pancreatic neuroendocrine 
tumors (pNET) in China 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
01 (Clean) 
Development phase 
IV 
Document status 
Final 
Release date 
31-May-2017
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 15-Jan-2017 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of appendices ................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 11 
1 
Background ........................................................................................................................ 15 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 15 
1.2 
Introduction to investigational treatment ............................................................... 17 
1.2.1 
Overview of everolimus ........................................................................ 17 
2 
Rationale ............................................................................................................................ 22 
2.1 
Study rationale and purpose................................................................................... 22 
2.2 
Rationale for the study design ............................................................................... 22 
2.3 
Rationale for dose and regimen selection .............................................................. 22 
2.4 
Rationale for choice of combination drugs ............................................................ 22 
2.5 
Rationale for choice of comparators drugs ............................................................ 22 
2.6 
Risks and benefits .................................................................................................. 23 
3 
Objectives and endpoints ................................................................................................... 23 
4 
Study design ...................................................................................................................... 25 
4.1 
Description of study design ................................................................................... 25 
4.2 
Timing of interim analyses and design adaptations ............................................... 25 
4.3 
Definition of end of the study ................................................................................ 26 
4.4 
Early study termination.......................................................................................... 26 
5 
Population .......................................................................................................................... 26 
5.1 
Patient population .................................................................................................. 26 
5.2 
Inclusion criteria .................................................................................................... 26 
5.3 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 28 
6.1 
Study treatment ...................................................................................................... 28 
6.1.1 
Dosing regimen ..................................................................................... 28 
6.1.2 
Ancillary treatments .............................................................................. 28 
6.1.3 
Rescue medication ................................................................................ 28 
6.1.4 
Treatment duration ................................................................................ 28 
6.2 
Dose escalation guidelines ..................................................................................... 28 


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6.3 
Dose modifications ................................................................................................ 28 
6.3.1 
Dose modification and dose delay ........................................................ 28 
6.3.2 
Follow-up for toxicities ......................................................................... 32 
6.4 
Concomitant medications ...................................................................................... 33 
6.4.1 
Permitted concomitant therapy ............................................................. 34 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 34 
6.4.3 
Prohibited concomitant therapy ............................................................ 36 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) ........................ 37 
6.5 
Patient numbering, treatment assignment or randomization ................................. 37 
6.5.1 
Patient numbering ................................................................................. 37 
6.5.2 
Treatment assignment or randomization ............................................... 37 
6.5.3 
Not applicable. Treatment blinding ....................................................... 37 
6.6 
Study drug preparation and dispensation ............................................................... 37 
6.6.1 
Study drug packaging and labeling ....................................................... 37 
6.6.2 
Drug supply and storage ........................................................................ 38 
6.6.3 
Study drug compliance and accountability ........................................... 38 
6.6.4 
Disposal and destruction ....................................................................... 39 
7 
Visit schedule and assessments ......................................................................................... 39 
7.1 
Study flow and visit schedule ................................................................................ 39 
7.1.1 
Molecular pre-screening ........................................................................ 42 
7.1.2 
Screening ............................................................................................... 42 
7.1.3 
Run-in period ........................................................................................ 42 
7.1.4 
Treatment period ................................................................................... 42 
7.1.5 
Discontinuation of study treatment ....................................................... 43 
7.1.6 
Withdrawal of consent .......................................................................... 43 
7.1.7 
Follow up for safety evaluations ........................................................... 44 
7.1.8 
Lost to follow-up ................................................................................... 44 
7.2 
Assessment types ................................................................................................... 44 
7.2.1 
Efficacy assessments ............................................................................. 44 
7.2.2 
Safety and tolerability assessments ....................................................... 45 
7.2.3 
Pharmacokinetics .................................................................................. 46 
7.2.4 
Biomarkers ............................................................................................ 47 
7.2.5 
Resource utilization ............................................................................... 47 
7.2.6 
Patient reported outcomes ..................................................................... 47 
8 
Safety monitoring and reporting ........................................................................................ 47 
8.1 
Adverse events ....................................................................................................... 47 


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8.1.1 
Definitions and reporting ...................................................................... 47 
8.1.2 
Laboratory test abnormalities ................................................................ 48 
8.1.3 
Adverse events of special interest ......................................................... 49 
8.2 
Serious adverse events ........................................................................................... 49 
8.2.1 
Definitions ............................................................................................. 49 
8.2.2 
Reporting ............................................................................................... 50 
8.3 
Emergency unblinding of treatment assignment ................................................... 51 
8.4 
Pregnancies ............................................................................................................ 51 
8.5 
Warnings and precautions...................................................................................... 52 
8.6 
Data Monitoring Committee .................................................................................. 52 
8.7 
Steering Committee ............................................................................................... 52 
9 
Data collection and management ....................................................................................... 53 
9.1 
Data confidentiality ............................................................................................... 53 
9.2 
Site monitoring ...................................................................................................... 53 
9.3 
Data collection ....................................................................................................... 54 
9.4 
Database management and quality control ............................................................ 54 
10 Statistical methods and data analysis ................................................................................ 54 
10.1 
Analysis sets .......................................................................................................... 54 
10.1.1 
Full Analysis Set ................................................................................... 54 
10.1.2 
Safety Set .............................................................................................. 54 
10.1.3 
Per-Protocol Set .................................................................................... 55 
10.1.4 
Dose-determining analysis set ............................................................... 55 
10.1.5 
Pharmacokinetic analysis set ................................................................. 55 
10.1.6 
Other analysis sets ................................................................................. 55 
10.2 
Patient demographics/other baseline characteristics ............................................. 55 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 55 
10.4 
Primary objective ................................................................................................... 55 
10.4.1 
Variable ................................................................................................. 55 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 55 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 56 
10.4.4 
Supportive and Sensitivity analyses ...................................................... 56 
10.5 
Secondary objectives ............................................................................................. 56 
10.5.1 
Key secondary objective(s) ................................................................... 56 
10.5.2 
Other secondary efficacy objectives ..................................................... 56 
10.5.3 
Safety objectives ................................................................................... 56 
10.5.4 
Pharmacokinetics .................................................................................. 58 


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10.5.5 
Biomarkers ............................................................................................ 58 
10.5.6 
Resource utilization ............................................................................... 58 
10.5.7 
Patient-reported outcomes ..................................................................... 58 
10.6 
Exploratory objectives ........................................................................................... 58 
10.7 
Interim analysis ...................................................................................................... 58 
10.8 
Sample size calculation.......................................................................................... 59 
10.9 
Power for analysis of key secondary variables ...................................................... 59 
11 Ethical considerations and administrative procedures ...................................................... 59 
11.1 
Regulatory and ethical compliance ........................................................................ 59 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 59 
11.3 
Informed consent procedures ................................................................................. 59 
11.4 
Discontinuation of the study .................................................................................. 60 
11.5 
Publication of study protocol and results............................................................... 60 
11.6 
Study documentation, record keeping and retention of documents ....................... 61 
11.7 
Confidentiality of study documents and patient records ....................................... 61 
11.8 
Audits and inspections ........................................................................................... 62 
11.9 
Financial disclosures .............................................................................................. 62 
12 Protocol adherence ............................................................................................................ 62 
12.1 
Amendments to the protocol .................................................................................. 62 
13 References (available upon request) .................................................................................. 63 
14 Appendices ........................................................................................................................ 66 
14.1 
Appendix 1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Version 3.1 Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival and Overall Survival .......................................... 66 
14.1.1 
Introduction ........................................................................................... 68 
14.1.2 
Efficacy assessments ............................................................................. 68 
14.1.3 
Definitions ............................................................................................. 68 
14.1.4 
Disease measurability ............................................................................ 68 
14.1.5 
Eligibility based on measurable disease ................................................ 69 
14.1.6 
Methods of tumor measurement - general guidelines ........................... 69 
14.1.7 
Baseline documentation of target and non-target lesions ..................... 71 
14.1.8 
Follow-up evaluation of target and non-target lesions .......................... 72 
14.1.9 
Follow-up and recording of lesions ....................................................... 72 
14.1.10 
Non-nodal lesions.................................................................................. 72 
14.1.11 
Nodal lesions ......................................................................................... 72 
14.1.12 
Determination of target lesion response ................................................ 73 
14.1.13 
Determination of non-target lesion response ........................................ 75 


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14.1.14 
New lesions ........................................................................................... 75 
14.1.15 
Evaluation of overall lesion response ................................................... 76 
14.1.16 
Efficacy definitions ............................................................................... 76 
14.1.17 
Best overall response............................................................................. 77 
14.1.18 
Time to event variables ......................................................................... 79 
14.1.19 
Progression-free survival ...................................................................... 79 
14.1.20 
Overall survival ..................................................................................... 79 
14.1.21 
Time to progression............................................................................... 80 
14.1.22 
Time to treatment failure ....................................................................... 80 
14.1.23 
Duration of response ............................................................................. 80 
14.1.24 
Time to response ................................................................................... 81 
14.1.25 
Definition of start and end dates for time to event variables ................ 82 
14.1.26 
Handling of patients with non-measurable disease only at baseline ..... 83 
14.1.27 
Sensitivity analyses ............................................................................... 84 
14.1.28 
Data handling and programming rules .................................................. 85 
14.1.29 
Study/project specific decisions ............................................................ 85 
14.1.30 
End of treatment phase completion ....................................................... 86 
14.1.31 
End of post-treatment follow-up (study phase completion) .................. 86 
14.1.32 
Medical validation of programmed overall lesion response ................. 87 
14.1.33 
Programming rules ................................................................................ 87 
14.1.34 
Calculation of ‘time to event’ variables ................................................ 87 
14.1.35 
Incomplete assessment dates ................................................................. 87 
14.1.36 
Incomplete dates for last known date patient alive or death ................. 88 
14.1.37 
Non-target lesion response .................................................................... 88 
14.1.38 
Study/project specific programming ..................................................... 88 
14.1.39 
Censoring reason ................................................................................... 88 
14.1.40 
References (available upon request) ..................................................... 89 
 


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List of appendices 
Appendix 1: Efficacy guidelines (Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
List of figures 
Figure 4-1 
Study design .......................................................................................... 25 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 24 
Table 6-1 
Afinitor Dose Adjustment and Management Recommendation for 
Adverse Drug Reaction ......................................................................... 29 
Table 6-2 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A ................................................................................ 35 
Table 6-3 
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A dual inhibitors ............................... 36 
Table 6-4 
Preparation and dispensing ................................................................... 37 
Table 7-1 
Visit evaluation schedule ...................................................................... 40 
Table 14-1 
Response criteria for target lesions ....................................................... 73 
Table 14-2 
Response criteria for non-target lesions ................................................ 75 
Table 14-3 
Overall lesion response at each assessment .......................................... 76 
Table 14-4 
Overall lesion response at each assessment: patients with non-
target disease only ................................................................................. 83 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response .......... 84 
 


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List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
CFDA 
China Food and Drug Administration 
CMO&PS 
Chief Medical Office and Patient Safety 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or 
Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
EDD 
Estimated Deliver Date 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Package insert 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 


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


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Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 
Withdrawal of consent 
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact 


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Protocol summary 
Title 
Phase IV, open-label, multi-center, single-arm study of the safety and efficacy of 
everolimus (Afinitor) in adult patients with locally advanced, unresectable or 
metastatic, well differentiated progressive pancreatic neuroendocrine tumors 
(pNET) in China. 
Brief title 
Phase IV study of the safety and efficacy of everolimus (Afinitor) in adult patients 
with progressive pancreatic neuroendocrine tumors (pNET) in China. 
Sponsor and 
Clinical Phase 
Novartis 
IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
To evaluate safety and efficacy of everolimus (Afinitor®) in Chinese adult patients 
with locally advanced, unresectable or metastatic, well differentiated progressive 
pancreatic neuroendocrine tumors. 
Primary Objective(s) and 
Key Secondary Objective 
Primary: To evaluate the safety of treatment with Afinitor in Chinese adult patients 
with well differentiated progressive p-NET. 
No key secondary objective 
Secondary Objectives 
Secondary: To evaluate the overall efficacy of treatment with Afinitor in Chinese 
patients with well differentiated progressive p-NET 
Study design 
Open-label, multi-center, single-arm study of the safety and efficacy of everolimus 
(Afinitor) in adult patients with locally advanced, unresectable or metastatic, well 
differentiated progressive pancreatic neuroendocrine tumors (pNET) in China. 
Population 
Chinese adult patients with unresectable, locally advanced, unresectable or 
metastatic, G1 or G2 progressive pancreatic neuroendocrine tumors (pNET) (WHO 
2010). 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
Written informed consent must be obtained prior to any screening procedures. 
1. Chinese Adult patients ≥ 18 years of age 
2. Patients must have histological confirmed G1 or G2 pancreatic neuroendocrine 
tumors(pNETs) (WHO 2010) 
3. Patients must have radiological documentation of progression of disease per 
RECIST 1.1 within 12 months prior to enrollment. 
4. Measurable disease per RECIST 1.1 criteria using triphasic computed 
tomography (CT) scan or multiphase MRI for radiologic assessment. 
5. Afinitor treatment which is recommended by the treating physician. 
 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the 
excipients. 
2. Inability to attend scheduled clinic visits or scheduled tests. 
3. Patient who is unwilling to receive Afinitor treatment due to any reason. 
4. Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, confirmed 
by a positive hCG laboratory test. 
Women of child-bearing potential, who are or might become sexually active, must 
be informed of the need to prevent pregnancy during the study. Women of child-
bearing potential, defined as all women physiologically capable of becoming 
pregnant (including female pediatric patients who are menarcheal or who become 
menarcheal during the study), must use highly effective contraception during study 
treatment and for8 weeks after stopping treatment. 
Highly effective contraception methods include: 
 


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a. 
Total abstinence (when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception 
b. 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
c. 
Male sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that subject with the appropriate 
post-vasectomy documentation of the absence of sperm in the ejaculate 
d. 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository 
e. 
Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS), or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
5. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus). 
6. Use of an investigational drug within the 30 days prior to enrollment 
7. Any severe and/or uncontrolled medical conditions which could cause 
unacceptable safety risks or compromise compliance with the protocol, such as: 
Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of study drug (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, etc). 
8. Known history of seropositivity for human immunodeficiency virus (HIV) 
9. Any cause that the investigator considers will harm the patient’s benefit if 
participate in this study and please specify. 
 
Investigational and 
reference therapy 
everolimus 10mg/day 
Efficacy assessments 
● Overall Survival： defined as time from study treatment to death due to any 
cause. 
● Progression free survival：defined as time from first dose of study treatment to 
progression or death due to any cause 
Safety assessments 
Incidences of AEs, AE suspected to be related to Afinitor, Grade 3/4 AEs and 
SAEs 
Other assessments 
Not applicable to this study 
Data analysis 
Descriptive Statistics for safety variables and efficacy assessment, will be provided 
through tables and listings whereas applicable.  
Key words 
Everolimus (Afinitor®), locally advanced, unresectable or metastatic, well 
differentiated progressive pancreatic neuroendocrine tumors, safety, efficacy  


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Amendment 1 (31-May-2017) 
Amendment rationale 
The main purpose of the amendment is: 
• To increase the sample size from approximately 30 to 60 patients to collect additional 
safety and efficacy data of everolimus in Chinese adult patients with pNET to meet the 
post-approval commitment request from CFDA. 
• To update format according to new template. 
• To fix wording, spelling and punctuation. 
First patient first visit (FPFV) of this study was on 14-Mar-2016 and 31 patients had been 
enrolled by Nov 2016. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The following changes have been implemented: 
• Section 1.1, 2.1, 3, 5.1, 5.2, 10.8: To add “unresectable” to clearly identify 
population.Section 1.2.1 and 1.2.1.1: Update approved indication and registry study’s 
brief result. 
• Section 1.2.1.1: Add non-clinical experience. 
• Section 2.4, 2.5, 6.1.2, 6.1.3, 6.4.4, 7.1.1, 7.1.2.1, 7.1.3, 7.1.5.1, 7.1.7, 7.1.8, 7.2.2.6, 
7.2.2.7, 7.2.2.8, 8.6, 8.7, 10.1.6, 10.2, 10.5.6, 10.5.7 and 10.6: Insert related sections 
according to new template and most are not applicable. 
• Section 2.6: Replace original 6.3.3 section to section 2.6 risk and benefit according to new 
template. 
• Section 4.1: Add sentences to emphasize commercial drug shifting has no impact on 
participation in the study. 
• Section 4.2 and 10.7: To remove the license renewal specific date. 
• Section 4.3: Clearly identify end of treatment (EOT). 
• Section 5.1 and 10.7: The sample size has been increased to approximately 60 patients in 
total. 
• Section 5.3: Update contraceptive text (highly effective methods) 
• Section 6.1.1: Update dosing regimen according to new template. 
• Section 6.3: Add dose adjustments guidance for QTcF. 
• Section 6.3.2.1: Add drug-induced liver injury. 
• Section 6.4: Add permitted and prohibited concomitant therapy. 
• Section 7: Add a column for follow up on 30 day safety follow-up in Table 7-1 
• Section 7.2.2.3: Add text to describe screening measurement of height and body weight. 


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• Section 8.1.1, 8.1.3 and 8.2.2: Update safety monitoring and reporting wording according 
to new template. 
• Section 8.3 &10.5.3.2: Add 3 items of AESI 
• Section 10.1.2: Update safety set definition according to new template. 
• Section 10.5.3.2 and 10.5.3.3: Update description of AEs and laboratory abnormalities 
according to new template. 
• Section 10.5.3.1: Corrected the post-treatment period from “starting at day 31+1 after last 
dose of study medication” to “starting at day 31 after last dose of study medication” for 
safety analyses. 
• Section 10.7 Add text to describe interim analysis- both safety and efficacy. 
• Section 2.2, 2.3, 5.1, 6.61, 7.2.2 8.2.2, 8.4 and 9.4: Spelling and punctuation has been 
corrected. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Neuroendocrine tumors (NETs) are a genetically diverse group of rare malignant tumors that 
arise from neuroendocrine cells throughout the body, e.g. the pancreatic islet cells, 
neuroendocrine cells within the respiratory epithelium, parafollicular cells within the thyroid 
and from the diffuse neuroendocrine cells in the gastrointestinal (GI) tract. Their clinical 
course is often indolent but can also be highly aggressive and resistant to therapy (Yao 
2008b). Historically, they have been referred to as carcinoid tumors (with the exception of 
pancreatic islet cell tumors) and classified according to their point of origin in embryonic 
development as foregut (e.g.,bronchial or gastric carcinoid), midgut (e.g., small intestine or 
appendiceal carcinoid), or hindgut (e.g., rectal carcinoid) NETs. More recently the WHO 
designation has gained acceptance in the literature as it appears to have better prognostic 
relevance. In this modern anatomic nomenclature, NETs are classified on the basis of primary 
tumor location (e.g. gastrointestinal (jejunum, ileum, appendix, etc.), lung, or pancreas), rather 
than the previous classification based on the embryonic origin of the organ. Well-
differentiated neuroendocrine tumors of unknown origin are generally considered to be of 
gastrointestinal origin (Klöppel et al 2004). 
The incidence of neuroendocrine tumors has been increasing over the past several decades. 
Results from the National Cancer Institute Surveillance, Epidemiology and End Results 
(SEER) database show that in 2004, there were 5.25 new patients with NETs per 100,000 
people (age-adjusted US 2000 standard population), compared with the 1.09 new cases of 
NETs per 100,000 people in 1973 (Yao et al 2008a). NETs of the small intestine, lung and 
rectum are the most frequently diagnosed NETs in the US, and have had the greatest increase 
in incidence from 1973 to 2004 (Yao et al 2008a). Since most NETs are slow growing and the 
majority are not associated with characteristic symptoms associated with the secretion of 
peptides and other bioactive molecules, many NETs are discovered incidentally during routine 
colonoscopy or other endoscopic procedures, or during autopsy (Oberg and Jelic 2008). As 
such, commonly cited figures may underestimate the true incidence of NETs. 
The majority of patients with NETs present with advanced disease at diagnosis, with regional 
spread or distant metastasis seen in 50% of patients (Yao et al 2008a). Up to 75% of patients 
who present with NETs of the mid- or hindgut region, and approximately 60% of patients 
with pNETs have liver metastases (Falconi et al 2006). Metastases usually develop initially in 
regional lymph nodes, later in the liver and subsequently in distant sites, such as bone (Metz 
and Jensen 2008). 
pNET 
Pancreatic neuroendocrine tumors (pNETs), or islet cell tumors of the pancreas (ICT), 
comprise only 1-2% of all pancreatic tumors and less than 10% of all neuroendocrine tumors 
(Yao 2008a). Pancreatic NETs constitute a distinct subgroup of NETs characterized by a 
different genetic profile, more aggressive clinical evolution, and a different pattern of 


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response to cytotoxic chemotherapy (Yao 2008a). The annual incidence of pancreatic NET is 
approximately 3.5 to 4 per million population (Barakat 2004). The peak age of occurrence is 
from 40 to 60 years. The polypeptide hormones secreted by pancreatic neuroendocrine tumors 
(pNETs) vary depending upon the cell type of origin within the pancreatic islet; these can 
include insulin (insulinoma), gastrin (gastrinoma), vasoactive intestinal peptide (VIPoma), 
and glucagon (glucagonoma) (Barakat 2004). The apparently “nonfunctioning” (i.e., non-
secreting) pNETs tend to be more aggressive and present with symptoms of tumor bulk 
(Barakat 2004). Nonfunctioning tumors account for approximately 30% of all pancreatic 
neuroendocrine tumors (pNETs). 
Although pancreatic neuroendocrine tumors (pNETs) are sometimes considered to be indolent, 
patients with unresectable or metastatic tumors have a lethal disease, and all pancreatic 
neuroendocrine tumors (pNETs), with the exception of 90% of insulinomas, have long-term 
metastatic potential. Morbidity can arise both from secreted hormones as well as tumor bulk 
(Barakat 2004). The median survival for pancreatic neuroendocrine tumors (pNETs) patients 
with metastatic disease is 27 months (Yao 2008a). 
Gastrointestinal (GI) and Bronchopulmonary neuroendocrine tumors 
GI NETs can arise from neuroendocrine cells throughout the gastrointestinal tract. The most 
frequent sites of origin include the small intestine, stomach, cecum, appendix, colon and 
rectum (Yao 2008a). Approximately 10% of patients with carcinoid tumors suffer from the 
classical symptoms of carcinoid syndrome, caused by elevated levels of serotonin ([Barak 
2004]). While advanced GI NETs have a reputation for being slowly progressive compared 
with other tumor types (such as adenocarcinomas), the median survival for patients with 
metastatic GI NETs varies from 13 months for patients with a gastric primary to 65 months 
for NETs of small intestinal origin (Yao 2008a). 
The bronchopulmonary tree represents another common site of origin of carcinoid tumors, 
with an annual incidence of approximately 1.4 cases per 100,000 (Yao 2008a). The median 
survival for patients with lung NETs following metastatic spread is 27 months (Yao 2008a). 
Treatment of neuroendocrine tumors 
The primary treatment goal for patients with neuroendocrine tumors (NETs) is complete 
resection of the tumor. If inoperable, the goal is to control tumor growth, to control symptoms 
if the tumor is functional, and to prolong survival time. Surgical resection represents the 
traditional first-line therapy of NETs (Plockinger and Wiedenmann 2007). The prognosis 
following complete surgical resection is generally favorable (Schurr et al 2007). However, 
curative surgery is often not possible because the majority of patients present with locally 
advanced, unresectable or metastatic disease. When radical surgery cannot be performed, 
debulking procedures and resection of metastases (i.e. in liver) may improve the outcome of 
patients. Guidelines state that surgical resection of liver metastases should be undertaken only 
if at least 90% of the tumor mass can be removed (Plockinger et al 2004; Eriksson et al 2008). 
Cytoreductive surgery (tumor debulking) may also render medical therapy more effective by 
decreasing the secretion of bioactive substances. In patients with jejuno-ileal NETs and liver 
metastases, the post-surgical 5-year survival rate is approximately 60% compare to 30% in 
those patients without surgical treatment (Eriksson et al 2008). 


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Biotherapy with somatostatin (SMS) analogs (SSAs) remains the mainstay of symptomatic 
therapy for neuroendocrine tumors (NETs). Most neuroendocrine tumors (NETs) highly 
express somatostatin receptors (SSTRs). In addition to its recognized antisecretory effects, 
octreotide appears to induce antiproliferative effects on the tumor. Direct effects are mediated 
through binding directly to the tumor cell, whereas indirect effects may occur via inhibition of 
growth factors and angiogenesis and through effects on the immune system. Subsequent to the 
approval of octreotide for the treatment of symptoms of functional GI NETS and pNETs, 
evidence of antitumor activity of octreotide was observed in small series of patients (Arnold et 
al 1993; Arnold et al 1996; Evers et al 1991; Pollak et al 1989; Arnold et al 1992). 
Subsequently, the PROMID trial, a randomized, double-blind, placebo-controlled, multicenter 
trial in patients with well differentiated inoperable or metastatic embryonic midgut NET 
showed significant delay in time to tumor progression (TTP) in patients treated with 
octreotide LAR 30 mg compared to placebo (Rinke et al 2009). 
For patients who experience disease progression, therapeutic options are limited. For 
gastrointestinal (GI) NETs, despite the many chemotherapy trials that have been conducted, 
no regimen has demonstrated a response rate of more than 15% using the criterion of a 50% 
reduction of bidimensionally measurable disease (Schnirer Yao and Ajani 2003). Interferon 
has also been widely studied in this disease setting. Pooling the data from patients with 
carcinoid tumors involved in these trials, only 37 (12%) of 309 had objective tumor responses 
(Schnirer Yao and Ajani 2003). 
Despite the approval of streptozocin in 1976 by the US FDA, the role of chemotherapy for 
patients with advanced neuroendocrine tumors continues to be debated. Clinical trials using 
streptozocin alone and in combination with agents such as doxorubicin have reported 
objective responses, but most studies did not use currently accepted methods such as cross-
sectional radiological imaging in conjunction with RECIST or WHO criteria. 
Chemotherapeutic regimens used for treatment of pancreatic neuroendocrine tumors (pNETs) 
can be associated with significant toxicity, and no published data have documented 
improvements in progression-free or overall survival (Yao 2010a). 
1.2 
Introduction to investigational treatment 
1.2.1 
Overview of everolimus 
Everolimus first entered clinical development for one of numerous oncology indications in 
2002. 
It was approved by the FDA on 30-Mar-2009 under the trade name Afinitor® for the treatment 
of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib 
or sorafenib. The European Commission (EC) approved Afinitor® on 03-Aug-2009 for the 
treatment of patients with advanced RCC, whose disease has progressed on or after treatment 
with vascular endothelial growth factor (VEGF)-targeted therapy. Everolimus has been 
approved in 122 countries worldwide for the treatment of patients with advanced RCC. 
On 05-May-2011, FDA approved Afinitor® for the treatment of progressive neuroendocrine 
tumors of pancreatic origin (pNET) in patients with unresectable, locally advanced or 
metastatic disease. The EC approved Afinitor® on 24-Aug-2011 for the treatment of 
unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumors of 


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pancreatic origin in adults with progressive disease. Everolimus has been approved in 112 
countries worldwide for the treatment of patients with advanced pNET/NET. 
On 26-Feb-2016, FDA approved Afinitor® for advanced non-functional NET of 
gastrointestinal (GI) or lung origin based on the results of Phase III study T2302. On 20-Jul-
2012, FDA approved Afinitor® for the treatment of postmenopausal women with advanced 
hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative 
(HER2-) breast cancer in combination with exemestane, after failure of treatment with 
letrozole or anastrozole. The EC approved Afinitor® on 23-Jul-2012 for the treatment of HR+, 
HER2- advanced breast cancer, in combination with exemestane, in postmenopausal women 
without symptomatic visceral disease after recurrence or progression following a non-
steroidal aromatase inhibitor. Everolimus has been approved in 115 countries worldwide for 
the treatment of patients with advanced HR+, HER2- breast cancer. 
Everolimus received accelerated approval from FDA on 29-Oct-2010 for the treatment of 
patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis 
that require therapeutic intervention but are not candidates for curative surgical resection. 
Subsequently on 26-Apr-2012, the indication was slightly revised by FDA to “Afinitor® is 
indicated for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA 
associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are 
not candidates for curative surgical resection”. The EC conditionally approved everolimus on 
02-Sep-2011 under the trade name Votubia® for the treatment of patients aged 3 years and 
older with SEGA associated with TSC who require therapeutic intervention but are not 
amenable to surgery. 
On 29-Aug-2012, FDA revised the indication to “Afinitor® Tablets and Afinitor® Disperz are 
indicated in pediatric and adult patients with TSC for the treatment of SEGA that requires 
therapeutic intervention but cannot be curatively resected”. 
Under the trade name of Votubia®, on 15-Nov-2013, based on M2301 study, the indication 
was revised with the removal of the age restriction to “Votubia is indicated for the treatment 
of patients with SEGA associate with TSC who require therapeutic intervention but are not 
amendable to surgery”. 
The follow-up data from studies C2485 and M2301 demonstrated sustained efficacy and 
safety of everolimus in this patient population. In 2015/2016, these data allowed the 
conversion of the conditional marketing authorization to full approval in the EU and 
fulfillment of post-marketing requirements by the FDA. 
Everolimus has been approved in 100 countries worldwide for the treatment of patients with 
TSC who have SEGA. 
Everolimus received accelerated approval from FDA on 26-Apr-2012 for the treatment of 
adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. On 31-
Oct-2012, the EC granted a decision for Votubia® for the treatment of adult patients with renal 
angiomyolipoma associated with TSC who are at risk of complications (based on factors such 
as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do 
not require immediate surgery. 


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Finally in 2017, everolimus received approval in Europe for the treatment of patients 2 years 
and older with refractory partial onset seizures associated with TSC. 
In China, everolimus has received approval in the advanced RCC on 22 Jan 2013, advanced 
pNET and TSC-SEGA on 13 Feb 2014 and TSC-AML on 29 Nov 2016. 
1.2.1.1 
Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including 
lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range 
from sub/low nM to µM. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The anti-
angiogenic activity of everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and 
metastatic tumors treated with everolimus showed a significant reduction in blood vessel 
density when compared to controls. 
The potential of everolimus as an anti-cancer agent was shown in rodent models. Everolimus 
is orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse 
xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. 
The pharmacokinetic profile of everolimus indicates sufficient tumor penetration, above that 
needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
everolimus in vitro. 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung 
and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). 
These models included tumor lines considered sensitive and “relatively resistant” in vitro. In 
general, everolimus was better tolerated in mouse xenograft models than standard cytotoxic 
agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. 
Additionally, activity in a VEGF-impregnated subcutaneous implant model of angiogenesis 
and reduced vascularity (vessel density) of everolimus-treated tumors (murine melanoma) 
provided evidence of in vivo effects of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and 
the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with 
PTEN status. 
In vivo studies investigating the anti-tumor activity of everolimus in experimental animal 
tumor models showed that everolimus monotherapy typically reduced tumor cell growth rates 
rather than produced regressions. These effects occurred within the dose range of 2.5 mg to 10 
mg/kg, orally once a day. 
In preclinical models, the administration of everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) 
and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein upstream 
of mTOR signaling pathway. 


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All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes. 
Further details can be found in the [everolimus IB] and/or the locally approved prescribing 
information. 
1.2.1.2 
Clinical experience 
Several lines of evidence suggest that the mTOR pathway is involved in the pathogenesis of 
NETs. For example, patients with defects in the TSC2 gene, whose protein product inhibits 
mTOR activation, develop pancreatic neuroendocrine tumours (pNETs). Loss of the NF1 
gene, which also regulates mTOR activity, is associated with the development of GI NETs in 
patients with neurofibromatosis. Sporadic NETs have been shown to coexpress insulin-like 
growth factor (IGF-1) and the IGF1 receptor (IGF-1R). Activation of the IGF-1/IGF-1R 
pathway activates mTOR leading to increased cell proliferation (Yao 2008b). Lastly, gene 
expression profiling studies show inhibition of the TSC2 and PTEN genes, both of which act 
as negative regulators of the PI3K/Akt/mTOR pathway, in most tumor samples from patients 
with pNETs, with lower levels of expression being associated with shorter disease-free and 
overall survival (Missiaglia 2010). 
Based on these observations, a phase II clinical trial conducted by J. Yao at the MD Anderson 
Cancer Center studied everolimus and octreotide LAR in advanced low grade neuroendocrine 
carcinoma (Yao 2008b). A total of 60 evaluable patients were treated in two cohorts; patients 
received either everolimus at 5mg/day or 10 mg/day. Out of the sixty treated patients, 30 had 
carcinoid, and 30 islet cell tumours. Sixty-five percent of the patients were in progression at 
the time of study entry. Overall, 12 (20%) patients were reported to have partial response (4 
carcinoids and 8 islet cell tumours, respectively), 43 (72%) had stable disease (25 in 
carcinoids and 18 in islet cell, respectively) and 5 (8%) had progressive disease (1 in 
carcinoids and 4 in islet cell, respectively) per RECIST. Overall median progression free 
survival (PFS) was 59 weeks (64 weeks in carcinoids and 50 in islet cell tumours, 
respectively). Median overall survival (OS) was not reached, with a 2 yrs survival rate of 78%. 
The combination of everolimus and octreotide LAR 30 mg appears to have been well 
tolerated. The most common toxicity reported was mucositis. CTC Grade 3/4 toxicities 
reported included: anemia, thrombocytopenia, aphthous ulcer, diarrhea, edema, fatigue, 
hypoglycemia, nausea, pain, and rash. 
Subsequently, a second phase II open label, parallel group study was conducted in patients 
with advanced pancreatic neuroendocrine tumors (pNETs). Patients received either 
everolimus 10 mg daily as monotherapy (stratum 1; n = 115) or everolimus 10 mg daily in 
combination with ≤30 mg octreotide LAR q 28 days (stratum 2; n = 45), based on prior 
octreotide LAR treatment (Yao 2010a). In stratum 1, there were 11 partial responses (9.6%), 
78 patients with stable disease (67.8%), and 16 patients with progressive disease (13.9%); 
median progression-free survival was 9.7 months. In stratum 2, there were two partial 
responses (4.4%), 36 patients with stable disease (80%), and no patient with progressive 
disease. Median progression-free survival (PFS) was 16.7 months. 


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Two Phase III studies have recently provided additional evidence that everolimus has 
promising activity in patients with advanced neuroendocrine tumors. 
[CRAD001C2324] is a phase III randomized double blind study of everolimus + best 
supportive care (BSC) vs. placebo + BSC in patients with pancreatic neuroendocrine tumors 
who have radiological documentation of disease progression within 12 months prior to 
randomization (Yao 2011). Patients were randomized 1:1 to receive either everolimus 10 mg 
once daily (n = 207) or placebo (n = 203). Patients in the placebo arm were allowed to 
crossover upon disease progression. Patients were stratified by prior cytotoxic chemotherapy 
and WHO performance status. The primary endpoint was progression free survival. Median 
progression free survival was 11.04 months for everolimus compared to 4.60 months for 
placebo (HR=0.35; 95% confidence interval, 0.27 to 0.45; p <0.0001). No statistically 
significant difference in overall survival between the two arms was seen. The most common 
adverse reactions (occurring > 20%) in the everolimus arm included: stomatitis (53.9%), rash 
(52.5%), diarrhea (46.6%), fatigue (43.6%), peripheral edema (35.8%), nausea (31.9%), 
headache (29.9%), pyrexia (29.4%), decreased appetite (28.9%), vomiting (28.4%), weight 
loss (27.9%), abdominal pain (23.5%), anemia (22.1%), cough (21.6%) and epistaxis (21.1%). 
Study [CRAD001C2325] is a Phase III randomized double blind study of everolimus in 
combination with octreotide LAR versus placebo + octreotide LAR in patients with advanced 
low or intermediate grade NET with a history of secretory symptoms and radiological 
documentation of disease progression within 12 months prior to randomization (Pavel 2011). 
Patients were randomized 1:1 to receive either everolimus 10 mg once daily + octreotide LAR 
30 mg once every 28 days (n = 216) or placebo + octreotide LAR 30 mg once every 28 days 
(n = 213). Patients in the placebo + octreotide LAR arm were allowed to crossover to 
treatment with open label everolimus + octreotide LAR upon disease progression. The 
primary endpoint was progression free survival (PFS) by central radiology review 
(adjudicated central review). Median progression free survival was 16.4 months for 
everolimus + octreotide LAR compared to 11.3 months for placebo + octreotide LAR 
(HR=0.77; 95% confidence interval, 0.59 to 1.00; p=0.026 vs. P=0.0246 pre-specified). 
Median PFS by investigator assessment was 12.0 months for everolimus + octreotide LAR 
compared to 8.6 months for placebo + octreotide LAR (HR=0.78; 95% confidence interval, 
0.62 to 0.98; p=0.018). Adjusting for different censoring patterns, loss of power, and baseline 
imbalances between the two treatment arms, the Inverse Probability of Censoring Weights 
(IPCW) adjusted PFS, which was pre-specified in the study, demonstrated a consistent benefit 
in favor of everolimus + octreotide LAR (HR=0.60; 95% confidence interval, 0.44 to 0.84; 
p=0.0014). No statistically significant difference in overall survival between the two arms was 
seen. The most common adverse reactions (occurring ≥ 20%) in the everolimus + octreotide 
LAR arm included: stomatitis (62%), rash (37%), fatigue (31%), diarrhea (27%), nausea (20%) 
and infections (20%). 
Study [CRAD001T2302] included patients with advanced, progressive non-functional NET of 
GI or lung origin. Everolimus demonstrated superiority over placebo in terms of PFS showing 
a 52% relative risk reduction of progression/death in favor of everolimus (HR: 0.48; 95% CI: 
0.35, 0.67) (p<0.001) (Yao 2016)). Based on these results, submissions worldwide have led to 
marketing authorization of everolimus in progressive, nonfunctional NET of GI or lung origin 
in over 41 countries including the US, EU, Canada, and Japan. 


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2 
Rationale 
2.1 
Study rationale and purpose 
In China, everolimus (Afinitor) has been approved for the treatment of patients with local 
advanced, 
unresectable 
or 
metastatic, 
well 
differentiated 
progressive 
pancreatic 
neuroendocrine tumors (pNET) without safety and efficacy data in Chinese patients. 
Thus this study is a post-approval commitment to China CFDA’s request to collect the safety 
and efficacy data of everolimus in Chinese adult patients within this indication. 
2.2 
Rationale for the study design 
This is a single arm, open-label study. The inclusion and exclusion criteria, as well as the 
dosing and dose modification criteria are designed according to the approved Chinese 
Package Insert (PI). 
The primary variable corresponding to the main objective of the study is the safety profile in 
terms of adverse events, serious adverse events, adverse events suspected to be related to 
study drug and Grade 3 and 4 AEs. In addition, the incidences of specific adverse events of 
non-infectious pneumonitis as requested by CDE will be determined. For a complete list of 
the adverse events of special interest refer to Section 8.1.3. 
Efficacy endpoint will be the same as the primary endpoint in global phase 3 study 
CRAD001C2324, i.e. progression free survival (PFS), and the 5 year OS data as required by 
CDE in the approval letter. 
This is an interventional study. In order to minimize the risk of low data quality, interval of 
visit schedule is relatively fixed. The population and dosing chosen for this study are all 
within label indication and the test are all suggested by approved Chinese PI for safety 
consideration. 
2.3 
Rationale for dose and regimen selection 
Starting dose and dose adjustment will follow the approved Chinese Package Insert. The 
starting dose is 10 mg once daily. The subsequent dose levels are subject to change due to 
severe or intolerable adverse reactions, change of liver function, changes in concomitant drug 
use (refer to Section 6.3.1). 
2.4 
Rationale for choice of combination drugs 
Not applicable 
2.5 
Rationale for choice of comparators drugs 
Not applicable 


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2.6 
Risks and benefits 
Appropriate eligibility criteria as well as specific dose modification and stopping rules, are 
included in this protocol. Recommended guidelines for prophylactic or supportive 
management of study-drug induced adverse events are provided in Section 6.3.1. The risk to 
subjects in this trial may be minimized by compliance with the eligibility criteria and study 
procedures, as well as, close clinical monitoring and targeted follow up checklist use for 
specific adverse events. There may be unforeseen risks with study treatment which could be 
serious including: Onset of benign or malignant tumors; potential risks related to missing 
information for the specific study population, e.g. Patients with uncontrolled cardiac disease 
etc. 
3 
Objectives and endpoints 
To evaluate safety and efficacy of everolimus (Afinitor®) in Chinese adult patients with local 
advanced, 
unresectable 
or 
metastatic, 
well 
differentiated 
progressive 
pancreatic 
neuroendocrine tumors. 
Objectives and related endpoints are described in Table 3-1. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To evaluate the safety of treatment with Afinitor 
in Chinese adult patients with well differentiated 
progressive p-NET 
Incidences of AEs, AE suspected to be related to 
Afinitor, Grade 3/4 AEs and SAEs 
Listing of AEs with special interest: 
Non-infectious pneumonitis 
 
Secondary 
 
Refer to Section 10.5 
To evaluate the overall efficacy of treatment with 
Afinitor in Chinese patients with well 
differentiated progressive p-NET 
● Overall Survival：defined as time from study 
treatment to death due to any cause. 
● Progression free survival ： defined as time 
from first dose of study treatment to progression 
or death due to any cause 
 
Other secondary 
 
 
 
Not applicable 
Not applicable 


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4 
Study design 
4.1 
Description of study design 
Patient who are eligible will be provided with everolimus by sponsor to treat pNET and will 
follow the visit schedule in Table 7-1 to collect safety and efficacy data until disease 
progression, unacceptable toxicity, death, protocol deviation or other reason that may lead to 
discontinuation before the end of study. All patients will be followed-up for survival status 
every 6 months by the investigator until death, lost to follow-up, withdrawal of consent for 
survival or end of study. If the patient is still on treatment after 2 years, he/she will be shifted 
to commercial drug. However, this shift has no impact on participation in the study, all 
assessments will continue as before. 
Figure 4-1 
Study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
Timing of interim analyses and design adaptations 
Interim analysis is planned for this study to provide a snapshot of data available to CFDA for 
license renewal. Based on the license renewal timeline, an interim analysis is planned in July 
2017 with approximate 30 patients enrolled. 
Screening/Baseline 
(Day-28 to Day0)
Visit 1 (first dose) 
End of treatment 
Survival follow-up 
(until the end of study)  
Treatment phase 
Follow-up phase 
Screening/Baseline 
(Day-28 to Day0)
Visit 1 (first dose) 
Treatment phase 
End of treatment 
Follow-up phase 
Survival follow-up 
(until the end of study)  
Screening/Baseline 
(Day-28 to Day0)
Visit 1 (first dose) 
Treatment phase 
End of treatment 
Follow-up phase 
Survival follow-up 
(until the end of study)  
Screening/Baseline 
(Day-28 to Day0) 
Visit 1 (first dose) 
Treatment phase 
End of treatment 
Follow-up phase 
Survival follow-up 
(until the end of study) 


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4.3 
Definition of end of the study 
The “End of study” is defined as either at least 75% of patients have completed survival 
follow up or all patients discontinued study treatment or the last patient finished 5-year 
survival follow up, whichever comes first. Final analysis will be conducted at the end of the 
study. Additional analyses between interim analyses (IA) and final analysis might be 
performed per Center for Drug Evaluation (CDE)’s request. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
5 
Population 
5.1 
Patient population 
 The patient population includes Chinese adult patients with unresectable, locally advanced or 
metastatic, G1 or G2 progressive pancreatic neuroendocrine tumors (pNET) (WHO 2010). 
The planned sample size will be approximately 60patients with 30 additional patients enrolled 
after protocol amendment (v01). 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
Written informed consent must be obtained prior to any screening procedures 
1. Chinese Adult patients ≥ 18 years of age 
2. Patients must have histological confirmed G1 or G2 locally advanced, unresectable 
pancreatic neuroendocrine tumors(pNETs) (WHO 2010) 
3. Patients must have radiological documentation of progression of disease per RECIST 1.1 
within 12 months prior to enrollment. 
4. Measurable disease per RECIST 1.1 criteria using triphasic computed tomography (CT) 
scan or multiphase MRI for radiologic assessment. 
5. Afinitor treatment which is recommended by the treating physician. 


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5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. 
2. Inability to attend scheduled clinic visits or scheduled tests. 
3. Patient who is unwilling to receive Afinitor treatment due to any reason. 
4. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
Women of child-bearing potential, who are or might become sexually active, must be 
informed of the need to prevent pregnancy during the study. Women of child-bearing 
potential, defined as all women physiologically capable of becoming pregnant (including 
female pediatric patients who are menarcheal or who become menarcheal during the study), 
must use highly effective contraception during study treatment and for 8 weeks after 
stopping treatment. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate) 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
5. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus). 
6. Use of an investigational drug within the 30 days prior to enrollment. 
7. Any severe and/or uncontrolled medical conditions which could cause unacceptable safety 
risks or compromise compliance with the protocol, such as: Impairment of gastrointestinal 
function or gastrointestinal disease that may significantly alter the absorption of study 
drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, etc). 
8. Known history of seropositivity for human immunodeficiency virus (HIV) 
9. Any cause that the investigator considers will harm the patient’s benefit if participate in 
this study and please specify. 


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6 
Treatment 
6.1 
Study treatment 
This is a single arm, open-label study, and the investigational drug used in the course of this 
trial is Afinitor® (everolimus, 2.5 mg tablet, 5 mg tablet). 
6.1.1 
Dosing regimen 
Everolimus will be dosed starting on Treatment Day 1 (Visit 1). Patients will be instructed to 
take Everolimus at a starting dose of 10 mg orally once daily. Everolimus should be 
administered orally once daily at the same time every day, either consistently with or 
consistently without food and be swallowed whole with a glass of water and should not be 
chewed or crushed. A change of dose might be required during the treatment, please refer to 
Section 6.3 and the Package Insert for more details. 
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be 
instructed that if they miss a dose on one day, they must not take any extra dose the next day, 
but instead to immediately contact the study center as soon as possible to ask for advice. 
6.1.2 
Ancillary treatments 
Not applicable. 
6.1.3 
Rescue medication 
Not applicable. 
6.1.4 
Treatment duration 
Patient may continue treatment with the study drug until the patient experiences unacceptable 
toxicity, disease progression and/or treatment is discontinued at the discretion of the 
investigator or withdrawal of consent, if the patient is still on treatment after 2 years, he/she 
will be shifted to commercial drug. 
6.2 
Dose escalation guidelines 
Not applicable. 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. 
These changes must be recorded on the Dosage Administration Record CRF. 
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary 
dose interruption (with or without dose reduction) or discontinuation of everolimus therapy. If 
dose reduction is required, the suggested dose is approximately 50% lower than the daily dose 


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previously administered. For dose reductions below the lowest available tablet strength, 
alternate day dosing should be considered. 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. 
Patients who need an additional dose reduction will be required to discontinue 
everolimus/placebo or comparator drug. 
Table 6-1 summarizes the recommendations for dose interruption, reduction, or 
discontinuation of everolimus in the management of ADRs. General management 
recommendations are also provided as applicable. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment. 
Table 6-1 
Afinitor Dose Adjustment and Management Recommendation for 
Adverse Drug Reaction 
Adverse Drug 
Reaction 
Severity a 
Everolimus Dose Adjustment b and Management 
Recommendations 
Non-infectious 
pneumonitis 
Grade 1 
Asymptomatic, 
radiographic findings only 
No dose adjustment required. 
Initiate appropriate monitoring. 
Grade 2 
Symptomatic, 
not interfering with ADLc 
Consider interruption of therapy, rule out infection and 
consider treatment with corticosteroids until symptoms 
improve to ≤ grade 1. 
Re-initiate Everolimus at a lower dose. 
Discontinue treatment if failure to recover within 4 
weeks. 
Grade 3 
Symptomatic, 
interfering with ADLc; 
O2 indicated 
Interrupt Everolimus until symptoms resolve to ≤ grade 
1. 
Rule out infection, and consider treatment with 
corticosteroids. 
Consider re-initiating Everolimus at a lower dose. If 
toxicity recurs at grade 3, consider discontinuation. 
Grade 4 
Life-threatening, 
ventilatory support indicated 
Discontinue Everolimus, rule out infection, and 
consider treatment with corticosteroids. 


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Adverse Drug 
Reaction 
Severity a 
Everolimus Dose Adjustment b and Management 
Recommendations 
Stomatitis 
Grade 1 
Minimal symptoms, 
normal diet 
No dose adjustment required. 
Manage with non-alcoholic or salt water (0.9%) mouth 
wash several times a day. 
Grade 2 
Symptomatic but can eat and 
swallow modified diet 
Temporary dose interruption until recovery to grade ≤1. 
Re-initiate Everolimus at the same dose. 
If stomatitis recurs at grade 2, interrupt dose until 
recovery to grade ≤1. Re-initiate Everolimus at a lower 
dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral 
paste).d 
Grade 3 
Symptomatic and unable to 
adequately aliment or 
hydrate orally 
Temporary dose interruption until recovery to grade ≤1. 
Re-initiate Everolimus at a lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral paste).d 
Grade 4 
Symptoms associated with 
life-threatening 
consequences 
Discontinue Everolimus and treat with appropriate 
medical therapy. 
Other 
nonhematologic 
toxicities 
(excluding 
metabolic 
events) 
Grade 1 
If toxicity is tolerable, no dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
Grade 2 
If toxicity is tolerable, no dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
If toxicity becomes intolerable, temporary dose 
interruption until recovery to grade ≤1. Re-initiate 
Everolimus at the same dose. 
If toxicity recurs at grade 2, interrupt Everolimus until 
recovery to grade ≤1. Re-initiate Everolimus at a lower 
dose. 
Grade 3 
Temporary dose interruption until recovery to grade ≤1. 
Initiate appropriate medical therapy and monitor. 
Consider re-initiating Everolimus at a lower dose. If 
toxicity recurs at grade 3, consider discontinuation. 
Grade 4 
Discontinue Everolimus and treat with appropriate 
medical therapy. 


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Adverse Drug 
Reaction 
Severity a 
Everolimus Dose Adjustment b and Management 
Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. Initiate appropriate 
medical therapy and monitor 
Grade 2 
No dose adjustment required. Manage with appropriate 
medical therapy and monitor 
Grade 3 
Temporary dose interruption. 
Re-initiate Everolimus at a lower dose. 
Manage with appropriate medical therapy and monitor. 
Grade 4 
Discontinue Everolimus and treat with appropriate 
medical therapy. 
Physicians should always manage patients according to their medical judgment based on the particular clinical 
circumstances. 
a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-
threatening symptoms, 
b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously 
administered. 
c Activities of daily living (ADL) 
d Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as 
they may worsen mouth ulcers. 
Renal Impairment 
No clinical studies were conducted with everolimus in patients with decreased renal function. 
Renal impairment is not expected to influence drug exposure and no dosage adjustment of 
everolimus is recommended in patients with renal impairment. 
Hepatic Impairment 
Hepatic impairment will increase the exposure to everolimus. Dose adjustments are 
recommended: 
• Mild hepatic impairment (Child-Pugh class A): The recommended dose is 7.5 mg daily; 
the dose may be decreased to 5mg if not well tolerated. 
• Moderate hepatic impairment (Child-Pugh class B): The recommended dose is 5 mg daily; 
the dose may be decreased to 2.5 mg if not well tolerated. 
• Severe hepatic impairment (Child-Pugh class C): If the desired benefit outweighs the risk, 
a dose of 2.5 mg daily maybe used but must not be exceeded. 
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during 
treatment. 
Dose adjustments for QTcF prolongation. 
1. Assess the quality of the ECG recording and the QT value and repeat if needed 
2. Interrupt study treatment 
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsade de Pointes”, and drugs with the 
potential to increase the risk of study drug exposure related QT prolongation 


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5. Check study drug dosing schedule and treatment compliance 
6. Consider collecting a time-matched PK sample, and record time and date of last study 
drug intake. 
After confirming ECG reading at site, if QTcF > 500 msec 
• Interrupt study treatment 
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 msec: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT as per the ECG 
and QTc Clinical Safety Standards Guidelines Section 3.3.1. 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec. 
• After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose, and 
increase ECG monitoring for the next treatment(s): 
• If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG 
monitoring during subsequent treatment 
If QTcF recurs > 500 msec after dose reduction, discontinue patient from trial. 
6.3.2 
Follow-up for toxicities 
All patients will be followed for adverse events and serious adverse events for 30 days 
following the last dose of study drug. Beyond these 30 days, any serious adverse events that 
are suspected to be related to the study drug will also be collected. 
6.3.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 


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In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented 
6.4 
Concomitant medications 
In clinical trials and post-marketing spontaneous reports, angioedema has been reported with 
and without concomitant use of angiotensin-converting-enzyme (ACE) inhibitors. The risk of 
angioedema events may be increased with concomitant administration of ACE inhibitors. 
Patients must be instructed not to take any additional medications (over-the-counter, herbal or 
other products) during the study without prior consultation with the investigator. All 
medications taken within 30 days of starting study treatment and during the study until the last 
dose should be reported on the Concomitant Medication/Significant Non-drug Therapy CRF. 
Co-administration with strong CYP3A4 inhibitors, strong CYP3A4 inducers, St. John’s Wort 
(Hypericum perforatum), and grapefruit, grapefruit juice, and other foods that are known to 
inhibit cytochrome P450 and PgP activity should be avoided during the treatment (refer to 
Package Insert for more details). Contraindications include hypersensitivity to the active 
substance, to other rapamycin derivatives, or to any of the excipients. 
For concomitant medications deemed necessary for the care of the patient, dose modifications 
may be required and please refer to Section 6.3 and Package Insert for detailed instructions. 
The concomitant medications should be documented in CRF. 


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6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Cytochrome P450 and P-glycoprotein (PgP) inhibitors/inducers/substrates 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Therefore, the following are recommended: 
Co-administration with strong inhibitors of CYP3A4/PgP should be avoided and may cause 
increased everolimus concentrations.Co-administration with moderate CYP3A4/PgP 
inhibitors should be used with caution. If a patient requires co-administration of moderate 
CYP3A4/PgP inhibitors, reduce the dose of study drug to half the currently used dose. 
Additional dose reductions may be required to manage toxicities. If the inhibitor is 
discontinued, consider a washout period of at least 2-3 days (average for the most commonly 
used moderate inhibitors), before the study drug dose is returned to the dose used prior to 
initiation of the moderate CYP3A4/PgP inhibitor. 
If a patient requires co-administration of strong CYP3A4 inducer, an increase in the dose of 
study drug up to twice the currently used daily dose should be considered, using 5 mg 
increments or less. This dose adjustment of study drug is predicted to achieve similar AUC to 
the range observed without inducers. However, there are no clinical data with this dose 
adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is 
discontinued, consider a washout period of at least 3-5 days (reasonable time for significant 
enzyme de-induction), before the study drug dose is returned to the dose used prior to 
initiation of the strong CYP3A4/PgP inducer. 
Please refer to Table 6-2 listing relevant inducers and inhibitors of CYP3A and to Table 6-3 
for a list of relevant substrates, inducers, and inhibitors of PgP. 


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Table 6-2 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A 
Inducers 
Strong inducers: 
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort, rifabutin, phenobarbital, mitotane, enzalutamide 
 
Moderate inducers: 
bosentan, efavirenz, etravirine, modafinil, nafcillin, genistein, ritonavir, thioridazine, tipranavir, semagacestat, 
talviraline, lopinavir, lersivirine, 
 
Weak inducers: 
amprenavir, aprepitant, armodafinil bexarotene, clobazam, danshe, dexamethasone, echinacea, garlic , gingko 
(ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, pleconaril, 
primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, topiramate, troglitazone, vinblastine, 
eslicarbazepine, ginseng, vemurafenib, boceprevir, sulfinpyrazone, ticagleror, vicriviroc/ritonavir, ritonavir, 
ticlopidine, brivacetam, Stribild (combo of elvitegravir, cobicistat, emtricitabine, and tenofovir), quercetin. 
 
Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, sequinavir/ritonavir, telaprevir, 
telithromycin, voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, cobicistat, troleandomycin, danoprevir/ritonavir, 
eltegravir/ritonavir, 
 
Moderate inhibitors: 
amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, nilotinib imatinib, tofisopam, cyclosporin, ciprofloxacin, verapamil, dronedarone, 
crizotinib, casopitant, amprenavir, atazanavir/ritonavir, duranavir, netupitant, schisandra sphenanthera , 
cimetidine, lomitapide 
 
Weak inhibitors: 
tabimorelin, ranolaxine, fosaprepritant, Seville orange, amlodipine, clozoxazone, fluvoxamine, ranitidine, 
goldenseal ,clotrimazole, tacrolimus, cilostazol, ticagrelor, ivacaftor, roxithromycin, propiverine, isoniazid, 
berberine, oral contraceptives, peppermint oil, delavirdine, simeprevir, atorvastatin, tolvaptan, almorexant, 
linagliptin, resveratrol, lacipidine, cranberry juice, nilotinib, pazopanib, evrolimus, blueberry juice, alprazolam, 
bicalutamide, sitaxentan, azithromycin, ginkgo, teriflunomide, alprazolam, amiodarone, amlodipine, bicalutamide, 
cilostazol, cimetidine, cyclosporine, fluoxetine, isoniazid, ranitidine, ranolazine, tipranavir/ritonavir, zileuton 
 


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Table 6-3 
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A dual inhibitors 
Substrates 
digoxin, quinidine, paclitaxel, cyclosporine, sirolimus, tacrolimus, fentanyl, pphenytoin, aliskiren, ambrisentan, 
atorvastatin, atorvastatin acid, azithromycin, cerivastatin, colchicine, CP-481,715, cyclosporine, dabigatran, 
digoxin, docetaxel, domperidone, doxorubicin, fentanyl, fexofenadine, lapatinib, linezolid, loperamide, maraviroc, 
nevirapine, paclitaxel, proguanil, quinidine, ranolazine, ritonavir, saquinavir, simvastatin, sirolimus, sofosbuvir, 
tacrolimus, ticagrelor, voclosporin, afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, boceprevir, bosentan, carvedilol, carvedilol, caspofungin, ceritinib, citalopram, colchicine, cyclosporine, 
dabigatran, digoxin, doxepin, doxorubicin, eribulin, everolimus, fidaxomicin, fluvastatin, fosamprenavir, 
gatifloxacin, idelalisib, iloperidone, indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, levofloxacin, 
linagliptin, losartan, maraviroc, mirabegron, moxifloxacin, naloxegol, nateglinide, nintedanib, olodaterol, 
pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, quinine, ranolazine, riociguat, risperidone, 
rivaroxaban, saquinavir, silodosin, simeprevir, sirolimus, sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, vincristine, voriconazole 
 
Inducers 
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, rifampin, St. John’s wort extract 
 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
PgP Inhibitors 
alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole, lapatinib, lopinavir/ritonavir, mirabegron, 
propafenone, simepravir, valspodar, vandetanib, voclosporin 
 
PgP/CYP3A Dual Inhibitors 
amiodarone, azithromycin,captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fluvoxamine, ginko, indinavir, indinavir/ritonavir, itraconazole, mibefradil, milk thisle, 
nelfinavir, nifedipine, nitredipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, 
sequinavir/ritonavir, schisandra chinesis extract, St. John’s wort extract, talinolol, telaprevir, telmisartan, ticagrelor, 
tipranavir/ritonavir, tolvaptan, verapamil 
 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated April-2015 which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine's Drug 
Interaction Table. 
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with everolimus. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid 
vaccines. 
6.4.3 
Prohibited concomitant therapy 
Anti-neoplastic therapies 
Treatment with systemic anticancer agents (chemotherapy, hormone therapy, targeted or 
biologic agents) other than the protocol treatment is not permitted until disease progression is 
documented per RECIST. Palliative radiotherapy or surgery may be allowed and should be 
discussed with Novartis prior to administration. 


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6.4.4 
Use of Bisphosphonates (or other concomitant agents) 
Not applicable. 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator. 
Once assigned to a patient, the Subject No. will not be reused. 
6.5.2 
Treatment assignment or randomization 
6.5.3 
Not applicable. Treatment blinding 
This study is an open-label study, thus it is not applicable. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Table 6-4 
Preparation and dispensing 
Study treatments 
Dispensing 
Preparation 
Afinitor 
Tablets including instructions for 
administration are dispensed by study 
personnel on an outpatient basis. 
 
Patients will be provided with adequate 
supply of study treatment for self-
administration at home until at least their 
next scheduled study visit. 
Not applicable 
6.6.1 
Study drug packaging and labeling 
Study treatment, [everolimus], will be sourced as local commercial supply (in the locally 
approved formulation and packaging configuration) and labeled in the country when possible. 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to the treatment arm and a specific visit. Responsible 
site personnel will identify the study treatment package(s) to dispense to the patient and 
obtaining the medication number(s). Site personnel will add the patient number on the label. 
Immediately before dispensing the package to the patient, site personnel will detach the outer 


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part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
Everolimus tablet, 2.5mg/tablet, 5 mg/ tablet, 1 tablet per blister 
6.6.2 
Drug supply and storage 
Everolimus tablet will be supplied by Novartis, and it must be received by designated 
personnel at the study site, handled and stored safely and properly, and kept in a secured 
location to which only the investigator and designated site personnel have access. Upon 
receipt, the study treatment should be stored according to the instructions specified on the 
drug labels and in the Chinese PI. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
• All doses taken by the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record CRF. 
• The investigator or his/her designee must keep documentation (overall drug accountability 
log for the study as well as individual study drug accountability records for each patient) 
of tablets administered, tablets used, dose changes, dates dispensed and intervals between 
visits. 
• Drug accountability will be monitored by the field monitor during site visits and at the 
completion of the study. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
6.6.3.3 
Handling of other study treatment 
Not applicable. 


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6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
No CRF will be used as a source document. 
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column). Tests, procedures and visits 
should occur on schedule whenever possible. However, tests, procedures, and visits that occur 
outside the prescribed allowable windows indicated in Table 7-1 will not constitute protocol 
deviations. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
7.2 
Screening/
Baseline 
(-28~0day) 
Visit 1 
(day1) 
Visit 2 
(day28±2d ) 
Visit 3 
(week 
12±1wk) 
Subsequent 
visits 
(every 
12wk±1wk) 
End of 
study 
treatment 
(EOT) 
30-day 
Safety 
Follow-up 
Survival 
follow up 
(every 6 
months) 
Obtain Informed Consent 
D 
 
X 
 
 
 
 
 
 
 
Patient history 
D 
 
X 
 
 
 
 
 
 
 
Demography 
D 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
 
X 
 
 
 
 
 
 
 
Relevant medical 
history/current medical 
conditions  
D 
 
X 
 
 
 
 
 
 
 
Diagnosis of cancer 
D 
 
X 
 
 
 
 
 
 
 
Prior/concomitant medications 
D 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
S 
7.2.2.1  
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
D 
7.2.2.2  
X 
X 
X 
X 
X 
X 
 
 
Height/Weight 
D 
7.2.2.3  
X 
 
 
 
 
 
 
 
Laboratory assessments 
 
7.2.2.4  
 
 
 
 
 
 
 
 
Hematology a 
D 
7.2.2.4.1  
X 
X 
X 
X 
X 
X 
 
 
Liver function tests b 
D 
7.2.2.4.2  
X 
 
X 
X 
X 
X 
 
 
Coagulation 
S 
7.2.2.4.3  
X 
 
X 
X 
X 
X 
 
 
Other laboratory test c 
S 
7.2.2.4.6  
 
Only to be done if clinically indicated 
 
 
 
Urinalysis c 
S 
7.2.2.4.4  
X 
Only to be done if clinically indicated 
 
 
 
Pregnancy test d 
D 
7.2.2.4.5  
X 
 
 
 
 
X 
 
 
Tumor evaluation(MRI or CT) e 
D 
7.2.1  
X 
 
 
X 
X 
 
 
 Xf 
Pulmonary function tests, Chest 
CTg 
D 
7.2.2.5  
 
Only to be done if clinically indicated 
 
 
Adverse events 
D 
 
X 
Continuously 
X 
 
Study Drug administration  
D 
 
 
X 
X 
X 
X 
X 
 
 


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Category 
Protocol 
Section 
7.2 
Screening/
Baseline 
(-28~0day) 
Visit 1 
(day1) 
Visit 2 
(day28±2d ) 
Visit 3 
(week 
12±1wk) 
Subsequent 
visits 
(every 
12wk±1wk) 
End of 
study 
treatment 
(EOT) 
30-day 
Safety 
Follow-up 
Survival 
follow up 
(every 6 
months) 
Reason for discontinuation/ 
withdrawal 
D 
 
 
 
 
 
 
X 
 
 
Survival Follow-up 
D 
 
 
 
 
 
 
 
 
X 
a. Fasting hematology include: hemoglobin, hematocrit, platelets, red blood cell count (RBC) total white blood cell count (WBC) absolute & differential including 
neutrophils, lymphocytes, monocytes, eosinophils and basophils. Absolute Neutrophil Count (ANC) will be calculated by the laboratory. 
b. Liver function tests include: AST, ALT, total bilirubin, alkaline phosphatase, serum albumin. 
c. Clinically significant findings will be noted in the Medical history/ Current medical condition pages or Adverse Events pages. Urinalysis assessment could include but 
not limited to: pH, protein, glucose, blood, ketones, and leukocytes. Other laboratory test could include but not limited to: total LDH, GGT, fasting glucose, fasting serum 
lipid, sodium, magnesium, phosphate, potassium, chloride, bicarbonate, creatinine, BUN, total protein, uric acid, calcium. 
d. A serum pregnancy test will be conducted locally at screening /baseline in all females of child-bearing potential, urine pregnancy test will be conducted at the end of 
treatment visit. 
e. 
Repeat scans (multiphase MRI or triphasic CT) at baseline and every 12 weeks thereafter. The same type of scan should be used at baseline and follow-up. 
f. Efficacy assessment will be collected until progression of disease (PD). 
g. If an investigator suspects a patient may be developing pneumonitis, investigations such as pulmonary function tests, CT chest and referral to a pulmonologist should 
be considered. 
 


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7.1.1 
Molecular pre-screening 
Not applicable. 
7.1.2 
Screening 
Screening examination must include serum hCG laboratory test (Section 5.3 exclusion 
criteria-4), and confirmation of diagnosis according to inclusion criteria. 
Informed consent must be signed prior to any screening procedure. 
Re-screening is allowed for no more than 3 times within 6 months only when the previous 
severe and/or uncontrolled medical conditions mentioned in Section 5.3 Exclusion Criteria 
(except for bullet point 1, 5 and 8) has been resolved. 
7.1.2.1 
Eligibility screening 
Not applicable. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered as screen failure. The reason for not being started on treatment will be entered 
on the Screening Phase Disposition Page. The demographic information, informed consent, 
and Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other 
data will be entered into the clinical database for patients who are screen failures, unless the 
patient experienced a Serious Adverse Event during the Screening Phase (see Section 8 for 
SAE reporting details). 
7.1.2.3 
Patient demographics and other baseline characteristics 
Data will be collected on patient characteristics including demographic information (age, sex, 
race, weight, height) and other background or relevant medical history (disease history, family 
history of disease, prior anti-neoplastic therapies, and any other assessments that are done for 
the purpose of determining eligibility for inclusion in the study [i.e., complete physical 
examination, pregnancy test for women of child-bearing potential, CT/MRI]. 
Medical history will include family history of disease. 
7.1.3 
Run-in period 
Not applicable. 
7.1.4 
Treatment period 
Patients will start study treatment at Visit 1 (Treatment Day 1) and continue to be treated per 
protocol until documentation of disease progression, unacceptable toxicity, death, withdrawal 
of consent or sponsor decision to stop the study. However, study treatment may prematurely 
be discontinued for other reasons as well. Please refer to Section 7.1.5. And patients should 
follow the visit schedule in Table 7-1. If the patient is still on treatment after 2 years, he/she 
will be shifted to commercial drug. 


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7.1.5 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment (everolimus) for any reason at 
any time. If a patient decides to discontinue from the study treatment (everolimus) the 
investigator should make a reasonable effort (e.g. telephone, e-mail, letter) to understand the 
primary reason for this decision and record this information in the patient’s chart and on the 
appropriate CRF pages. They may be considered withdrawn if they state an intention to 
withdraw, fail to return for visits, or become lost to follow-up for any other reason. 
The investigator may discontinue study treatment (everolimus) for a given patient if, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
The term “interruption” refers to a patient stopping the study medication during the course of 
the study, but then re-starting it at a later time in the study. 
The term “discontinuation” refers to a patient’s premature and permanent withdrawal from the 
study treatment. The reason for discontinuation from treatment will be recorded. 
At the time patients discontinue study treatment, a visit should be scheduled as soon as 
possible, at which time all of the assessments listed for the End of Treatment (EOT) visit will 
be performed. An End of Treatment Phase Disposition CRF page should be completed, giving 
the date and reason for stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
For criteria for premature withdrawal refer to Section 7.1.6. 
End of treatment/Premature withdrawal visit is not considered as the end of the study. 
7.1.5.1 
Replacement policy 
Not applicable. 
7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• pregnancy; 
• discovery of patient ineligibility; 
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation: 
• Any other protocol deviation that results in a significant risk for the patient’s safety 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Adverse events including laboratory abnormalities which required discontinuation of 
study treatment listed in Table 6-1; 


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• Compliance problems other than dose interruption as described above; 
• Unsatisfactory therapeutic effect as the investigator consider the subject’s condition no 
longer benefit from study treatment (be specified in the CRF) 
• Use of prohibited treatment 
If a patient has discontinued the study drug due to an unacceptable adverse event (AE) 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 
an AE or abnormal laboratory value. 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor assessments are to be performed for screening purposes and are needed to determine 
the eligibility of the patient. Last available results of scans performed within 28 days prior to 
first dose of study drug will be used as baseline values. Negative scans at screening need not 
be repeated unless warranted by signs and symptoms suggesting disease progression. The 
assessment data will be collected until disease progression, unacceptable toxicity, death, 
protocol deviation or other reason that may leads to discontinuation or the end of study. 
The following tumor assessments are to be performed and assessed prior to enrollment: 
• Abdominal and pelvic triphasic CT or multiphase MRI; 
• Chest X-ray (and/or chest CT if disease is present in chest). 
To determine eligibility, measurable and non-measurable lesions must be assessed and target 
lesions identified prior to enrollment. For definition of measurable and target lesions please 
refer to RECIST 1.1 (Appendix 1) 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and after every 12 weeks while on-study. All 
radiology evaluations will be performed initially by the local radiologist. 


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Details of response assessment are provided in full protocol based on RECIST1.1, and are 
based exclusively on radiological findings obtained at tumor assessments. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing as well as collecting of the adverse events at every visit. 
For details on AE collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination will include the examination of general appearance, height 
and weight, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance and vital signs. A 
short physical exam will be at all visits starting from Visit 3 except where a complete physical 
examination is required (see above). 
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF. 
7.2.2.2 
Vital signs 
Pulse, respiration rate, blood pressure and temperature will be measured as indicated in the 
Assessment schedule (Table 7-1) and will be recorded on source documents, and entered on 
CRF pages. 
Blood pressure, pulse and respiration rate should be measured on patients after at least 3 
minutes in the sitting position. 
7.2.2.3 
Height and weight 
Height and Body weight (in indoor clothing, but without shoes) will be measured at screening. 
7.2.2.4 
Laboratory evaluations 
Local laboratory will be used for analysis of all specimens collected. 
7.2.2.4.1 Hematology 
Hemoglobin, hematocrit, white blood cell count with differential, and platelet count will be 
measured. 
7.2.2.4.2 Liver function tests 
Total bilirubin, AST, ALT, serum albumin and alkaline phosphatase will be measured. 


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7.2.2.4.3 Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT). 
7.2.2.4.4 Urinalysis 
During screening, a standard urinalysis assessment (pH, protein, glucose, blood), any 
significant findings on dipstick shall be followed up with a microscopic evaluation where 
WBC and RBC sediments should also be considered per the investigator’s clinical practice 
routine. 
7.2.2.4.5 Pregnancy and assessments of fertility 
All females must have a negative serum pregnancy test at screening/baseline, while at the end 
of treatment visit urinary pregnancy tests are sufficient. 
It is recommended that female before come to age of menarche or women considered at 
postmenopausal status by investigator’s judgment according to local clinical practice or post-
surgical bilateral oophorectomy or hysterectomy are to be considered “of non-childbearing 
potential”. 
Highly effective contraception, must be used on-study and for up to 8 weeks after ending 
treatment for those patients who considered as with childbearing potential (definition of 
highly effective contraception is detailed in Section 5.3. 
Instruction in Section 8.4 should be followed when patients is confirmed of pregnancy. 
7.2.2.4.6 Other laboratory tests 
Other laboratory test should be done as clinically indicated, and could include but not limited 
to: total LDH, fasting glucose, fasting serum lipid, sodium, magnesium, phosphate, potassium, 
chloride, bicarbonate, creatinine, BUN, total protein, uric acid, calcium. 
7.2.2.5 
Radiological examinations (Pulmonary function tests) 
Individuals participating in this trial will be questioned at each visit as to the presence of new 
or changed pulmonary symptoms consistent with lung toxicity. If an investigator suspects a 
patient may be developing pneumonitis investigations such as pulmonary function tests, CT 
chest and referral to a pulmonologist should be considered. 
7.2.2.6 
Cardiac assessments 
Not applicable 
7.2.2.7 
Tolerability 
Not applicable 
7.2.3 
Pharmacokinetics 
Not applicable. 


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7.2.4 
Biomarkers 
Not applicable. 
Other assessments 
No additional tests will be performed on patients entered into this study. 
7.2.5 
Resource utilization 
Not applicable. 
7.2.6 
Patient reported outcomes 
Not applicable. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 


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(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 


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instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the [Investigator Brochure]. 
As a result of observations during the conduct of earlier studies with everolimus, several 
groups of events were defined as adverse events of special interest, AESIs. These groups 
consist of AEs for which there is a specific clinical interest in association with everolimus 
treatment and/or with inhibition of mTOR signaling. 
For this study the following adverse events are events of special interest: 
• Stomatitis/ oral mucositis 
• Reactivation of hepatitis B virus 
• Cardiac disorders: Cardiac failure; ejection fraction decreased 
Non-infectious pneumonitis. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 


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• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site Follow-up information is submitted in 
the same way as the original SAE Report. Each re-occurrence, complication, or progression of 
the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the patient continued or withdrew from study participation. 
For Everolimus the following adverse events are the AE that Novartis has committed to 
perform targeted follow up, for example in the Risk Management Plan , including: 1.Non-
infectious pneumonitis. 2. Severe Infections including Hepatitis Reactivation; 3. 
Hypersensitivity including Anaphylaxis; 4.Renal Impairment or Failure; 5. Acute and 
Congestive Heart Failure; 6. Female fertility (including secondary amenorrhea); 7. 
Reactivation, Aggravation, Exacerbation of Background Disease; 8. Postnatal developmental 
toxicity; 9. Pregnant or breast-feeding women; 10. Onset of benign or malignant tumors. 


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently 
require further information from the investigator for Health Authority reporting. Novartis may 
need to issue an Investigator Notification (IN), to inform all investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
8.3 
Emergency unblinding of treatment assignment 
Not Applicable. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Preclinical data regarding reproductive toxicity is described in the most recent [Investigator 
Brochure]. The potential reproductive risk for humans is unknown. Women of childbearing 
potential should be advised to use highly effective contraception methods while they are 
receiving everolimus and up to 8 weeks after treatment has been stopped. If a pregnancy 
occurs while on study treatment, the newborn will be followed for at least 12 months. 
The potential for everolimus to cause infertility in male and female patients is unknown. 
However, menstrual irregularities, secondary amenorrhea and associated luteinizing hormone 
(LH)/follicle stimulating hormone (FSH) imbalance has been observed. Blood levels of FSH 
and LH increased, blood levels of testosterone decreased, and azoospermia have been 
observed in male patients receiving everolimus. 
Based on non-clinical and clinical findings, male and female fertility may be compromised by 
treatment. 
It is not known whether everolimus is excreted in human breast milk. However, in animal 
studies everolimus and/or its metabolites readily passed into the milk of lactating rats at a 
concentration 3.5 times higher than in maternal serum. Women taking everolimus should 
therefore not breast-feed. 


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In case of pregnancy during study treatment 
When pregnancy occurs in a patient in the study, as general rule the study drug must be 
discontinued. If a female patient or partner of a male patient become pregnant during the 
study they should immediately consult the study physician. Following appropriate medical 
advice the patient may stay in the study and follow the assessments, if she wishes to do so. 
However, any assessments that are considered as a risk during pregnancy must not be 
performed. The patient may continue all other protocol assessments. In exceptional cases, 
such as a woman responding to the lifesaving treatment, the study drug can be continued. 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications according to the following schedule. 
 
Timing of follow up attempt 
applicability 
EDD+1 month 
Mandatory for all cases 
EDD+2months 
Mandatory if no answer is obtained after request at 
EDD+1 months 
EDD+3 months 
Mandatory for all cases of live birth 
EDD+12months 
Mandatory for all cases of live birth 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates and/or the locally 
approved prescribing information will be communicated in the form of Investigator 
Notifications. This information will be included in the patient informed consent and should be 
discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee 
Not applicable. 
8.7 
Steering Committee 
Not applicable. 


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 


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9.3 
Data collection 
For studies using paper CRFs, designated investigator staff must record the information 
required by the protocol onto the Novartis CRFs that are printed on multi-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 harvested CRFs will 
be forwarded to the Medical Documents Reception Center or applicable CRO Document 
receipt location by field monitors or by the investigational site, with one copy being retained 
at the investigational site. 
The Principal Investigator is responsible for assuring that the data recorded on CRFs is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
 This study will use paper CRF, data will be entered into a fully validated study database by 
Novartis Data Management personnel (or designated CRO). Following entry from the CRFs, 
the data are systematically checked by Novartis Data Management personnel (or designated 
CRO) using programmed checks and data review tools/reports. Data Query Forms (DQF) are 
created for discrepancies or missing values and sent to the investigational site for resolution. 
Original signed responses to the DQFs must be returned to Novartis Data Management (or 
designated CRO) so that resolutions can be entered into the database. Copies of the resolved 
DQFs are kept with the CRFs at the investigator site. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
10 
Statistical methods and data analysis 
The data from all participating centers in this protocol will be combined. Novartis and/or a 
designated CRO will perform all analyses. Any data analyses performed independently by any 
investigator should be submitted to Novartis before publication or presentation. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of study 
treatment. Patients will be analyzed according to the treatment they received. The FAS will be 
the primary population in the assessment of efficacy. 
10.1.2 
Safety Set 
The Safety Set and the FAS are identical in this study. All safety analysis will be analyzed 
using the Safety Set. 


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10.1.3 
Per-Protocol Set 
Not applicable 
10.1.4 
Dose-determining analysis set 
Not applicable. 
10.1.5 
Pharmacokinetic analysis set 
Not applicable. 
10.1.6 
Other analysis sets 
Not applicable 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline characteristics will be listed and summarized using the FAS. 
Qualitative data (e.g., gender, race) will be summarized by means of contingency tables, and 
quantitative data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (mean, standard deviation, median, minimum and maximum). 
Relevant medical histories and current medical at baseline will be summarized by system 
organ class, preferred term and by treatment group. 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized. 
The number of patients with dose changes/interruptions will be presented, along with reasons 
for the dose change. 
Concomitant medications and significant non-drug therapies taken prior to and after the start 
of the study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
The safety population will be used for all above-mentioned concomitant medication tables and 
listings. 
10.4 
Primary objective 
The primary objective is to evaluate the safety of treatment with Afinitor in Chinese adult 
patients with well differentiated progressive p-NET 
10.4.1 
Variable 
The primary variable is the safety profile in terms of adverse events, serious adverse events, 
adverse events suspected to be related to study drug and Grade 3 and 4 AEs. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Please refer to Section 10.5.3. 


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10.4.3 
Handling of missing values/censoring/discontinuations 
Missing safety data will simply be noted as missing on appropriate tables/listings. 
10.4.4 
Supportive and Sensitivity analyses 
Not applicable 
10.5 
Secondary objectives 
The secondary objective is to evaluate the overall efficacy of treatment with Afinitor in 
Chinese patients with well differentiated progressive p-NET. All efficacy analyses will be 
performed based on the FAS, unless otherwise specified. 
The secondary variables include 
• Overall Survival (OS), defined as time from study treatment to death due to any cause. 
• Progression free survival (PFS), defined as time from first dose of study treatment to 
progression or death due to any cause. 
10.5.1 
Key secondary objective(s) 
Not applicable. 
10.5.2 
Other secondary efficacy objectives 
See the description in Section 10.5. 
10.5.2.1 Endpoint and analysis for other secondary objective 
Endpoints for other secondary objectives are Overall Survival (OS) and Progression free 
survival (PFS), as defined above, 
OS and PFS will be described using Kaplan-Meier methods and appropriate summary 
statistics. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. 
The overall observation period will be divided into three mutually exclusive segments, which 
all applicable listings and tables will be presented by: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 


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10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment 
Serious adverse events (SAE), non-serious adverse events and adverse events of special 
interest (AESI) during the on-treatment period will be tabulated 
All death (on-treatment and post-treatment) will be summarized. 
The adverse events of special interest (AESI) include the following categories 
• Non-infectious pneumonitis 
• Stomatitis/ oral mucositis 
• Reactivation of hepatitis B virus 
• Cardiac disorders: Cardiac failure; ejection fraction decreased 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged 
10.5.3.3 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria for adverse events (CTCAE, version 4.03) unless 
otherwise indicated. The calculation of CTCAE grades will be based on the observed laboratory 
values only, clinical assessments will not be taken into account. CTCAE Grade 0 will be 
assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. For 
laboratory tests where grades are not defined by CTCAE version 4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
A listing of all laboratory values will be provided by laboratory parameter and by patient. All 
notable lab abnormalities will be presented in a separate listing. 
For laboratory tests where grades are defined by CTCAE version 4.03: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE version 4.03: 
• Shift tables using the low/normal/high classification to compare baseline to the worst on-
treatment value. 


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10.5.3.4 Other safety data 
Safety data from other tests (e.g., vital signs) will be listed and summarized using descriptive 
statistics as appropriate. Notable values may be flagged. Notable/Abnormal values for safety 
data will be further specified in the analysis plan. 
Analyses will be performed on the safety set. 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable. 
10.5.3.6 Tolerability 
Tolerability will be summarized in terms of dose reductions or drug interruption due to an AE. 
10.5.4 
Pharmacokinetics 
Not applicable. 
10.5.5 
Biomarkers 
Not applicable. 
10.5.6 
Resource utilization 
Not applicable. 
10.5.7 
Patient-reported outcomes 
Not applicable. 
10.6 
Exploratory objectives 
Not applicable. 
10.7 
Interim analysis 
Interim analysis is planned for this study for the purpose of providing a snapshot of available 
data to CDE for license renewal. An interim analysis will be performed in July 2017 with 
approximate 30 patients enrolled. This interim analysis will focus on safety and preliminary 
efficacy, including but not limited to: 
• Safety: all adverse events observed by the data cutoff date will be summarized and listed. 
Separate summaries will be provided for SAE and death, respectively. Abnormal results 
on laboratory assessment and vital signs will be presented and listed in detail. 
• Efficacy: OS and PFS observed by the data cutoff will be described using Kaplan-Meier 
methods and appropriate summary statistics. 
Details of the analysis will be defined in statistical analysis plan (SAP). 


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10.8 
Sample size calculation 
Based on pre-marketing field survey, each year, approximately 6 to10 patients per site will be 
newly diagnosed as ‘locally advanced, unresectable or metastatic, well differentiated 
progressive pNET’, about 10% to 20% of diagnosed patients will be eligible and agree to 
participate the study. In order to speed up the enrollment, 5 major sites, where most patients 
are usually referred to, are selected. Approximately 30 patients were planned in the original 
protocol based on feasibility. Based on further evaluation after communication with CDE, the 
sample size was increased to approximately 60 patients to support license renewal. Due to the 
uncertainties during the enrollment, the actual number of patients may differ from estimations. 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 


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must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
Additional consent form 
Not applicable 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted in a publicly accessible database such as clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 


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11.6 
 Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 


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11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days. 


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13 
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Cancer Res; 64(9):3014-21 


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14. Hwang JP, Vierling JM, Zelenetz AD, Lackey SC, Loomba R. Hepatitis B virus 
management to prevent reactivation after chemotherapy: a review.Support Care Cancer. 2012 
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15. ISPE (2008) Guidelines for good pharmacoepidemiology practices (GPP). 
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16. Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system 
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17. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine 
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Washington, Department of Pharmaceutics (2008) www.druginteractioninfo.org (Last update: 
July, 2012)19. Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, Piemonti 
L, Capurso G, Di Florio A, delle Fave G, Pederzoli P, Croce CM, Scarpa A. Pancreatic 
endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin 
Oncol. 2010 Jan 10;28(2):245-55. 
20. Oberg K, Jelic S; ESMO Guidelines Working Group. Neuroendocrine 
gastroenteropancreatic tumors: ESMO clinical recommendations for diagnosis, treatment and 
follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii104-5. 
21. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, 
Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 
Everolimus plus octreotide long-acting repeatable for the treatment of advanced 
neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, 
placebo-controlled, phase 3 study. Lancet 2011 Dec 10; 378(9808):2005-12. 
22. Plöckinger U, Wiedenmann B. Endocrine tumours of the gastrointestinal tract. 
Management of metastatic endocrine tumours. Best Pract Res Clin Gastroenterol. 2005 
Aug;19(4):553-76. 
23. Plöckinger U, Wiedenmann B.Treatment of gastroenteropancreatic neuroendocrine 
tumors. Virchows Arch. 2007 Aug; 451 Suppl 1:S71-80. 
24. Pollak MN, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces 
serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer 
Res. 1989 Jul-Aug; 9(4):889-91. 
25. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, 
Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study 
Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of 
octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine 
midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1; 
27(28):4656-63. 
26. Schnirer II, Yao JC, Ajani JA. Carcinoid--a comprehensive review. Acta Oncol. 2003; 
42(7):672-92. 
27. Schurr PG, Strate T, Rese K, Kaifi JT, Reichelt U, Petri S, Kleinhans H, Yekebas EF, 
Izbicki JR. Aggressive surgery improves long-term survival in neuroendocrine pancreatic 
tumors: an institutional experience. Ann Surg. 2007 Feb; 245(2):273-81. 


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28. Vandenbroucke JP, von Elm E, Altman DG, et al (2007) Strengthening the reporting of 
observational studies in epidemiology (STROBE): explanation and elaboration. Ann Intern 
Med; 147: W-163-W-194. 
29. Velho S, Oliveira C, Ferreira A, et al (2005) The prevalence of PIK3CA mutations in 
gastric and colon cancer. Eur J Cancer; 41(11):1649-54. 
30. Watanabe T1, Tanaka Y. Reactivation of hepatitis viruses following immunomodulating 
systemic chemotherapy Hepatol Res. 2013 Feb;43(2):113-21. doi: 10.1111/hepr.12014. Epub 
2012 Nov 27 
31. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf 
AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in 
advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin 
Oncol. 2008a Sep 10; 26(26):4311-8. 
32. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, 
Vauthey JN, Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and 
prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin 
Oncol 2008b; 26(18): 3063-3072. 
33. Yao JC, Catena L, Colao A, Paganelli G. Perspectives in the development of novel 
treatment approaches. Tumori. 2010a Sep-Oct; 96(5):858-73. 
34. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St 
Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah 
MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients 
with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a 
phase II trial. J Clin Oncol. 2010b Jan 1; 28(1):69-76. 
35. Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine 
tumors. N Engl J Med 2011; 364: 514-523. 
36. Yao JC, Fazio N, Singh S et al. Lancet. 2016 Mar 5;387(10022):968-77. 


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14 
Appendices 
14.1 
Appendix 1: Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) Version 3.1 Guidelines for Response, Duration of 
Overall Response, TTF, TTP, Progression-Free Survival and 
Overall Survival 
 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.1: 29-Nov-2011 
Version 3:0: 19-Oct-2009 
Version 2:0: 18-Jan-2007 
Version 1:0: 13-Dec-2002 
Release date: 
29-Nov-2011 
 
 
Authors (Version 3.1): 
 
 
 
Authors (Version 3): 
 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 
 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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14.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.28 
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming. 
14.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247. 
14.1.3 
Definitions 
14.1.4 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 14.1.26. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 


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• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with  
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
14.1.5 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.1.26. 
14.1.6 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 


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• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared. 


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• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
14.1.7 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.4. 
• Nodal target: See Section 14.1.4. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 


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14.1.8 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-3) as well as the presence or absence of new lesions. 
14.1.9 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number. 
14.1.10 Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
14.1.11 Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 


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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
14.1.12 Determination of target lesion response 
Table 14-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR 
3. Methodology change See Section 14.1.6. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 


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• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters. 


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14.1.13 Determination of non-target lesion response 
Table 14-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline. 
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair). 
Notes on non-target lesion response 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e.  10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
14.1.14 New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 


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• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to  10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.6. 
14.1.15 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3. 
Table 14-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 14.1.8. 
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK). 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
14.1.16 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 


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14.1.17 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• -For non-randomized trials where response is the primary endpoint, confirmation is 
needed. 
• -For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 


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Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower status 
other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 


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Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach). 
14.1.18 Time to event variables 
The protocol should state which of the following variables is used in that study. 
14.1.19 Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
14.1.20 Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive. 


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14.1.21 Time to progression 
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment. 
14.1.22 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment. 
14.1.23 Duration of response 
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988) 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates. 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in Ellis et al (2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response. 


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For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression. 
14.1.24 Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 14.1.23. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 


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14.1.25 Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.26). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 


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• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.1.26 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4. 
Table 14-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 14.1.8. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease. 


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14.1.27 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 14.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered: 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in 
the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next scheduled 
assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or more 
missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim 
(1) N/A 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
Ignored 
Progressed 
F 
New anticancer therapy given 
(1) Date of last adequate assessment 
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censored 
Censored 
Event 
Ignored 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP and 
duration of 
response) 
1.=Definitions can be found in Section 14.1.25 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25. 
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 


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• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-5 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation. 
14.1.28 Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
14.1.29 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
14.1.30 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
14.1.31 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 


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• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
14.1.32 Medical validation of programmed overall lesion response 
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
14.1.33 Programming rules 
The following should be used for programming of efficacy results: 
14.1.34 Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
14.1.35 Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used. 


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Protocol No. CRAD001PCN31 
 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
14.1.36 Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
14.1.37 Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
14.1.38 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.39 Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 14-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted: 


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Protocol No. CRAD001PCN31 
 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
14.1.40 References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 
 

SAP_001.pdf: 
 
Official Title: 
Phase IV, open-label, multi-center, single-arm study of the safety and 
efficacy of everolimus (Afinitor) in adult patients with locally 
advanced, unresectable or metastatic, well differentiated progressive 
pancreatic neuroendocrine tumors (pNET) in China. 
NCT Number: 
NCT02842749 
Document Date: 
Statistical Analysis Plan Final Version 4.0: 13-May-2024 
 
 
 
 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
Page 1 of 25 
Statistical Analysis Plan 
Phase IV, open-label, multi-center, single-arm study of the safety 
and efficacy of everolimus (Afinitor) in adult patients with locally 
advanced, unresectable or metastatic, well differentiated 
progressive pancreatic neuroendocrine tumors (pNET) in China 
Study drug: 
Everolimus (Afinitor®) 
Comparator: 
None 
Indication: 
Chinese adult patients with unresectable, locally advanced or 
metastatic, G1 or G2 progressive pancreatic neuroendocrine tumors 
(pNET) (WHO 2010) 
Phase: 
IV 
Authors: 
 
Release date: 
May 13, 2024 
Version: 
4.0 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 2 of 25 
Statistical Analysis Plan Signature Page 
Authors: 
 
 
 
 
 
Statistician 
 
 
Date (DD/MM/YYYY) 
 
Reviewed by: 
 
 
 
 
 
 
 
 
Date (DD/MM/YYYY) 
 
Approved by: 
 
 
 
 
 
 
China Novartis Institutes for BioMedical Research 
Co., Ltd. 
 
Date (DD/MM/YYYY) 
 
Approved by: 
 
 
 
 
 
 
China Novartis Institutes for BioMedical Research 
Co., Ltd. 
 
Date (DD/MM/YYYY) 
 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 3 of 25 
Amendment Record 
Version No. 
Effective Date 
Modification/Amendment Rationale 
Substituted Version 
Final Version 1.1 
May 22, 2017 
Added analysis of laboratory tests and 
adverse events of special interest based 
on comments from the sponsor 
Final Version 1.0 
Final Version 1.2 
June 14, 2017 
Protocol was updated to add analysis of 
AE as required by sponsor's Medical 
Writer and Clinical Lead 
Final Version 1.1 
Final Version 2.0 
July 14, 2017 
1. Title was updated in accordance with 
the latest Chinese protocol 
2. Protocol was updated involving 
violation analysis to tabulate only 
major protocol violations 
Final Version 1.2 
Final Version 3.0 
May 12, 2021 
1. Updated PFS censoring rules; 
2. Added imputation rules regarding 
dates of death in Section 5.4.2.4.1 
3. Added Section 5.5.5 Additional 
Analysis for Assessment the Impact of 
COVID-19 
4. Added imputation rules on the end 
date of administration in Section 5.4.1 
5. In Section 5.4.2, added the description 
of "In the causality assessment between 
the investigational drug and the adverse 
event, if the result is missing or 
unknown, that AE will be assessed as 
"suspected to be related to the 
investigational drug" " 
6. The Chinese name of “progressive 
pancreatic neuroendocrine tumor” was 
unified throughout the document 
Final Version 2.0 
Final Version 3.1 
October 11, 2023 
1. Based on Novartis SOP requirements, 
the definitions of full analysis set and 
safety set were updated to align with the 
protocol 
Final Version 3.0 
Final Version 3.2 
April 12, 2024 
1. Section 5.4.2, updated the 
determination principle of the period 
to which adverse events fall into 
2. Section 5.3.5, added imputation rules 
for start date and end date of 
concomitant drugs 
3. Section 5.4.2.4.1, added last known 
alive date definition. 
4. Section 5.5.2, added the definition of 
new anticancer therapy 
5. Update case 5 of the censoring rules 
for PFS in Table 2, the censoring 
date of new anticancer therapy was 
adjusted from “date of last adequate 
tumor assessment prior to initiation 
of subsequent anticancer therapy” to 
Final Version 3.1 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 4 of 25 
“date of last adequate tumor 
assessment prior to initiation of 
subsequent anticancer therapy (start 
date of the study treatment if there is 
no post-baseline imaging 
examination)”. 
Final Version 4.0 
May 13, 2024 
Finalized Version 
Final Version 3.2 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 5 of 25 
Table of contents 
Abbreviations ............................................................................................................................. 7 
1 
Project Introduction ............................................................................................................. 8 
2 
Study objectives and study endpoints .................................................................................. 8 
2.1 
Primary study objective ........................................................................................... 8 
2.2 
Secondary study objective ....................................................................................... 8 
2.3 
Primary study endpoints .......................................................................................... 8 
2.4 
Secondary study endpoints ...................................................................................... 8 
3 
Study design ........................................................................................................................ 8 
4 
Sample size calculation ....................................................................................................... 9 
5 
Statistical Analysis .............................................................................................................. 9 
5.1 
General Principle ..................................................................................................... 9 
5.1.1 
Visit Window .......................................................................................... 9 
5.2 
Analysis Population ............................................................................................... 10 
5.3 
Study Participants .................................................................................................. 10 
5.3.1 
Patient Distribution ............................................................................... 10 
5.3.2 
Protocol Violations ............................................................................... 11 
5.3.3 
Demographic and Baseline Characteristics ........................................... 11 
5.3.4 
Medical History ..................................................................................... 11 
5.3.5 
Concomitant medications ...................................................................... 12 
5.4 
Safety Analysis (Primary Analysis) ...................................................................... 13 
5.4.1 
Drug administration .............................................................................. 13 
5.4.2 
Adverse events (AEs) ............................................................................ 13 
5.4.2.1 
Overview of adverse events .................................................................. 15 
5.4.2.2 
All treatment-emergent adverse events ................................................. 15 
5.4.2.3 
Adverse events of special interest ......................................................... 16 
5.4.2.4 
Death, SAE and other significant AE ................................................... 17 
5.4.3 
Laboratory tests ..................................................................................... 19 
5.4.4 
Vital signs ............................................................................................. 20 
5.4.5 
Other safety measurements ................................................................... 20 
5.5 
Efficacy analyses (secondary analyses) ................................................................. 20 
5.5.1 
Overall Survival (OS) ........................................................................... 20 
5.5.2 
Progression-Free Survival (PFS) .......................................................... 21 
5.5.3 
Overall response assessment ................................................................. 22 
5.5.4 
Tumor assessment ................................................................................. 22 
5.5.5 
Additional analysis for assessment the impact of COVID-19 .............. 22 


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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 6 of 25 
6 
Interim analysis ................................................................................................................. 23 
7 
Modification of the Analytical Method for the Protocol Plan ........................................... 23 
8 
Statistical Analysis Form Template Statistics ................................................................... 23 
9 
Reference ........................................................................................................................... 23 
10 Appendix ........................................................................................................................... 24 
Appendix 1 Visit Evaluation Schedule ..................................................................................... 24 
 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 7 of 25 
Abbreviations 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
CR 
Complete response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CTCAE 
Common Terminology Criteria for Adverse Events 
FAS 
Full Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
OS 
Overall survival 
PD 
Progression of disease 
PFS 
Progression-free survival 
pNET 
Pancreatic neuroendocrine tumors 
PR 
Partial response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SMQ 
Standard MedDRA query 
SOC 
System organ class 
WHO 
World Health Organization 


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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 8 of 25 
1 
Project Introduction 
The Statistical Analysis Plan (SAP) provides and describes the statistical analysis methods and 
data processing principles for the Phase IV clinical study (protocol number: CRAD001PCN31) 
sponsored by Novartis Pharma AG to analyze and report on the efficacy and safety of this study. 
This SAP was formulated based on the revised clinical study protocol of version 01 (version 
date: May 31, 2017). 
2 
Study objectives and study endpoints 
2.1 
Primary study objective 
• 
To evaluate the safety of treatment with Afinitor in Chinese adult patients with well 
differentiated progressive pancreatic neuroendocrine tumors (pNET). 
2.2 
Secondary study objective 
• 
To evaluate the overall efficacy of treatment with Afinitor in Chinese patients with 
well differentiated progressive pNET. 
2.3 
Primary study endpoints 
• 
Incidences of adverse events (AEs), AEs suspected to be related to Afinitor, Grade 3 
or 4 AEs and serious adverse events (SAEs); 
• 
AEs of special interest: Non-infectious pneumonitis. 
• 
Other safety endpoints. 
2.4 
Secondary study endpoints 
• 
Overall Survival (OS): defined as time from the start of study treatment to death due 
to any cause; 
• 
Progression Free Survival (PFS): defined as time from the start of study treatment to 
progression or death due to any cause. 
3 
Study design 
This is an open-label, multi-center, single-arm study of the safety and efficacy of Afinitor in 
adult patients with locally advanced, well differentiated progressive pNET in China. 
Patient who are eligible will be provided with everolimus by sponsor to treat pancreatic 
neuroendocrine tumors and will follow the visit schedule in Appendix 1 Visit Evaluation 
Schedule to collect safety and efficacy data until disease progression, unacceptable toxicity, 
death, visit deviation or other reason that may lead to discontinuation before the end of study. 
All patients will be followed-up for survival status every 6 months by the investigator until 
death, lost to follow-up, withdrawal of consent for survival or end of study. 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 9 of 25 
4 
Sample size calculation 
The sample size was determined based on feasibility rather than statistical considerations. 
Based on pre-marketing field survey, each year, approximately 6 to 10 patients at each of the 5 
to 10 study sites selected for this study will be newly diagnosed as ‘locally advanced or 
metastatic, well differentiated pancreatic neuroendocrine tumor’, about 10% to 20% of 
diagnosed patients will be eligible and agree to participate the study. Approximately 30 patients 
were initially planned to be enrolled, and approximately 60 patients are now planned to be 
enrolled after further communication with the Center for Drug Evaluation. Due to the 
uncertainties during the enrollment, the actual number of patients may differ from estimations. 
5 
Statistical Analysis 
5.1 
General Principle 
All statistical analysis were done by using SAS 9.4 or updated version. 
In general, continuous variables were descriptively summarized using number of subjects, mean, 
median, SD, minimum and maximum. Categorical variables and rank variables were 
descriptively summarized using the frequency and percentage under each category or rank. 
Unless otherwise specified, missing data were not included for the calculation of percentage. 
The analytical method of this study was predominantly descriptive, without predetermined 
hypothesis test regarding the comparison of various observation periods. 
5.1.1 
Visit Window 
Treatment day is defined as the number of days on which safety/efficacy assessments are 
performed relative to the initiation of study drug treatment. The day on which the study drug 
treatment is initiated will be recorded as Study Treatment Day 1. Treatment day will be 
calculated as follows: 
• 
Treatment day = date of assessment − date of initiation of study drug treatment + 1 
(assessment occurs after study drug treatment) 
• 
Treatment day = date of assessment − date of initiation of study drug treatment 
(assessment occurs before study drug treatment). 
Since there may be deviations from the visit schedule during the actual trial operation, visit 
windows were created based on the scheduled treatment day of the visits in order that these 
deviated data could also be included in the visits for pooled analysis. If multiple assessments 
fall into the same visit window, the assessment closest to the scheduled treatment day in the 
visit window will be used in the pooled analysis. If there are multiple assessments that are 
equally close to the scheduled treatment date, the latest assessment will be used in the pooled 
analysis. The table below defines the scheduled treatment days and the width of window for 
visits at different assessment endpoints: 
(I) Safety assessment endpoints (vital signs, laboratory tests) 


China Novartis Institutes for BioMedical Research Co., Ltd. 
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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 10 of 25 
Scheduled visits 
Visit labels in tables/lists 
Scheduled treatment 
days 
Visit window (days) 
Screening/Baseline, 
Visit 1 
Baseline 
1 
≤ 1 
Visit 2 
Week 4 
29 
2 - 57 
Visit 3 
Week 12 
85 
58 - 127 
Visit 4 
Week 24 
169 
128 - 211 
Visit 5 
Week 36 
253 
212 - 295 
Visit 6 
Week 48 
337 
296 - 379 
…. 
... 
 
 
Visit n 
Week 12* (n-2) 
12 * (n - 2) * 7 + 1 
12 * (n - 2) * 7 + 1 - 41 - 
12 * (n - 2) * 7 + 1 + 42 
(II) Tumor assessments (only for division of the analysis visits for summary of the diameters 
of target lesions) 
Scheduled visits 
Visit labels in tables/lists 
Scheduled treatment 
days (Day) 
Visit window (days) 
Screening/Baseline, 
Visit 1 
Baseline 
1 
≤ 1 
Visit 3 
Week 12 
85 
2 - 127 
Visit 4 
Week 24 
169 
128 - 211 
Visit 5 
Week 36 
253 
212 - 295 
Visit 6 
Week 48 
337 
296 - 379 
…. 
…. 
 
 
Visit n 
Week 12* (n-2) 
12 * (n - 2) * 7 + 1 
12 * (n - 2) * 7 + 1 - 41 - 
12 * (n - 2) * 7 + 1 + 42 
5.2 
Analysis Population 
• 
Full Analysis Set (FAS): including all patients who received at least one study 
treatment. Patients will be analyzed according to the treatment they received. The 
FAS will be the primary population in the assessment of efficacy. 
• 
Safety Analysis Set (SS): same as FAS. All safety analyses will be analyzed using 
the Safety Set. 
5.3 
Study Participants 
5.3.1 
Patient Distribution 
All patients will be summarized according to the analysis datasets. The number and percentage 
of patients in the FAS and SAF will be summarized separately. 
The number of patients undergoing treatment, and in the FAS, the number and percentages of 
patients who ended the treatment and who ended the treatment for different reasons, and the 
numbers and percentages of patients who ended the trial and who ended the trial for different 
reasons will be separately summarized. The total number of patients screened in each study site 
and the number of patients in the different analysis sets will also be summarized separately. 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 11 of 25 
The disposition of all patients in the FAS set will be tabulated. 
5.3.2 
Protocol Violations 
Protocol violations of patients in the FAS analysis set will be tabulated for analysis. In addition, 
major protocol violations will also be tabulated for analysis. 
5.3.3 
Demographic and Baseline Characteristics 
Demographic characteristics and baseline characteristics will be summarized and tabulated 
based on the FAS. 
The following demographic characteristics and baseline characteristics will be summarized and 
tabulated separately: 
Demographic characteristics 
• 
Age and age group (18 to < 65 years, ≥ 65 years) 
• 
Gender 
• 
Height 
• 
Weight 
• 
Body mass index (weight (kg) / (height (cm) / 100) 2) 
Baseline disease characteristics 
• 
Type according to histological diagnosis 
• 
Tumor staging 
• 
Duration of illness (years, time from initial diagnosis to start of study treatment): if 
the day is missing in the patient’s initial diagnosis date (year and month known), it 
will be imputed using the median value of the dates in that month, i.e., it will be 
imputed as 15th if that month consists of 30 days, or as 16th if that month consists of 
31 days; if the month and day are missing in the patient’s initial diagnosis date (year 
known), it will be imputed with June 30 of that year. 
In addition, the following baseline tumor lesion examinations will be summarized by means of 
contingency tables or descriptive statistics (number of cases, mean, median, standard deviation, 
minimum, and maximum) according to the distribution of data types: 
• 
Total number of lesions, number of target lesions, and number of non-target lesions 
(1, 2, 3, 4, 5 and > 5) 
• 
Number of organs affected (1, 2 and ≥ 3) 
• 
Distribution of organs affected 
• 
Type of lesion (only target lesion, both target lesions and non-target lesions) 
• 
Diameter of target lesion (short diameter of the nodular lesion or the longest diameter 
of other target lesions) 
5.3.4 
Medical History 
The medical history will be summarized and listed based on the FAS. 


China Novartis Institutes for BioMedical Research Co., Ltd. 
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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 12 of 25 
The medical history will be coded using the Medical dictionary for regulatory activities 
(MedDRA) 23.0 or the latest version of the coding dictionary before database lock. The number 
and percentage of patients with at least 1 history will be summarized by System Organ Class 
(SOC) (in alphabetical order) and Preferred Term (PT) (in descending frequency). 
All medical history was tabulated by patient. 
5.3.5 
Concomitant medications 
Combined medications will be summarized and listed based on the SAF. 
Combined medications will be using the latest version of World Health Organization (WHO) 
dictionary and Anatomical Therapeutic Chemical (ATC) codes prior to database lock. 
Combined medications will be categorized into prior and concomitant medications based on 
whether they are used at the start of study treatment: 
• 
Prior medications, refer to medications used only prior to study treatment (i.e., 
medications ended before the start of study treatment) 
• 
Concomitant medications, refer to medications used concurrently during study 
treatment (i.e., medications received at or after the start of study treatment, or 
medications used prior to the start of study treatment and continued after the start of 
study treatment). If the time of a combined medication relative to the start of study 
treatment cannot be determined, it will be considered concomitant. 
If the start date of a combined medication is missing, it will be imputed according to the 
following rules: 
• 
Missing days only: if the year and month are the same as the first dose of study drug, 
the date of the first dose of study drug will be used, otherwise it will be imputed with 
the first day of that month 
• 
Missing month and day: if the year is the same as the first dose of study drug, the 
date of the first does of study drug will be used, otherwise it will be imputed as 
January 1 
• 
If the year, month, and day are all missing, it will be imputed directly with the date of 
the first dose of study drug 
If the end date of a combined medication is missing and it is unknown if the combined 
medication is still in use at the end of study treatment, it will be imputed according to the 
following rules: 
• 
Missing days only: impute with the last day of the month 
• 
Missing month and day: impute with December 31 
• 
If the year, month, and day are all missing, it will be imputed with the date of the last 
dose of study drug 
For concomitant medications, the number and percentage of patients using at least 1 dose will 
be summarized according to ATC 2nd level (in alphabetical order) and Preferred Term (in 
descending frequency). Concomitant medications will be listed. Prior medication was only 
tabulated. 


China Novartis Institutes for BioMedical Research Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 13 of 25 
5.4 
Safety Analysis (Primary Analysis) 
All safety analyses were based on SAF. 
5.4.1 
 Drug administration 
Duration of study treatment exposure, cumulative dose, dose intensity, and relative dose 
intensity were summarized descriptively. Where: 
• 
Dose intensity (mg/day) = cumulative dose (mg) / duration of exposure (days), where 
duration of exposure (days) = time of last dose of Afinitor − time of first dose of 
Afinitor + 1. 
• 
Relative dose intensity (%) = dose intensity / planned daily dose (10 mg/day) × 
100%. 
Patients with a certain duration of exposure (< 12 weeks, 12 - < 24 weeks, 24 - < 36 weeks, 36 
- < 48 weeks, 48 - < 60 weeks, 60 - < 72 weeks, 72 - < 84 weeks, and ≥ 84 weeks) were 
summarized; patients with certain relative dose intensity (0 - < 50%, 50% - < 70%, 70% - < 
90%, 90% - < 110%, and ≥ 110%) were summarized. 
In addition, the number and percentage of patients with dose adjustments/dose interruptions (1 
and ≥ 2) were summarized, and the reasons for dose adjustments were summarized by number 
and percentage of patients. 
If the end date is missing, the following rules are used to impute: 
• 
Missing days only: if the year and month are the same as the last visit, the date of the last 
visit will be used, otherwise it will be imputed with the last day of that month 
• 
Missing month and day: if the year is the same as the last visit, the date and month of the 
last visit will be used, otherwise it will be imputed as December 31. If the imputed date is 
later than the withdrawal date, the end-of-medication date is adjusted to withdrawal date - 
1 day. 
• 
If all year, month and day are missing, it will be imputed directly with the date of the last 
visit 
Drug administration was tabulated by patient. 
5.4.2 
Adverse events (AEs) 
Adverse events (AEs) were coded according to the latest version of MedDRA prior to database 
lock. 
If an outcome is missing and there is no outcome date, the outcome of that adverse event will 
be considered "ongoing". In the causality assessment between the investigational drug and the 
adverse event, if the result is missing or unknown, that AE will be assessed as "suspected to be 
related to the investigational drug". Other missing data will be treated as missing. 
Adverse events were classified by onset time of AE relative to start time of study treatment as: 
• 
Pre-treatment period: from day of patient’s informed consent to the day before first 
dose of study medication; 


China Novartis Institutes for BioMedical Research Co., Ltd. 
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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
Page 14 of 25 
• 
On-treatment period: from day of first dose of study medication to 30 days after last 
dose of study medication; 
• 
Post-treatment period: starting from 30 + 1 days after last dose of study medication. 
In addition to the overview of adverse events, only treatment-emergent adverse events were 
summarized by the number and percentage of patients with AEs. However, all AEs (including 
pre-treatment and post-treatment AEs) were tabulated with data indicating whether the AE 
occurred before or during or after the treatment period. For AE with missing dates, the available 
information should be used as much as possible when determining the period to which the AE 
belongs. If it is still impossible to distinguish, please refer to Table 1. 
Table 1 Handling of missing adverse event onset date 
Known date 
information 
Missing date 
information 
Case 
Period belonging 
to 
[None] 
DDMMYYYY 
 
Treatment period 
DDMM 
YYYY 
 
Treatment period 
YYYY 
DDMM 
If year < year of time of the first dose of the study 
drug 
Pre-treatment 
If year ≥ year of time of the first dose of the study 
drug and ≤ year of time of the lase dose of the study 
drug 
Treatment period 
If year > year of time of the lase dose of the study 
drug 
Post-treatment 
MMYYYY 
Day 
If year < year of time of the first dose of the study 
drug 
Pre-treatment 
If year = year of time of the first dose of the study 
drug, and month < month of time of the first dose of 
the study drug 
Pre-treatment 
If year = year of time of the first dose of the study 
drug and month ≥ month of time of the first dose of 
the study drug 
Treatment period 
If year > year of time of the first dose of the study 
drug and < year of time of the lase dose of the study 
drug 
Treatment period 
If year = year of time of the last dose of the study 
drug and month ≤ month of time of the last dose of 
the study drug + 2 
Treatment period 
If year > year of time of the lase dose of the study 
drug 
Post-treatment 
If year = year of time of the last dose of the study 
drug and month > month of time of the last dose of 
the study drug + 2 
Post-treatment 
DDYYYY 
Month 
If year < year of time of the first dose of the study 
drug 
Pre-treatment 
If year ≥ year of time of the first dose of the study 
drug and ≤ year of time of the lase dose of the study 
drug 
Treatment period 


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Protocol No.: CRAD001PCN31 
Final Version 4.0 (May 13, 2024) 
 
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Known date 
information 
Missing date 
information 
Case 
Period belonging 
to 
If year > year of time of the lase dose of the study 
drug 
Post-treatment 
Note: If the end date of the adverse event is prior to the first dose, the adverse event is a pre-treatment adverse 
event, even if the onset date of the adverse event is missing. 
5.4.2.1 
Overview of adverse events 
The overview of adverse events included the number and percentage of patients with the 
following AE (reported by all grades and Grade 3/4, respectively): 
• 
All death events 
• 
Treatment-emergent deaths (all grades only reported) 
• 
Treatment-emergent AE 
• 
AE suspected to be related to the study drug 
• 
Treatment-emergent SAE 
• 
SAE suspected to be related to the study drug 
• 
AE leading to discontinuation of medication 
• 
AE leading to discontinuation of medication, suspected to be related to the study drug 
• 
Other significant treatment-emergent AE (AE leading to interruption or change in 
dose or frequency of Afinitor, AE requiring additional treatment) 
5.4.2.2 
All treatment-emergent adverse events 
The number and percentage of patients with treatment-emergent AE (including all grades and 
Grade 3/4) (regardless of study drug-related or not) were summarized by SOC (in descending 
order of incidence). 
The number and percentage of patients with treatment-emergent AE (including all grades and 
Grade 3/4) (regardless of study drug-related or not) were summarized by PT (in descending 
order of incidence). 
The number and percentage of patients with common treatment-emergent AE (incidence ≥ 5%) 
were summarized by PT (in descending order of incidence). 
The number and percentage of patients with treatment-emergent AE (regardless of study drug-
related or not) were summarized by PT (in descending order of incidence) and CTCAE grade 
(Grade 1, Grade 2, Grade 3, Grade 4, and Grade 3/4). A patient would be categorized and 
analyzed based on the most severe one if he/she experiences an AE of different severities for 
many times. 
The number and percentage of patients with treatment-emergent AE suspected to be related to 
the study drug were summarized by PT (in descending order of incidence) and CTCAE grade 
(Grade 1, Grade 2, Grade 3, Grade 4, and Grade 3/4). A patient would be categorized and 
analyzed based on the most severe one if he/she experiences an AE of different severities for 
many times. 


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The number and percentage of patients with treatment-emergent AE (regardless of study drug-
related or not) were summarized by SOC (in descending order of incidence) and CTCAE grade 
(Grade 3, Grade 4, and Grade 3/4). A patient would be categorized and analyzed based on the 
most severe one if he/she experiences an AE of different severities for many times. 
The number and percentage of patients with common treatment-emergent AE (incidence ≥ 5%) 
(regardless of study drug-related or not) were summarized by PT (in descending order of 
incidence) and CTCAE grade (Grade 3, Grade 4, and Grade 3/4). A patient would be 
categorized and analyzed based on the most severe one if he/she experiences an AE of different 
severities for many times. 
The number and percentage of patients with treatment-emergent AE suspected to be related to 
the study drug were summarized by PT (in descending order of incidence) and CTCAE grade 
(Grade 3, Grade 4, and Grade 3/4). A patient would be categorized and analyzed based on the 
most severe one if he/she experiences an AE of different severities for many times. 
The number and percentage of patients with treatment-emergent AE (excluding SAE) 
(regardless of study drug-related or not) were summarized by SOC (in alphabetical order) and 
PT (in descending order of incidence). 
The number and percentage of patients with treatment-emergent AE (regardless of study drug-
related or not) were summarized by SOC (in alphabetical order), PT (in descending order of 
incidence), and CTCAE grade (all grades). A patient would be categorized and analyzed based 
on the most severe one if he/she experiences an AE of different severities for many times. 
5.4.2.3 
Adverse events of special interest 
Adverse events of special interest in this study included: non-infectious pneumonitis, 
stomatitis/oral mucositis, hepatitis B virus reactivation and cardiac disease: heart failure; 
ejection fraction decreased. 
For non-infectious pneumonitis, SMQ (standard MedDRA query) (broad) "interstitial lung 
disease" was used to help retrieve relevant adverse events in the database. 
For stomatitis/oral mucositis, the following terms were used as preferred terms to identify 
adverse events in the database. 
• 
Mucosal inflammation 
• 
Lip ulceration 
• 
Glossitis 
• 
Gingival ulceration 
• 
Gingival swelling 
• 
Mucosal ulceration 
• 
Tongue ulceration 
• 
Gingival pain 
• 
Glossodynia 
• 
Stomatitis 
• 
Mouth ulceration 


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• 
Aphthous ulcer 
For hepatitis B virus reactivation, the following terms were used as preferred terms to identify 
adverse events in the database. 
• 
Hepatitis viral test positive 
• 
Hepatitis B 
• 
Infection reactivation 
• 
Hepatitis B antibody 
• 
Hepatitis B surface antibody positive 
• 
Hepatitis B virus test positive 
• 
Viral hepatitis carrier 
For cardiac diseases: heart failure and the ejection fraction decreased, SMQ (narrow) "cardiac 
failure" was used to help retrieve relevant adverse events in the database. 
The number and percentage of patients with non-infectious pneumonitis were tabulated and 
summarized by: 
• 
At least one non-infectious pneumonitis 
• 
Non-infectious pneumonitis suspected to be related to the study drug 
• 
At least one severe (Grade 3 or 4) non-infectious pneumonitis 
• 
Severe (Grade 3 or 4) non-infectious pneumonitis suspected to be related to the study 
drug. 
In addition, the following AE was individually tabulated and summarized by the number and 
percentage of patients: 
• 
Non-infectious pneumonitis, regardless of study drug-related or not graded by 
CTCAE 
• 
Non-infectious pneumonitis leading to discontinuation of treatment, interruption or 
change in dose or frequency of Afinitor, suspected to be related to the study drug 
Non-infectious pneumonitis was tabulated by patient. 
Similar methods were used for analysis of stomatitis/oral mucositis, hepatitis B virus 
reactivation and cardiac diseases: heart failure; ejection fraction decrease. 
5.4.2.4 
Death, SAE and other significant AE 
5.4.2.4.1 Death 
The number and percentage of patients who died during different time periods were summarized, 
and the causes of deaths during treatment were summarized: 
• 
All deaths 
• 
Treatment-emergent deaths, defined as deaths that occurred between the start of 
study treatment and within 30 days after the end of treatment 
• 
Deaths during the follow-up period, defined as those that occurred at or after 30 + 1 
days after the end of study treatment. 


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In addition, deaths due to AE were summarized by MedDRA SOC (in alphabetical order) and 
PT (in descending order of incidence). 
For confirmed deaths only, the date of death is imputed with the following rules: 
• 
If the year is missing (or all missing), it is imputed with the last known survival date 
+ 1; 
• 
If the month and day are missing, they are imputed with January 1st of the current 
year; 
• 
If only the day is missing, it is imputed with the 1st of the current month. 
The last known survival date is defined as the latest of the following dates: 
• 
All test/examination dates including all laboratory tests, vital sign tests, imaging 
examinations 
• 
Treatment dates including the date of treatment with the investigational drug, 
concomitant drugs, concomitant non-drugs 
• 
Onset date of adverse event and end date of adverse event with an outcome other 
than death 
• 
Date of last survival in which the subject's status is not "dead" on the Survival 
Follow-up page 
• 
The study completion date on the end of study page or the withdrawal date for which 
the reason for the withdrawal is not "lost to follow-up" and "death" 
If the imputed date of death is before the last known survival date, the imputed date is modified 
to the last known survival date + 1. If the imputed date of death is after the referencable date of 
death (date of follow-up visit in which the survival follow-up status is “dead”), the imputed date 
is modified to the referencable date of death - 1. 
5.4.2.4.2 SAE 
The number and percentage of patients with following SAE were tabulated and summarized 
separately by SOC (in alphabetical order) and PT (in descending order of incidence): 
• 
Treatment-emergent SAE regardless of whether related to the study drug or not 
• 
Treatment-emergent SAE suspected to be related to the study drug 
• 
SAE leading to withdrawal, regardless of whether related to the study drug or not. 
The number and percentage of patients with following SAE were tabulated and summarized 
separately by PT (in descending order of incidence) and CTCAE grade (Grade 3/4): 
• 
Treatment-emergent SAE regardless of whether related to the study drug or not 
• 
Treatment-emergent SAE suspected to be related to the study drug 
• 
SAE leading to withdrawal, regardless of whether related to the study drug or not. 
A patient would be categorized and analyzed based on the most severe one if he/she experiences 
an AE of different severities for many times. 
The number and percentage of patients with following SAE were tabulated and summarized 
separately by SOC (in alphabetical order), PT (in descending order of incidence), and CTCAE 
grade (all grades): 


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Final Version 4.0 (May 13, 2024) 
 
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• 
Treatment-emergent SAE regardless of whether related to the study drug or not 
• 
Treatment-emergent SAE suspected to be related to the study drug 
• 
SAE leading to withdrawal, regardless of whether related to the study drug or not. 
A patient would be categorized and analyzed based on the most severe one if he/she experiences 
an AE of different severities for many times. 
5.4.2.4.3 Other significant AE 
Other significant AE included: AE leading to discontinuation of medication, AE leading to 
withdrawal from the trial, and AE leading to interruption or changes in dose or frequency of 
Afinitor. 
The number and percentage of patients with following significant AE were tabulated and 
summarized separately by SOC (in alphabetical order) and PT (in descending order of 
incidence): 
• 
AE leading to discontinuation of medication, regardless of whether related to the 
study drug or not 
• 
AE leading to withdrawal, regardless of whether related to the study drug or not 
• 
AE leading to interruption or changes in dose or frequency of Afinitor, regardless of 
whether related to the study drug or not 
The number and percentage of patients with following significant AE were tabulated and 
summarized separately by PT (in descending order of incidence) and CTCAE grade (Grade 3/4): 
• 
AE leading to discontinuation of medication, regardless of whether related to the 
study drug or not 
• 
AE leading to withdrawal, regardless of whether related to the study drug or not 
• 
AE leading to interruption or changes in dose or frequency of Afinitor, regardless of 
whether related to the study drug or not 
A patient would be categorized and analyzed based on the most severe one if he/she experiences 
an AE of different severities for many times. 
The number and percentage of patients with following significant AE were tabulated and 
summarized separately by SOC (in alphabetical order), PT (in descending order of incidence), 
and CTCAE grade (all grades): 
• 
AE leading to discontinuation of medication, regardless of whether related to the 
study drug or not 
• 
AE leading to withdrawal, regardless of whether related to the study drug or not 
• 
AE leading to interruption or changes in dose or frequency of Afinitor, regardless of 
whether related to the study drug or not 
A patient would be categorized and analyzed based on the most severe one if he/she experiences 
an AE of different severities for many times. 
5.4.3 
Laboratory tests 
Baseline is defined as the last valid assessment value prior to dosing. 


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Laboratory test results were converted to International Standard Units and values were graded 
for severity, if applicable, using commonly used toxicity criteria (CTCAE version 4.03). 
Grade 3, grade 4 and all grade tables of all laboratory test abnormal values were provided, and 
the number and percentage of subjects corresponding to the grade of each test value were 
calculated. 
Shift tables of CTCAE grades from baseline to each visit during treatment, last result during 
treatment, and the worst case during treatment were provided. In the shift table, the total number 
of patients and the number and percentage of patients with a change in CTCAE grade at each 
visit were tabulated. 
Those laboratory test values that could not be evaluated by CTCAE grading were analyzed 
using "low", "normal" and "high" based on the range of normal values provided by the local 
laboratory, giving a shift table from baseline to each visit during the treatment period. 
All laboratory test values were tabulated separately for each laboratory parameter by patient 
and visit. All test values outside the laboratory normal range were tabulated separately. 
5.4.4 
Vital signs 
Baseline is defined as the last valid assessment value prior to dosing. 
The measured values of each of vital signs at baseline and different time points after baseline 
were described and analyzed, and the changes in measured results of each vital sign at different 
time points after baseline relative to baseline were given. 
Results for vital signs were tabulated separately for each vital sign parameter by patient and 
visit. 
5.4.5 
Other safety measurements 
Other safety measurements were collected according to clinical indications. However, only 
pulmonary function test and chest CT assessment data were recorded in CRF, and other data 
was only be kept in the source file. 
The assessment data of pulmonary function test and chest CT were tabulated by patient only 
and not summarized in tables. 
5.5 
Efficacy analyses (secondary analyses) 
All efficacy analyses were based on FAS. 
5.5.1 
Overall Survival (OS) 
Overall survival is defined as time from study treatment to death due to any cause. 
If a patient was alive at the data cutoff, the last known survival date was used as the censored 
date for analysis. The definition of the last known survival date is detailed in Section 5.4.2.4.1. 
If the data permits, the Kaplan-Meier method was used to obtain the survival function estimate 
and the median OS estimate, the survival curve was plotted, and the error of the survival 
function was estimated using the Greenwood formula [1], resulting in a 95% confidence interval 


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Protocol No.: CRAD001PCN31 
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of the median OS. In addition, the survival probabilities and their 95% confidence intervals at 
different time points such as at Month 3 and Month 6 were also calculated. 
5.5.2 
Progression-Free Survival (PFS) 
Progression-free survival is defined as time from the start of study treatment to progression of 
disease (PD) or death due to any cause (whichever occurs first). 
Time to progression of disease is defined as the time when progression is first observed: 
• 
At least a 20% increase in the sum of diameter of all measured target lesions, taking 
as reference the smallest sum of diameter of all target lesions recorded at or after 
baseline. In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of 5 mm; 
Or 
• 
Unequivocal progression of existing non-target lesions; 
Or 
• 
Emergence of new lesions. 
The calculation of PFS was based on the date of the imaging examination, not the date of the 
RECIST tumor evaluation or the date of the visit. 
For calculation of PFS, if imaging examinations were completed on multiple dates, the 
progression date or censored date was determined according to the following rules: 
• 
For patients with progression of disease, the date of progression is defined as the 
earliest date when it is assessed that there is progression. 
• 
For patients without progression of disease, the censored date is defined as the date 
of the latest imaging examination within the visit. 
If the patient was alive and progression-free at the time of data cutoff, the date of the last 
imaging examination of the measurable lesion was used as the date of the last evaluation in the 
PFS analysis, i.e., the censored date. If the patient had no PFS data available or was missing 
baseline data assessment and was still alive at the data cutoff, the study treatment start date was 
used as the censored date in the PFS analysis. Detailed censoring rules for PFS are shown in 
Table 2. 
Table 2 Censoring rules for PFS 
# 
Situation 
Progression or censored date 
Result 
1 
No baseline or post-baseline tumor assessment 
Study treatment start date 
Censored 
2 
Documented progression of disease 
Progression date 
Progression 
3 
No progression based on RECIST assessment 
(i.e. clinical progression based on investigator’s 
assessment) leading to end of treatment 
Date of discontinuation of treatment 
Progression 
4 
No events occurred 
Date of last adequate tumor assessment 
Censored 
5 
Initiation of new anti-cancer therapy 
Date of last adequate tumor assessment 
prior to initiation of subsequent 
anticancer therapy (start date of the 
Censored 


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study treatment if there is no post-
baseline imaging examination) 
6 
Death a 
Date of death 
Progression 
7 
Event b documented after two or more missing 
tumor assessments 
Date of last adequate tumor assessment 
prior to two or more consecutive tumor 
assessments not performed as per 
protocol 
Censored 
Note 1: Adequate assessment included tumor assessment in the following situations: CR, PR, SD, PD 
Note 2: a Including cases where no tumor evaluation was conducted after enrollment and death occurred 
during two consecutive scheduled tumor evaluation visits (i.e., date of death is less than or equal to 24 weeks 
+ 2 weeks from the start date of study treatment). 
Note 3: b Indicating that the date of death or progression of disease is greater than 24 weeks + 2 weeks from 
the last tumor assessment. 
New anticancer therapy is defined as the following drugs received at or after the start of study 
treatment: 
• 
The name of the drug is Capecitabine, Temozolomide, or Sandostatin LAR 
• 
Indication or reason for administration is chemotherapy or anti-tumor 
Baseline is defined as the last RECIST1.1 assessment prior to the start of study treatment. 
PFS was analyzed using statistical methods similar to those used for OS analysis. 
5.5.3 
Overall response assessment 
The number and percentage of patients with complete response, partial response, stable disease, 
and progression of disease were summarized according to the best response determined by the 
investigator. 
5.5.4 
Tumor assessment 
The sum of the diameters of target lesions at baseline and at different visits after baseline was 
summarized by descriptive statistics (number, mean, median, standard deviation, minimum, and 
maximum). 1) the change from baseline in the sum of diameters at different visits after baseline 
and 2) the relative change in the sum of diameters at different visits after baseline from the 
minimum value of the sum of diameters among previous visits were summarized by descriptive 
statistics, respectively. 
Tumor assessments were tabulated by patient and visit. 
5.5.5 
Additional analysis for assessment the impact of COVID-19 
Considering that the outbreak of COVID-19 in 2020 has affected the work of each study site to 
varying degrees, protocol deviations due to COVID-19 were collected for this study, including 
visit assessments completed at other hospitals, visit assessments and tests not completed or out-
of-window due to COVID-19, changes in drug supply methods, interruption or discontinuation 
of study drug treatment, etc. Patients seriously affected by COVID-19 were identified at the 
data review meeting, and patients whose response was seriously affected by COVID-19 were 
excluded from the sensitivity analysis of efficacy, with the purpose of exploring the potential 
impact of COVID-19 on the efficacy assessment results of this study. 


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6 
Interim analysis 
Interim analysis was conducted during the study as needed. In order to obtain an outline of the 
data submitted to the China Food and Drug Administration when the drug license was renewed 
in February 2018, the project team planned to conduct the first interim analysis around July 
2017. Moreover, during the study, based on the requirements of the Center for Drug Evaluation, 
clinical data was submitted every 5 years for license renewal, so the project team planned to 
conduct the second interim analysis in February 2021. 
The contents of the interim analysis included all primary and secondary endpoints covered by 
the statistical analysis plan. The analytical methods of this study are predominantly descriptive, 
so alpha spending function is not applicable. For interim analysis, data will be analyzed 
according to the content and methods of analysis described in this SAP, and there is no plan to 
formulate a separate SAP of interim analysis. 
7 
Modification of the Analytical Method for the Protocol Plan 
None. 
8 
Statistical Analysis Form Template Statistics 
The analysis form template will be provided in a separate document. 
9 
Reference 
1. Collett, D. (2003), Modeling Survival Data in Medical Research, Second Edition, 
London: Chapman & Hall. 
 


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10 
Appendix 
Appendix 1 Visit Evaluation Schedule 
 
Category 
Screening/Baseline 
(-28 - 0 day) 
Visit 1 
(day 
1) 
Visit 2 
(day 28 ± 
2 d) 
Visit 3 
(week 12 
± 1 wk) 
Subsequent 
visits (every 
12 wk ± 1 wk) 
End of 
study 
treatment 
(EOT) 
30-day 
Safety 
Follow-up 
Survival 
follow up 
(every 6 
months) 
Obtain Informed Consent 
D 
X 
 
 
 
 
 
 
 
Patient medical history 
D 
X 
 
 
 
 
 
 
 
Demography 
D 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
X 
 
 
 
 
 
 
 
Relevant medical 
history/current medical 
conditions 
D 
X 
 
 
 
 
 
 
 
Diagnosis of cancer 
D 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
S 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
D 
X 
X 
X 
X 
X 
X 
 
 
Height/Weight 
D 
X 
 
 
 
 
 
 
 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
Hematology a 
D 
X 
X 
X 
X 
X 
X 
 
 
Liver function tests b 
D 
X 
 
X 
X 
X 
X 
 
 
Coagulation 
S 
X 
 
X 
X 
X 
X 
 
 
Other laboratory test c 
S 
 
Only to be done if clinically indicate 
 
 
 
Urinalysis c 
S 
X 
Only to be done if clinically indicate 
 
 
 
Pregnancy test d 
D 
X 
 
 
 
 
X 
 
 


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Category 
Screening/Baseline 
(-28 - 0 day) 
Visit 1 
(day 
1) 
Visit 2 
(day 28 ± 
2 d) 
Visit 3 
(week 12 
± 1 wk) 
Subsequent 
visits (every 
12 wk ± 1 wk) 
End of 
study 
treatment 
(EOT) 
30-day 
Safety 
Follow-up 
Survival 
follow up 
(every 6 
months) 
Tumor assessment (MRI or 
CT) e 
D 
X 
 
 
X 
X 
 
 
X f 
Pulmonary function tests, 
Chest CT g 
D 
 
Only to be done if clinically indicate 
 
 
Adverse event 
D 
X 
Continuously 
X 
 
Study Drug administration 
D 
 
X 
X 
X 
X 
X 
 
 
Reason for 
discontinuation/withdrawal 
D 
 
 
 
 
 
X 
 
 
Survival follow-up 
D 
 
 
 
 
 
 
 
X 
a. 
Fasting hematology include: hemoglobin, hematocrit, platelets, red blood cell count (RBC) total white blood cell count (WBC), absolute & differentiated cells 
including lymphocytes, monocytes, eosinophils and basophils. Absolute Neutrophil Count (ANC) will be calculated by the laboratory. 
b. 
Liver function tests include: AST, ALT, total bilirubin, alkaline phosphatase, serum albumin. 
c. 
Clinically significant findings will be noted in the Medical history/Current medical condition pages or Adverse Events pages. Urinalysis assessment could include 
but not limited to: pH, protein, glucose, occult blood, ketones, and leukocytes. Other laboratory test could include but not limited to: total LDH, GGT, fasting 
glucose, fasting serum lipid, sodium, magnesium, phosphate, potassium, chloride, bicarbonate, creatinine, BUN, total protein, uric acid, calcium. 
d. 
A serum pregnancy test will be conducted locally at screening/baseline in all females of child-bearing potential, urine pregnancy test will be conducted at the end 
of treatment visit. 
e. 
Repeat scans (multiphase MRI or triphasic CT) at baseline and every 12 weeks thereafter. The same type of scan should be used at baseline and follow-up. 
f. 
Efficacy assessment will be collected until progression of disease (PD). 
g. 
If an investigator suspects a patient may be developing non-infectious pneumonitis, investigations such as pulmonary function tests, CT chest and referral to a 
pulmonologist should be considered.