OBSERVATIONAL STUDY EVALUATING THE EFFICACY OF TARGETED TREATMENTS FOLLOWING TYROSINE KINASE INHIBITORS IN METASTATIC RENAL CELL CARCINOMA PATIENTS AND EFFECTS ON QUALITY OF LIFE: A NATIONAL, MULTICENTER STUDY
Conditions: Renal Cell Carcinoma
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Observational Study Evaluating The Efficacy of Targeted 
Treatments Following Tyrosine Kinase Inhibitors in 
Metastatic Renal Cell Carcinoma Patients And Effects on 
Quality of Life: A National, Multicenter Study
Protocol number
A4061086
Protocol version identifier
2.1
Date of last version of protocol
09 March 2016
Active substance
Aksitinib, Everolimus, Sunitinib, Sorafenib, Pazopanib, 
Temsirolimus
Research question and 
objectives
Primary objective of this study is; measurement of 
health-related quality of life and efficacy of targeted 
therapies used after second line Tyrosine Kinase 
Inhibitors  (TKIs) in metastatic renal cell carcinoma 
patients.
Due to the reimbursement rules for TKIs in Turkey, the 
use of cytokines (interferon alpha) is mandatory in the 
first-line treatment. The TKI therapy is applied after 
interferon alpha in Turkey as second line therapy. 
Therefore, in this study, the data will be collected to 
observe the quality of life and efficacy with targeted 
therapies used as third line treatment after first line 
interferon alpha and second line TKIs.
Author
, MD: Prof at 
 
, MD, PhD: Medical Manager
PPD
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS ....................................................................................................... 4
2. RESPONSIBLE PARTIES .......................................................................................................... 6
3. ABSTRACT.............................................................................................................................. 7
4. AMENDMENTS AND UPDATES............................................................................................ 12
5. MILESTONES........................................................................................................................ 13
6. RATIONALE AND BACKGROUND ......................................................................................... 13
7. RESEARCH QUESTION AND OBJECTIVES............................................................................. 13
8. RESEARCH METHODS.......................................................................................................... 14
8.1. Study design ........................................................................................................... 14
8.2. Setting..................................................................................................................... 15
8.2.1. Inclusion criteria ........................................................................................ 16
8.2.2. Exclusion criteria........................................................................................ 16
8.3. Variables................................................................................................................. 16
8.4. Data sources........................................................................................................... 19
8.5. Study size................................................................................................................ 19
8.6. Data management.................................................................................................. 20
8.7. Data analysis........................................................................................................... 20
8.8. Quality control........................................................................................................ 21
8.9. Limitations of the research methods..................................................................... 21
8.10. Other aspects ....................................................................................................... 22
9. PROTECTION OF HUMAN SUBJECTS ................................................................................... 22
9.1. Patient Information and Consent........................................................................... 22
9.2. Patient withdrawal................................................................................................. 22
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)................ 22
9.4. Ethical Conduct of the Study.................................................................................. 23
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS............... 23
10.1. Single reference safety document ....................................................................... 31
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........................... 31
12. REFERENCES...................................................................................................................... 32
13. LIST OF TABLES.................................................................................................................. 32
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14. LIST OF FIGURES................................................................................................................ 32
ANNEX 1. LIST OF STAND ALONE DOCUMENTS...................................................................... 32
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ......................................................... 32
ANNEX 3. ADDITIONAL INFORMATION................................................................................... 32
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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
mRCC
Metastatic Renal Cell Carcinoma
FSFV
First Subject First Visit
LSLV
Last Subject Last Visit
LSFV
Last Subject First Visit
SAE
Serious Adverse Event
NCI
National Cancer Institute
NIS
Non-Interventional Study
TKIs
Tyrosine Kinase Inhibitors
CTCAE 
Common Terminology Criteria for Adverse Events
FKSI-15
The Functional Assessment of Cancer Therapy 
Kidney Symptom Index - 15
EQ5D-3L
EuroQol-5 dimension – 3 level
FKSI-DRS
The Functional Assessment of Cancer Therapy 
Kidney Symptom Index—Disease-Related Symptoms
RECIST version 1.1
Response Evaluation Criteria in Solid Tumors
PFS
Progression-Free Survival
QoL
Quality of Life
ORR
Overall Response Rate
OS
Overall Survival
IFN
Interferon
KM
Kaplan Meier
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SD
Standard Deviation
NUTS
Nomenclature D’unites Territoriales Statistiques
IRB
Institutional Review Board
WHO
World Health Organization
MedDRA
Medical Dictionary for Regulatory Activities
ADRs
Adverse Drug Reaction
e-CRF
Electronic Case Report Form
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2. RESPONSIBLE PARTIES
Sponsor: Pfizer
Sponsor Affiliate: 
, MD, PhD Medical Manager
Drug Safety: 
, Pharm; Pharmacovigilance Country Lead
CRO: Trio Grup Clinical Research
CRO Affiliate:
, Bio
Participating Countries: Turkey
Coordinating Investigator: Prof. Dr 
 
Coordinator Investigator(s) of the Study
Name, degree(s)
Title
Affiliation
Address
, 
Prof
MD
 
 
Country Coordinating Investigators
Not applicable 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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3. ABSTRACT
Observational Study Evaluating The Efficacy of Targeted Treatments Following Tyrosine 
Kinase Inhibitors in Metastatic Renal Cell Carcinoma Patients And Effects on Quality of Life: 
A National, Multicenter Study
Protocol Version: 2.1
Protocol Date: 09 March 2016
Main Author: 
, Prof. at 
, MD, PhD at Pfizer
Background
Metastatic renal cell carcinoma (mRCC) is the most common malignant tumour of the 
kidneys. Targeted therapies, which were recently introduced in the treatment of mRCC, 
have become the standard treatment in these patients [1]. With improved survival rate and 
a tolerable side effect profile, Tyrosine Kinase Inhibitors (TKIs) have largely replaced 
conventional immunotherapies worldwide. [2-3]  
In Turkey, due to reimbursement conditions defined by the authority, cytokine (interferon 
alpha) treatment is the standard treatment as first-line therapy [4]. 
Rationale
TKI therapy is used after interferon alpha in Turkey due to current reimbursement status. 
Therefore, the data on quality of life (QoL) from the pivotal studies with standard TKI 
treatment does not reflect the QoL status of patients treated with TKIs as second or third 
line treatment in Turkey. In this study, the clinical outcomes and the impact on quality of 
life of targeted treatments following TKIs will be explored. To our knowledge, since there is 
no similar reimbursement condition in the world placing IFN as the first line standard 
treatment, this will be the first study evaluating the QoL status with targeted therapies used 
as 3rd line treatment in mRCC patients.
PPD
PPD
PPD
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Research Question and Objectives
Research Question: 
There is no data available in the literature explaining the effect of targeted therapies used 
as 3rd line treatment following IFN and TKIs in metastatic renal cell carcinoma patients. 
Therefore, it is essential to understand health-related quality of life and efficacy of targeted 
therapies used as 3rd line treatment due to current reimbursement conditions in Turkey.
Primary Objective: 

Measurement of health-related quality of life with targeted therapy used as 3rd line 
treatment

Overall response rate at the end of follow up

Median progression free survival according to RECIST version 1.1
Secondary Objectives:

Overall survival rate

Effect of quality of life on prognosis.

Adverse events during 3rd line targeted treatment according to CTCAE.4.03 

Dose modifications due to adverse events

Correlation between efficacy (overall response rate at month 12 and median PFS) 
and dose modifications due to adverse events

Correlation between efficacy (overall response rate at month 12 and median PFS) 
and blood pressure 
Study Design
This is a multi-center, national, non-interventional/observational study. It has been defined 
according to the NUTS (Nomenclature of Territorial Units for Statistics: Nomenclature 
d'unites Territoriales Statistiques, French) criteria, which is a regional classification, created 
in order to reduce interregional disparities in socio-economic analysis of the regions, and to 
produce data comparable to that of the European Union (EU). Turkey has been divided into 
12 NUTS regions depending on the economic, social, cultural, and geographical aspects, and 
the population size. In this study, patients with metastatic renal cell carcinoma from centers 
in 12 NUTS regions of Turkey will be included, who meet the inclusion criteria. In this study, 
approximately 152 patients planned to be recruited in 12 months and followed-up for 12 
months. Additionally, every patient will be followed-up once for survival follow-up  in order 
to assess the overall survival before the site close out visit. Survival follow-up will be 
performed via telephone visit or site visit if exist.
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Study Population
Metastatic renal cell carcinoma patients under 3rd line targeted therapy following 1st line 
interferon alpha and 2nd line TKI. All patients will be ≥ 18 years old and have signed the 
informed consent document.
Variables
Age, gender, height, weight, and vital signs such as blood pressure
Socio-demographic characteristics
ECOG performance status
Concomitant diseases and medication
Medical history
Histopathological findings
Type of the surgical procedure 
Treatment history and current treatment information
Metastatic features
MSKCC risk factors
Laboratory findings
The quality of life questionnaire (FKSI-15, EQ5D-3L, FKSI-DRS) on each visit.
Blood pressure diary
Other treatment during follow-up, if any, the dose and the duration
Side effects (treatment of the side effects, interruption of the treatment, dose reduction, 
dose-elevation)
PFS, OS and ORR evaluation during 3rd, 6th, 9th and 12th months performed according to 
RECIST version 1.1, additionally, every patient will be followed-up once for survival follow-
up  in order to assess the overall survival before the site close out visit. Survival follow-up 
will be performed via telephone visit or site visit if exist.
ORR: The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
The patient’s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. 
PFS: The length of time during and after the treatment of a disease, that a patient lives with 
the disease but it does not get worse. In a clinical trial, measuring the progression-free 
survival is one way to see how well a new treatment works.
OS: 1 year Overall Survival (OS), defined as the time from the start of 3rd line treatment 
until death or  1 year due to any cause (measured at the end of follow-up). 
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Data Sources
The source of the data will be the electronic or the written patient records of the 
participating centers. The patient's data can be accessed through a patient file. In the 
centers, both systems can be used in conjunction. The data can be accessed using both 
systems.
Sample Size  
This is a multi-center, national, non-interventional/observational study. In this study, 
patients with metastatic renal cell carcinoma who meet the inclusion criteria will be 
included from centers in 12 NUTS regions of Turkey. Since this is a non-interventional 
observational study, there is no specific follow-up protocol. In this study, approximately 152 
patients will be evaluated.
According to Turkish Statistical Institute data at the end of 2013 population of Turkey is 
approximately 80 million [5].  In the project of Turkey Association of Cancer Research 
Control which was named Cancer Record and Incidence shows that cancer incidence is 100-
150 in 100.000 [6] and 2% of all new cancers are renal cell carcinoma [7]. There would be 
1800 new RCC patients in 1 year, and according to the OS of the disease, there would be 
4000 RCC patients in Turkey. 15% of these are metastatic at the time of diagnosis and 30-
40% of these are metastatic after a period of a time [8]. Presuming that there are 1800 
patients with metastatic renal carcinoma in Turkey, the minimum sample size with 7,6
confidence interval, 95% confidence level and 80% power was calculated as 152.
Data Analysis
Data Analysis:
Statistical analyses will be primarily of explorative and descriptive nature. Patients who 
received at least one dose of 3rd line therapy and have sufficient information whether they 
had an adverse event or not will be valid for safety analysis. Patients who received at least 
one dose of 3rd line therapy and have any information regarding efficacy of therapy will be 
valid for intent-to-treat efficacy analysis.
Demographic data, baseline characteristics, diagnosis and prior treatment of RCC, 
concomitant diseases, and concomitant medication will be described with summary 
statistics such as mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent quartiles, median, 
maximum for continuous variables, and category counts and frequencies (percentages) for 
categorical variables. Concomitant diseases on the case report form correspond to MedDRA 
terms. Concomitant medication will be coded using WHO's drug dictionary.
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Descriptive summaries of Kaplan-Meier (KM) estimates (including number of failed, number 
censored, 25th and 75th percentiles with respective 95% confidence level and median with 
95%Confidence level) and KM curves will be presented for time-to-event efficacy variables 
(PFS, TTP, time to treatment failure). Mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent 
quartiles, median, maximum will be produced for duration of treatment. Category counts 
and frequencies (percentages) will be calculated for tumor status at different visits and 
general subjective rating of efficacy of 3rd line therapy from the treating physician.
Adverse events will be summarized using the CTCAE.4.03 coding system. Event rates for 
single adverse events will be calculated based on the total number of patients valid for 
safety. Adverse events will be categorized according to relation, seriousness, CTCAE grade 
(version 4.03), and discontinuation of therapy, action taken and outcome. Special attention 
will be paid to serious adverse events and unexpected or unlisted ADRs.
Category counts and frequencies (percentages) will be calculated for overall tolerability.
Since the enrollment is after the initiation of the treatment, some information will be 
collected and analyzed retrospectively.
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
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4. AMENDMENTS AND UPDATES
None
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5. MILESTONES
Project Task or Milestone
Planned Timeframe for Completion
FSFV
May 2015
LSFV
December 2016
LSLV
December 2017
Database lock for interim analysis
March 2017
Final database lock
April 2018
Final results available
October 2018
6. RATIONALE AND BACKGROUND
Background
Metastatic renal cell carcinoma (mRCC) is the most common malignant tumour of the 
kidneys. Targeted therapies, which were recently introduced in the treatment of mRCC, 
have become the standard treatment in these patients [1]. With improved survival rate and 
a tolerable side effect profile, Tyrosine Kinase Inhibitors (TKIs) have largely replaced 
conventional immunotherapies worldwide. [2,3]  
These developments have led to new research to identify the effects of these therapies on 
the quality of life and the treatment-related side effects.
In Turkey, due to reimbursement conditions defined by authority, cytokine (interferon 
alpha) treatment is the standard treatment in the first-line therapy [4]. Therefore, the data 
on quality of life from the pivotal studies with standard TKI treatment doesn’t reflect QoL of 
the patients treated with TKIs as second or third line treatment in Turkey.
Rationale
TKI therapy is used after interferon alpha in Turkey due to current reimbursement status. 
Therefore, the data on quality of life from the pivotal studies with standard TKI treatment 
doesn’t reflect the QoL status of the patients treated with TKIs as second or third line 
treatment in Turkey. In this study, the clinical outcomes and the impact on quality of life of 
targeted treatments following TKIs will be explored. To our knowledge, since there is no 
similar reimbursement condition in the world placing IFN as the first line standard 
treatment, this will be the first study evaluating the QoL status with targeted therapies used 
as 3rd line treatment in this setting.
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7. RESEARCH QUESTION AND OBJECTIVES
Research Question: 
In this study, different from other studies in the literature, the data will be collected to 
observe the quality of life and efficacy after first line interferon alpha and second line TKI 
treatments.
Primary Objective: 

Measurement of health-related quality of life with targeted therapy used as 3rd
line.

Overall response rate at the end of follow up

Median progression free survival according to RECIST version 1.1
Secondary Objectives:

Overall survival rate

Effect of quality of life on prognosis.

Adverse events during 3rd line targeted treatment according to CTCAE.4.03 

Dose modifications due to adverse events

Correlation between efficacy (overall response rate at month 12 and median PFS) 
and dose modifications due to adverse events

Correlation between efficacy (overall response rate at month 12 and median PFS) 
and blood pressure 
8. RESEARCH METHODS 
8.1. Study design 
This is a multi-center post-marketing observational study. It has been defined according to 
the NUTS (Nomenclature of Territorial Units for Statistics: Nomenclature d'unites 
Territoriales Statistiques, French) criteria, which is a regional classification, created in order 
to reduce interregional disparities in socio-economic analysis of the regions, and to produce 
data comparable to that of the European Union (EU). Turkey has been divided into 12 NUTS 
regions depending on the economic, social, cultural, and geographical aspects, and the 
population size. In this study, patients with metastatic renal cell carcinoma from centers in 
12 NUTS regions of Turkey will be included, who meet the inclusion criteria. Since this is a 
non-interventional observational study, there is no specific follow-up protocol. In this study, 
approximately 152 patients planned to be recruited in a year and followed-up 12 months.
This is a multi-center post-marketing observational study. In this study, patients with 
metastatic renal cell carcinoma from centers in 12 NUTS regions of Turkey will be included, 
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who meet the inclusion criteria. Since this is a non-interventional observational study, there 
is no specific follow-up protocol.
Presuming that there are 1800 patients with metastatic renal carcinoma in Turkey, the 
minimum sample size was calculated as 152.
There will be a total of 25 centers in various cities of Turkey.
The centers will consist of medical oncology clinics.
In this study, the patient follow-up period is 12 months. Each patient will be followed up to 
5 times; the data will be collected at baseline, the 3rd, 6th, 9th and 12th months according to 
the routine practice. Additionally, every patient will be followed-up once for survival follow-
up  in order to assess the overall survival before the site close out visit. Survival follow-up 
will be performed via telephone visit or site visit if exist.
Because of the observational nature of the study, there is no predefined treatment 
protocol. The participating physician will continue to treat the patients at his/her own 
discretion. Frequency of visits will be continued per physician’s preference.
The patients will be asked to fill in the quality of life questionnaire (FKSI-15, EQ5D-3L, FKSI-
DRS) on each visit.
The assessment of the side effects will be based on the "Common Terminology Criteria for 
Adverse Events". The CTCAE V.4.03 will be used.
Outcome Measures are overall objective response rate (ORR) [Time frame: from enrollment 
to objective response], progression-free survival (PFS) [Time frame: from enrollment to 
disease 
progression 
or 
death, 
whichever 
occurs 
first], 
overall 
survival 
(OS) 
[Time frame: from enrollment to death or the end of the study duration] and probability of 
patient survival at 1 year [Time frame: from enrollment to 1 year]
8.2. Setting
Metastatic renal cell carcinoma patients who progressed after a TKI therapy following a 
cytokine (interferon alpha) treatment will be enrolled to the study. The study enrollment 
period is 12 months And the follow-up period of a patient is 12 months.The study period is 
36 months.
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8.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:

Histologically confirmed metastatic renal cell cancer patients who have already been 
using targeted therapies for up to 1 months as 3rd line treatment

Patients 18 years and older than 18 years

Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legal representative) has been informed of all pertinent aspects of the study.
8.2.2. Exclusion criteria
Patients meeting any of the following criteria will not be included in the study:

Patients with contraindications for the use of the study medications

Patients with (suspected) pregnancy or in lactation period

Patients who are investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by the Investigator, 
or patients who are Pfizer employees directly involved in the conduct of the trial.

Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks 
before included in the current study.
8.3. Variables
The outcome variables for the objective(s) are time to treatment failure (from start of 
treatment to progression or permanent discontinuation), overall survival (from start of 
treatment to the date of last follow up or death), therapeutic response to therapy based on 
response evaluation criteria in solid tumors (RECIST version 1.1), and safety (type, 
incidence, severity of adverse events graded by the National Cancer Institute [NCI] CTCAE 
V.4.03 )
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Variable
Role
Data source(s)
Operational 
definition
Age, gender, height, 
weight, blood pressure, 
socio-demographic 
characteristics
Baseline characteristic
Medical Records
Concomitant diseases
Baseline 
Characteristic
Medical Records
Medication
Baseline 
Characteristic
Medical Records
Histopathological findings
Baseline 
Characteristic
Medical Records / 
Pathology Reports
Surgical Operations
Baseline 
Characteristic
Medical Records
The cytokine (interferon 
alpha) usage in the first-
line treatment, TKI usage 
in the 2nd line treatment 
and the dosage and the 
duration of the treatment
Baseline 
Characteristic
Medical Records
Metastatic features
Baseline 
Characteristic
Medical Records
MSKCC risk factors
Baseline 
Characteristic
Follow-up 
Characteristic
Medical Records
3rd line treatment
Baseline 
Characteristic
Follow-up 
Characteristic
Medical Records
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Close–out 
Characteristic
The performance score 
before the second and 
third-line treatment
Medical Records
The quality of life 
questionnaire (FKSI-15, 
EQ5D-3L, FKSI-DRS) on 
each visit
Baseline 
Characteristic
Follow-up 
Characteristic
Close –out 
Characteristic
Patient interview
Blood pressure
Patient diary
Other treatment during 
follow-up, if any, the dose 
and the duration
Follow-up 
Characteristic
Medical Records
Treatment of the side 
effects, interruption of 
the treatment, dose 
reduction, dose-elevation
Baseline 
Characteristic
Follow-up 
Characteristic
Medical Records
Duration of PFS, OS and 
ORR
Follow-up 
Characteristic
Close-out 
Characteristic
Medical Records
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Schedule Procedure
Initial
visit
Follow-up 
3.month
Follow-up
6.month
Follow-up 
9.month
Follow-up 
12.month
Survival 
Follow-up
Demographic data
X
Histopathological Findigs
X
Medical history
X
Previous therapy of mRCC
X
MSKCC Risk Factors
X
X
X
X
X
Surgical Operations
X
Metastases Information
X
FKSI-15, EQ5D-3L, FKSI-DRS 
Questionnaire
X
X
X
X
X
Evaluation of PFS,OS and ORR
X
X
X
X
Concomitant medication
X
X
X
X
X
Visit date
X
X
X
X
X
ECOG and Karnofsky 
Performance Status
X
X
X
X
X
Prescribed TKI and dose
X
3rd line treatment
X
X
X
X
X
Assessment of Response
X
X
X
X
Adverse Events 
(Serious Adverse Events must 
be reported to the sponsor 
within 24 hours)
X
X
X
X
Survival status
X
8.4. Data sources 
The source of the data will be the electronic or the written patient records of the 
participating centers. The patient records form the basic source for the information about 
the state of a patient's health. For this reason, all the data of the patient are archived in 
various ways in the center. One of the most commonly used data source is the computer-
based patient record system. The patient data can be accessed using these systems 
generated with various computer programs. 
Another common use in the hospital is the hard-copy filing system in the form of log file. 
The patient's data can be accessed through a patient file with a specific code number. In the 
centers, both systems can be used in conjunction. 
The data can be accessed using both systems.
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8.5. Study size
Since this is a multi-center post-marketing observational study, there is no hypothesis to be 
tested.  In this study, patients with metastatic renal cell carcinoma from centers in 12 NUTS 
regions of Turkey will be included, who meet the inclusion criteria. Since this is a non-
interventional observational study, there is no specific follow-up protocol. In this study, 
approximately 152 patients will be evaluated.
According to Turkish Statistical Institute data at the end of 2013, Turkey population is 
approximately 80 million [5].  In the project of Turkey Association of Cancer Research 
Control which was named Cancer Record and Incidence shows that cancer incidence is 100-
150 in 100.000 [6] and 2% of all new cancers are renal cell carcinoma [7]. There would be 
1800 new RCC patients in 1 year, and according to the OS of the disease, there would be 
4000 RCC patients in Turkey. 15% of these are metastatic at the time of diagnosis and 30-
40% [8] of these are metastatic after a period of a time. Presuming that there are 1800 
patients with metastatic renal carcinoma in Turkey, the minimum sample size with 7,6 
confidence interval, 95% confidence level and 80% power was calculated as 152.
8.6. Data management 
The data will be analyzed using the statistical package program. The categorical variables 
will be given as number and percentages, and the continuous variables will be presented as 
averages and standard deviations. For between-group comparisons of categorical variables, 
the chi-square test will be used. The continuous variables will be tested for normal 
distribution using the Kolmogorov-Smirnov test and the Shapiro Wilks test. For the normally 
distributed continuous variables, the parametric tests (the t-test, the ANOVA, the repeated 
measures analysis of variance, etc.), and for the continuous variables without a normal 
distribution, the non-parametric tests (the Mann-Whitney U test, the Kruskal Wallis analysis 
of variance, the Friedman Analysis of Variance, etc.) will be used. The level of significance 
will be taken as p = 0.05.
8.7. Data analysis 
Statistical analyses will be primarily of explorative and descriptive nature. All issues 
concerning patient validity, data consistency checks, permissible data modifications will be 
described in detail in the Data Management Plan. 
Patients who took at least one dose of 3rd line treatment and have sufficient information 
whether they had an adverse event or not will be valid for safety analysis. Patients who 
took at least one dose of 3rd line treatment and have any information regarding efficacy of 
3rd line treatment will be valid for intent-to-treat efficacy analysis.
Demographic data, baseline characteristics, diagnosis and prior treatment of RCC, 
concomitant diseases, and concomitant medication will be described with summary 
statistics such as mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent quartiles, median, 
maximum for continuous variables, and category counts and frequencies (percentages) for 
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categorical variables. Concomitant diseases on the case report form correspond to MedDRA 
terms. Concomitant medication will be coded using WHO's drug dictionary.
Descriptive summaries of Kaplan-Meier (KM) estimates (including number of failed, number 
censored, 25th and 75th percentiles with respective 95% confidence level and median with 
95%confidence level) and KM curves will be presented for time-to-event efficacy variables 
(PFS, TTP, time to treatment failure). Mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent 
quartiles, median, maximum will be produced for duration of TKI treatment. Category 
counts and frequencies (percentages) will be calculated for tumor status at different visits 
and general subjective rating of efficacy of TKI from the treating physician.
Adverse events will be summarized using the MedDRA and the CTCAE coding system. Event 
rates for single adverse events will be calculated based on the total number of patients valid 
for safety. Adverse events will be categorized according to relation, seriousness, CTCAE 
grade (version 4.03), and discontinuation of therapy, action taken and outcome. Serious 
adverse events and unexpected or unlisted ADRs will be evaluated separately.
Category counts and frequencies (percentages) will be calculated for overall tolerability.
The factors, which might have an impacted the duration of treatment, will be studied by 
retrospectively.
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
On occasion a response may not be documented until after the end of therapy so protocols 
should be clear if post-treatment assessments are to be considered in determination of best 
overall response. Protocols must specify how any new therapy introduced before 
progression will affect best response designation. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. 
8.8. Quality control
Data will be captured with e-CRF. Missing data should be completed or commented upon by 
the physician. After data checked, missing or implausible data will be queried. A check for 
multiple documented patients will de done. The data will be verified by an error analysis. 
Finally source data verification will be conducted in all of patients, 100% SDV will be 
performed. All investigators will be sufficiently trained for participation in the study. 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, serious adverse event forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls reports).  The records 
should be retained by the investigator according to local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for 
the required period (e.g., retirement, relocation), Pfizer should be prospectively notified.  
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The study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  The 
investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
8.9. Other aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data.
The informed consent form must be in compliance with local regulatory requirements and 
legal requirements.
The informed consent form used in this study, and any changes made during the course of 
the study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  The investigator, or a person designated by the 
investigator, will obtain written informed consent from each patient or the patient’s legally 
acceptable representative before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent form.
9.2. Patient withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
subject outcome, if possible. The investigator should inquire about the reason for 
withdrawal and follow-up with the subject regarding any unresolved adverse events.  
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 
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the IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should 
be forwarded to Pfizer. 
9.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well 
as with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice (GEP) 
guidelines issued by the International Epidemiological Association (IEA).
This is a non-interventional study where the 3rd line targeted treatment are prescribed in the 
usual manner in accordance with the terms of the marketing authorization. There is no 
assignment of a patient to a particular therapeutic strategy, the treatment decision falls within 
current practice and the prescription of the medicines is clearly separated from the decision to 
include the patient in the study. No additional diagnostic or monitoring process is required 
for participation or during the study. Epidemiological methods shall be used for the analysis 
of the collected data.
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 
Safety event
Recorded on the case report 
form
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness
SAE
All
All
Non-serious AE
All
None
Scenarios involving exposure 
to a drug under study, 
including exposure during 
pregnancy, exposure during 
breast feeding, medication 
error, overdose, misuse, 
extravasation; lack of efficacy; 
and occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
All (regardless of whether 
associated with an AE)
For each AE, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a SAE (see section "Serious Adverse Events” below) 
Safety events listed in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the investigator regardless of whether the event is determined 
by the investigator to be related to a drug under study. In particular, if the SAE is fatal or
life-threatening, notification to Pfizer must be made immediately, irrespective of the extent 
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of available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the 
time of his/her first awareness of the events.
For those safety events that are considered serious or that are identified in the far right 
column of the table above that are reportable to Pfizer within 24 hours of awareness, the 
investigator is obligated to pursue and to provide any additional information to Pfizer in 
accordance with this 24-hour timeframe. In addition, an investigator may be requested by 
Pfizer to obtain specific follow-up information in an expedited fashion.  This information is 
more detailed than that recorded on the case report form. In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Any 
information relevant to the event, such as concomitant medications and illnesses must be 
provided.  In the case of a patient death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative.
Reporting period 
For each patient, the safety event reporting period begins at the time of the patient’s first 
dose of 3rd line treatment or the time of the patient’s informed consent if s/he is already
exposed to 3rd line treatment, and lasts through the end of the observation period of the 
study, which must include at least 28 calendar days following the last administration of a 
drug under study; a report must be submitted to Pfizer Safety (or its designated 
representative) for any of the types of safety events listed in the table above occurring 
during this period. 
If the investigator becomes aware of a SAE occurring at any time after completion of the 
study and s/he considers the SAE to be related to 3rd line treatment, the SAE also must be 
reported to Pfizer Safety. 
Causality assessment
The investigator is required to assess and record the causal relationship.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each adverse event.  For AEs with a causal relationship to 3rd line treatment, follow-up by 
the investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment.  
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that 3rd line treatment caused or contributed to an adverse event. If 
the investigator’s final determination of causality is “unknown” and s/he cannot determine 
whether 3rd line treatment caused the event, the safety event must be reported within 24 
hours. 
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If the investigator cannot determine the etiology of the event but s/he determines that 3rd 
line treatment did not cause the event, this should be clearly documented on the case 
report form and the NIS AEM Report Form. 
DEFINITIONS OF SAFETY EVENTS
Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product.  
The event need not necessarily have a causal relationship with the product treatment or 
usage.  Examples of adverse events include but are not limited to:  

Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event);

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Lack of efficacy; 

Drug abuse; 

Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting 
from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Off-label use; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure during breast feeding;

Medication error;
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
Occupational exposure.
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported 
as an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error 
does not require reporting as an adverse event.
Serious adverse events
A serious adverse event is any untoward medical occurrence in a patient administered a 
medicinal or nutritional product (including pediatric formulas) at any dose  that:

Results in death;

Is life-threatening;

Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute adverse events);

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease progression 
should not be reported as a serious adverse event.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death must 
be recorded as an adverse event and as a serious adverse event with severity Grade 5.
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Medical and scientific judgment is exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately life-
threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as 
serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are considered 
synonymous.  These cases are considered unexpected and handled as serious expedited 
cases by PV personnel.  Such cases are also considered for reporting as product defects, if 
appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological floor 
to a tuberculosis unit). An emergency room visit does not necessarily constitute a 
hospitalization; however, an event leading to an emergency room visit should be assessed 
for medical importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For 
example, the following reports of hospitalization without a medical AE are not to be 
reported. 

Social admission (e.g., patient has no place to sleep)

Administrative admission (e.g., for yearly exam)

Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery)

Hospitalization for observation without a medical AE
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
Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (e.g., for 
work-up of persistent pre-treatment lab abnormality)

Protocol-specified admission during clinical study (e.g., for a procedure required by the 
study protocol)
Scenarios necessitating reporting to Pfizer Safety within 24 hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) 3rd line treatment, or the female becomes, or is 
found to be, pregnant after discontinuing and/or being exposed to 3rd line 
treatment (maternal exposure).
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and 
has been exposed to chemotherapeutic products).
2. A male has been exposed, either due to treatment or environmental exposure to 3rd 
line treatment prior to or around the time of conception and/or is exposed during 
the partner pregnancy (paternal exposure).
As a general rule, prospective and retrospective exposure during pregnancy reports from 
any source are reportable irrespective of the presence of an associated AE and the 
procedures for SAE reporting should be followed.
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with 3rd line treatment, this information must be 
submitted to Pfizer, irrespective of whether an adverse event has occurred using the NIS 
AEM Report Form and the EDP Supplemental Form. 
In addition, the information regarding environmental exposure to  3rd line treatment in a 
pregnant woman (e.g., a subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) must be submitted using the NIS AEM Report 
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Form and the EDP supplemental form. This must be done irrespective of whether an AE has 
occurred.  
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy, in addition, follow-
up is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy 
termination (e.g., induced abortion) and Pfizer is notified of the outcome.  This information 
is provided as a follow up to the initial EDP report.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, 
the reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in 
a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product
Additional information regarding the exposure during pregnancy may be requested.  
Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up 
on preterm infants to identify developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that 
the study participant was given this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence 
of an associated AE. An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (e.g., vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an AE associated with such 
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a drug’s administration, the AE is reported together with the exposure during 
breastfeeding.
Medication error
A medication error is any unintentional error in the prescribing, dispensing or 
administration of a medicinal product that may cause or lead to inappropriate medication 
use or patient harm while in the control of the health care professional, patient, or 
consumer.  Such events may be related to professional practice, health care products, 
procedures, and systems including: prescribing; order communication; product labeling, 
packaging, and nomenclature; compounding; dispensing; distribution; administration; 
education; monitoring; and use.  
Medication errors include:

Near 
misses, 
involving 
or 
not 
involving 
a 
patient 
directly 
(e.g., 
inadvertent/erroneous administration, which is the accidental use of a product 
outside of labeling or prescription on the part of the healthcare provider or the 
patient/consumer);

Confusion with regard to invented name (e.g., trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE :

Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE.

Medication errors that do not involve a patient directly (e.g., potential medication 
errors or near misses).  When a medication error does not involve patient exposure 
to the product the following minimum criteria constitute a medication error report:

An identifiable reporter;

A suspect product;

The event medication error.
Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product  
are reported to Pfizer by the investigator, irrespective of the presence of an associated 
AE/SAE.
Lack of Efficacy
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Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product.
Occupational Exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the 
investigator, irrespective of the presence of an associated AE/SAE.
10.1. Single reference safety document
The local product label information highlighted in the appendix 3 will serve as the single 
reference safety document during the course of the study, which will be used by Pfizer 
safety to assess any safety events reported to Pfizer Safety by the investigator during the 
course of this study. 
The SRSD should be used by the investigator for prescribing purposes and guidance.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Not applicable
COMMUNICATION OF ISSUES
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of.
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12. REFERENCES 
[1]  Hutson TE. Targeted therapies for the treatment of metastatic renal cell carcinoma: 
clinical evidence. Oncologist 2011; 16 Suppl 2:14-22.
[2]  Motzer RJ, et al. Overall survival and updated results for sunitinib compared with 
interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-
90.
[3]   Escudier B, et al. Sorafenib in advanced clear-cell renal cell carcinoma. New Engl J Med 
2007 Jan 11;356(2):125-34.
[4]   (Sağlık Uygulama Tebliği, 25.07.2014  tarihli değişiklik işlenmiş güncel SUT 2013)
[5]  (TUIK, Haber Bülteni, Sayı:13425, tarih:31.12.2012)  
[6]   Türk Kanseri Araştırma ve Savaş Derneğinin Kanser Kayıt ve İnsidansı Çalışması.  
[7] (McLaughlin JK, et al. Epidemiologic aspects of renal cell carcinoma.Semin Oncol. 
2006;33(5):527-533. )  
[8]   http://kanser.gov.tr/daire-faaliyetleri/kanser-istatistikleri.html
13. LIST OF TABLES 
Not applicable
14. LIST OF FIGURES
Not applicable
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
FKSI-15
EQ5D-3L
FKSI-DRS
Blood Pressure Diary
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Inlyta 1 mg product label for Turkey
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Inlyta 5 mg product label for Turkey
Afinitor 5 mg product label for Turkey
Afinitor 10 mg product label for Turkey
Nexavar 200 mg product label for Turkey
Sutent 12,5 mg product label for Turkey
Sutent 25 mg product label for Turkey
Sutent 37,5 mg product label for Turkey
Sutent 50 mg product label for Turkey
Votrient 200 mg product label for Turkey
Votrient 400 mg product label for Turkey
Votrient 800 mg product label for Turkey
Torisel 25 mg/ml i.v. product label for Turkey
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