Clinical trial NCT00625378
Conditions: Neoplasms
Keywords: Cancer Sorafenib Extension program
Sponsor: Bayer
Start date: 2007-12-21; Completion date: 2021-09-24
Enrollment: 206 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of program was to enable patients, currently receiving sorafenib (Nexavar) in a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their respective study had met its primary endpoint and/or had reached the end as defined in the original protocol. Patients were able to continue treatment until (i) the treating physician felt the patient was no longer benefiting from the treatment or (ii) the treatment becomes commercially available and reimbursed for the respective indication as applicable in the country in which the patient lived and the patient could obtain suitable amounts of drug for treatment through standard mechanisms of commercial availability (ie, there should be no interruption in the patient's treatment schedule when switching to commercially available product) or (iii) the patient could join a Post-Trial-Access Program, another study or can receive sorafenib through any other mechanism (e.g. local access program) in accordance with local legal and compliance rules, with no cost to the patient with respect to sorafenib.

An additional objective was the assessment of the safety of Nexavar or Nexavar combination treatment.

Detailed description:

Arms: arm 1: Participants receive single-agent sorafenib at the same dose and schedule as in their original clinical trials.
Interventions: intervention 1: Sorafenib (Nexavar, BAY43-9006)
Intervention descriptions: intervention 1: At the same dose and schedule as in the participants' original clinical trials

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
Sorafenib Long Term Extension Program (STEP) 
NCT Number: 
NCT00625378 
Document Date: 
26 MAY 2020 
 
 


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Cover page of the integrated protocola
Study title: Sorafenib Long Term Extension Program (STEP)
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 05 JUL 2007
Amendment 02 (global amendment described in Section 10.2)
forming integrated protocol Version 3.0, dated 16 MAR 2011
Amendment 03 (global amendment described in Section 10.3)
forming integrated protocol Version 4.0, dated 30 MAR 2012
Amendment 04 (global amendment described in Section 10.4)
forming integrated protocol Version 5.0, dated 25 MAR 2014
Amendment 07 (global amendment described in Section 10.5)
forming integrated protocol Version 6.0, dated 15 MAY 2018
Amendment 08 (global amendment described in Section 10.6)
forming integrated protocol Version 7.0, dated 26 MAY 2020
This protocol has also been amended for specific countries:
Local Amendment 01, Germany, dated 07 FEB 2008
Local Amendment 05, China, dated 19 JAN 2016
Local Amendment 06, Taiwan, dated 25 JUL 2017
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol.
                                                
a Cover page was added by Amendment 7. See Section 10.5.6, Modification 6.


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Title page – amended
Title:
Sorafenib Long Term Extension Program (STEP)
Test Drug:
Sorafenib/Nexavar®  BAY 43-9006
Sponsor:
Sponsor (Non-US): Bayer AG 
51368 Leverkusen, Germany
Sponsor (US territory): Bayer US LLC
100 Bayer Boulevard, P.O. Box 915, Whippany,
NJ 07981-0915, USAb
Senior Clinical Development 
Leader (CDL)c:
Müllerstr. 178
13353 Berlin, Germany
Phone:
Study Number/Version/Date:
12311/Version 7.0/26 MAY 2020
EudraCT-No.:
2007-002604-17
Development Phase:
3b
The undersigned confirm that they agree to conduct the study under the conditions 
described in this protocole
Date
Date
                                                
b The Sponsor’s address was updated by Amendment 7. See Section 10.5.1, Modification 1.
c The Sponsor’s Medical Expert’s role name was updated by Amendment 8. See Section 10.6.1, Modification 1.
d The Senior Clinical Development Leader’s address was updated by Amendment 8. See Section 10.6.1, 
Modification 1.
e:  Changes were made to the Study Manager, Statistician, and Medical Expert under Amendment 3.  See Section
10.3, Modification 6.
f The Study Manager changed and was modified by Amendment 7 and 8. See Section 10.5.1, Modification 1 and 
Section 10.6.1, Modification 1.
g The Statistician changed and was modified by Amendment 7. See Section 10.5.1, Modification 1.
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Date
i j
Confidentiality 
statement:
The following confidential information is the property of Bayer.  As long as the information contained in 
this protocol has not been published, it may only be used when permission has been obtained from Bayer.  
It is not possible to make reproductions of all or sections of this protocol.  Commercial use of the 
information is only possible with the permission of the proprietor and is subject to a license fee.
Additional Signatures
Name:k
Signature:
__________________
Function:
Principal Investigator
Date:
Address:
This document is electronically signed. The eSignature is archived in the Trial Master File 
(TMF) and can be provided upon request.l
                                                
h The signature of the Medical Expert was modified by Amendment 8. See Section 10.6.1, Modification 1.
i The Global Clinical Lead changed and was modified by Amendment 7. See Section 10.5.1, Modification 1. The 
signature of the Global Clinical Lead was removed by Amendment 8. See Section 10.6.1, Modification 1.
j Change of responsibility for the Study Manager and Medical Expert and a line was added for the signature of the 
Global Clinical Lead under Amendment 4.  See Section 10.4, Modification 1.
k The Principal Investigator’s name and address changed by Amendment 7. See Section 10.5.1, Modification 1.
l New eSignature text added with Amendment 8. See Section 10.6.2, Modification 2.
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Table of Contents
Cover page of the integrated protocol .............................................................................................1
Title page – amended ......................................................................................................................2
Table of Contents ............................................................................................................................4
Glossary and Abbreviations ............................................................................................................7
1.
Introduction .............................................................................................................................8
2.
Study objectives - amended.....................................................................................................8
3.
Investigator(s) and other study participants ............................................................................9
4.
Investigational plan .................................................................................................................9
4.1
Study Design and Plan - amended....................................................................................9
4.2
Selection of Study Population ........................................................................................12
4.2.1
Inclusion Criteria...............................................................................................13
4.2.2
Exclusion Criteria..............................................................................................14
4.3
Removal of Subjects from Study....................................................................................15
4.4
Premature Termination of Study/Closure of Centre.......................................................16
4.5
Treatments ......................................................................................................................17
4.5.1
Treatments to be Administered .........................................................................17
4.5.2
Dose Modification.............................................................................................18
4.5.2.1
Sorafenib monotherapy .....................................................................................18
4.5.2.2
Sorafenib and capecitabine combination...........................................................22
4.5.2.3
Sorafenib and TACE combination ....................................................................22
4.5.3
Identity of Investigational Product....................................................................23
4.5.3.1
Sorafenib ...........................................................................................................23
4.5.4
Method of Assigning Subjects to Treatment Groups........................................25
4.5.5
Selection of Doses in the Study.........................................................................25
4.5.6
Selection and Timing of Dose for Each Subject - amended..............................25
4.5.7
Blinding.............................................................................................................25
4.5.8
Prior and Concomitant Therapy ........................................................................25
4.5.9
Treatment Compliance ......................................................................................27
4.6
Study Variables...............................................................................................................27
4.6.1
Efficacy Variables - amended ...........................................................................27
4.6.2
Safety Variables ................................................................................................27
4.6.3
Assessment Periods - amended .........................................................................29
4.7
Data Quality....................................................................................................................31
4.8
Documentation................................................................................................................31
4.9
End of Study ...................................................................................................................32
5.
Ethical and legal aspects........................................................................................................32
5.1
Ethics Committee (EC) or Institutional Review Board (IRB)........................................32
5.2
Ethical Conduct of the Study..........................................................................................33


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5.3
Subject Information and Consent ...................................................................................34
5.4
Insurance.........................................................................................................................34
5.5
Confidentiality................................................................................................................34
6.
Statistical methods and determination of sample size...........................................................35
6.1
Statistical and Analytical Plans- amended......................................................................35
6.2
Determination of Sample Size........................................................................................35
7.
Adverse events ......................................................................................................................35
7.1
Warnings/Precautions.....................................................................................................35
7.2
Adverse Event Monitoring .............................................................................................35
7.3
Adverse Event Definitions..............................................................................................36
7.3.1
Adverse Event ...................................................................................................36
7.3.2
Serious Adverse Event ......................................................................................37
7.3.3
Unexpected Adverse Event ...............................................................................38
7.3.4
Relationship of Adverse Event to Investigational Product ...............................39
7.3.5
Severity of the Serious Adverse Event..............................................................40
7.3.6
Adverse Event Documentation..........................................................................41
7.4
Reporting of Serious Adverse Events/Pregnancy...........................................................41
8.
Use of data and publication...................................................................................................42
9.
References .............................................................................................................................43
10. Protocol amendments ............................................................................................................43
10.1
Amendment 1..................................................................................................................44
10.1.1
Overview of Changes ........................................................................................44
10.1.2
Changes to the Protocol Text ............................................................................45
10.2
Amendment 2..................................................................................................................48
10.2.1
Overview of Changes ........................................................................................48
10.2.2
Changes to the Protocol Text ............................................................................48
10.3
Amendment 3..................................................................................................................50
10.3.1
Overview of Changes ........................................................................................50
10.3.2
Changes to the Protocol Text ............................................................................53
10.4
Amendment 4................................................................................................................102
10.4.1
Overview of Changes ......................................................................................102
10.4.2
Changes to the Protocol Text ..........................................................................105
10.5
Amendment 7................................................................................................................139
10.5.1
Modification 1: Change of responsibility for Sponsor’s Medical Expert, Study 
Manager, Statistician, Global Clinical Lead and Principal Investigator..............................139
10.5.2
Modification 2: Overall survival (OS) evaluation removed from the study 
objectives
139
10.5.3
Modification 3: Safety visits ...........................................................................139
10.5.4
Modification 4: Laboratory evaluations..........................................................140
10.5.5
Modification 5: Follow-up period changed.....................................................140
10.5.6
Modification 6: Editorial changes, corrections and clarifications...................141
10.6
Amendment 8................................................................................................................141


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10.6.1
Modification 1: Change of responsibility for Sponsor’s Medical Expert, Study 
Manager, Statistician, Medical Expert, and Global Clinical Lead ......................................141
10.6.2
Modification 2: Added new eSignature text....................................................141
10.6.3
Modification 3: Added Post-Trial Access Program ........................................142
10.6.4
Modification 4: Removal of the instructions for dose modifications for the 
combination of sorafenib with capecitabine and TACE......................................................142
10.6.5
Modification 5: Added clarification for continuation on study drug ..............142
10.6.6
Modification 6: Added clarification for ending the study...............................143
10.6.7
Modification 7: Added clarification on last patient last visit date ..................143
10.6.8
Modification 8: Removed reference to Study Sites in Japan ..........................143
10.6.9
Modification 9: Corrected timepoint...............................................................144
10.6.10
Modification 9: Editorial changes, corrections and clarifications...................144
11. Appendices ..........................................................................................................................145
11.1
Study Flow Chart..........................................................................................................145
11.2
New York Heart Association Criteria...........................................................................146
11.3
ECOG Performance Status ...........................................................................................147


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Glossary and Abbreviations
AE
Adverse Event
ADR
Adverse Drug Reaction
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
Bid
Bis in die (Latin), Twice a day
CRF
Case Report Form either paper or electronic
EC
Ethical Committee
ECOG
Eastern Cooperative Oncology Group
eg
For Example
FU
Follow-up
IB
Investigator’s Brochure
GCP
Good Clinical Practice
Gr
Grade
HCT
Hematocrit
Hgb
Hemoglobin
ICH
International Conference on Harmonisation
ie
That is
IRB
Institutional Review Board
MI
Myocardial Infarction
NCI
National Cancer Institute
NCI-CTC
National Cancer Institute – Common Terminology Criteria Version 3.0
NCI-
CTCAE
National Cancer Institute – Common Terminology Criteria Adverse 
Event
NYHA
New York Heart Association
OS
Overall survival
PI
Principal Investigator
PMF
Pregnancy Monitoring Form
RBC
Red Blood Cells
RK
Raf Kinase
RKI
Raf Kinase Inhibitor
SAE
Serious Adverse Event
STEP
Sorafenib Long Term Extension Program
TACE
Transarterial Chemoembolization
TMF
Trial Master File
WBC
White Blood Cells
WHO
World Health Organization 


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1.
Introduction
Experience has shown that in nearly all clinical trials with sorafenib (Nexavar®) there are patients 
who are continuing to receive sorafenib after the study has met its primary endpoint. The options
to provide sorafenib to these patients who have a non-approved/reimbursed tumor type are
through a clinical trial, through a Post-Trial Access Program or through any other mechanism
(e.g. local access program) in accordance with local legal and compliance rules. m The intention 
of this clinical study 12311 (STEP program) is to enable patients who are still benefiting from 
treatment in a completed clinical trial to continue to receive treatment.n  
Please refer to the sorafenib Investigator Brochure and any additional data supplied by the 
Sponsor.
2.
Study objectives - amended
The primary purpose of the STEP program is to enable patients, currently receiving sorafenib 
(Nexavar) in a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their 
respective study has met its primary endpoint and/or has reached the end as defined in the 
original protocol. Patients will be able to continue treatment until (i) the treating physician feels 
the patient is no longer benefiting from the treatment or (ii) the treatmentn becomes
commercially available and reimbursed for the respective indication as applicable in the country 
in which the patient lives and the patient can obtain suitable amounts of drug for treatment 
through standard mechanisms of commercial availability (ie, there should be no interruption
in the patient’s treatment schedule when switching to commercially available product)o or (iii)
the patient can join a Post-Trial-Access Program, another study or can receive sorafenib through 
                                                
m: Added Post-Trial Access Program with Amendment 8. See Section 10.6.3, Modification 3.
n:  Reference to subjects receiving single-agent sorafenib was modified under Amendment 3 to allow inclusion of
subjects receiving sorafenib in combination with other drugs, specifically, subjects from the SEARCH trial receiving 
sorafenib and erlotinib and subjects from the RESILIENCE trial receiving sorafenib and capecitabine.  See Section 
10.3, Modification 5.
o: Under Amendment 3, it was clarified that there should be no interruption in a patient’s treatment schedule when 
switching to commercially available product.  See Section 10.3, Modification 6.


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any other mechanism (e.g. local access program) in accordance with local legal and compliance 
rules, with no cost to the patient with respect to sorafenib.p
An additional objective is the assessment of the safety of Nexavar or Nexavar combination 
treatment.q r
3.
Investigator(s) and other study participants
Information regarding additional key personnel involved in the conduct of the study, including 
names and contact details of participating Investigators, monitors, clinical laboratories, technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the Sponsor and on site if requested.
4.
Investigational plan 
4.1
Study Design and Plan - amended
This is an open label clinical trial that will enable patients receiving sorafenib (Nexavar) in a 
completed Bayer/Onyx sponsored clinical trial to continue treatment. A completed study is one 
that has passed the official statistical and regulatory endpoints and/or has reached its end, as 
outlined in that protocol.  
The patients in this open-label clinical trial will continue receiving single-agent sorafenib 
(Nexavar)s or sorafenib and capecitabine combination if transferred from Study 12444 
(RESILIENCE)t at the same dose and schedule as in their original Clinical Trial.  
                                                
p: Added clarification for continuation on study drug with Amendment 8. See Section 10.6.5, Modification 5.
q: These additional objectives were added in Amendment 3. See Section 10.3 Modification 1 and Modification 2.
r: Objective modified by Amendment 7 to remove overall survival (OS). See Section 10.5.2, Modification 2.
s: Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to erlotinib
from study 12917. See Section 10.4, Amendment 4, Modification 2.
t:  Reference to subjects receiving single agent sorafenib was modified under Amendment 3 to allow inclusion of 
subjects receiving sorafenib in combination with other drugs, specifically, subjects from the SEARCH trial receiving 
sorafenib and erlotinib and subjects from the RESILIENCE trial receiving sorafenib and capecitabine.  See Section 
10.3, Amendment 3, Modification 5.


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Patients will continue receiving sorafenib (Nexavar; as single agent or combination treatment),t
as long as the treating physician feels the patient is continuing to benefit from treatment or until 
sorafenib (as single agent or combination treatment) becomes commercially available and 
reimbursed for the respective indication in the country in which the patient lives or until being 
switched to any other form of drug supply with no interruption in the patient’s treatment 
schedule.u The patient may also continue treatmentv until he/she withdraws consent, is non-
compliant, is lost to follow up, or if an unacceptable toxicity occurs.
Prior to being dispensed study medication for this long term extension clinical trial, patients will 
be required to complete their End of Treatment visit in their originating study.  Once the End of 
Treatment visit in the originating study is complete, patients will be required to provide informed 
consent for this long term extension clinical trial.  Patients will continue with single agent 
sorafenib (Nexavar)w or sorafenib and capecitabine if transferred from Study 12444 
(RESILIENCE)x yat the same dose and schedule the patient was receiving in their original 
clinical trial.  
Sorafenib (Nexavar) will be provided as 200 mg tablets. z Capecitabine is available in many 
countries including generic sources and will be commercially supplied 150 mg and 500mg 
tablets aa for patients receiving the sorafenib/capecitabine combination and transferring from 
                                                
u: Added clarification for continuation on study drug with Amendment 8. See Section 10.6.5, Modification 5.
v:  Reference to subjects receiving single agent sorafenib was modified under Amendment 3 to allow inclusion of 
subjects receiving sorafenib in combination with other drugs, specifically, subjects from the SEARCH trial receiving 
sorafenib and erlotinib and subjects from the RESILIENCE trial receiving sorafenib and capecitabine.  See Section 
10.3, Modification 5.
w Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to erlotinib 
from study 12917. See Section 10.4, Modification 2.
x:  Reference to subjects receiving single agent sorafenib was modified under Amendment 3 to allow inclusion of 
subjects receiving sorafenib in combination with other drugs, specifically, subjects from the SEARCH trial receiving
sorafenib and erlotinib and subjects from the RESILIENCE trial receiving sorafenib and capecitabine.  See Section 
10.3, Modification 5.
y Reference to capecitabine was removed with Amendment 8. See Section 10.6.4, Modification 4.
z Sentence removed since none of the subjects that transferred into this study were assigned to erlotinib. See Section
10.4, Amendment 4, Modification 2.
aa Text changed to clarify that capecitabine will be supplied commercially and not by the sponsor under Amendment 
4.  See Section 10.4, Modification 3.


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Study 12444 (RESILIENCE).bb The patient should be evaluated according to Good Medical
Practices as well as local therapeutic and diagnostic standards. The patients should be evaluated 
by a study physician for safety at least once every 8 weeks and more frequently as needed. The 
protocol allows for a ±7 days window when scheduling any visit. Physicians can choose to 
continue to see the patients every 8 weeks in a face to face visit. At least every other visit must be
a mandatory on site visit for examination and drug dispensing, with the other visit being either in 
person or as a phone call. It is at the discretion of the investigator based on the patient’s current 
condition and adverse event profile to determine if the next visit will be performed on site or as a
phone visit. Any scheduled phone visit is mandatory and it will be at the discretion of the 
investigator to decide if that phone visit is sufficient. If the patient needs a physical examination, 
the visit will be performed on site. If the investigator feels the patient is stable with no new safety 
concerns nor new AEs in between visits, a phone call with labs, ECOG and review of AEs would 
be enoughcc. Once every 8 weekscc safety evaluations include vital signs (ie, heart rate, blood 
pressure, temperature) only when the visit is on site, Eastern Cooperative Oncology Group 
(ECOG) performance status, laboratory evaluations may be performed by local accredited lab
which need to have PI signoff within a week of drawingdd (hematology, ALT, AST, lipase and 
amylase, PT-INR as applicable for anticoagulated patients) and a review of any new or ongoing 
adverse event or concomitant medications as well as study medication taken during the visit 
interval.  All adverse events, laboratory data, ECOG performance status and survival status 
(dead or alive and date of death or date of last contact),ee as well as End of Treatment 
information and study medication taken must be clearly and accurately recorded in the Case 
Report Form provided.  All other data, including but not limited to, vital signs, concomitant 
                                                
bb:  Information on the erlotinib and capecitabine formulations was added under Amendment 3. See Section 10.3, 
Modification 5. Reference to capecitabine was removed with Amendment 8. See Section 10.6.4, Modification 4.
cc Safety follow-up adjusted by Amendment 7 to lessen the travel burden on patients. See Section 10.5.3, 
Modification 3.
dd Laboratory evaluations have been adjusted by Amendment 7 to ensure these are not missed. See Section 10.5.4, 
Modification 4.
ee:  Survival and ECOG performance status were added to the Case Report Form as of Amendment 3. See Section 
10.3 Modification 1 and Modification 2.


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medications must be recorded in the patient’s source documents and may be requested at the 
discretion of the Sponsor.  
Following the End of Treatment assessments from the original study, the following information 
will be recorded in the long term extension CRF:  demography, date of first dose of sorafenib 
(Nexavar) in originating studyff date of first dose of capecitabine if the patient is transferred from 
RESILIENCE (Study 12444),gg originating study number, ECOG performance status and 
survival status (dead or alive and date of death or date of last contact)hh and ongoing adverse 
events.
In the event the patient experiences a treatment related Serious Adverse Event, based on the 
definition outlined in Section 7 of this document, this event must be reported to Bayer Global 
Drug Safety immediately (within 24 hours of awareness) using the forms provided, and recorded 
in the CRF.
In the event that another mechanism of continued drug supply is established, the present study 
will end when all patients have transitioned to any new drug supply program or discontinued 
from this study for another reason (e.g. consent withdrawal, lost to follow-up, death, sponsor 
decision). Until the transition, patients will continue to follow all the procedures and visits 
required in the current version of the protocol.ii
4.2
Selection of Study Population
Patients who remain ongoing in a Bayer/Onyx sponsored Clinical Trial that has reached its 
statistical, regulatory and/or study end and who, in the opinion of the Investigator, still benefiting 
from treatment, will be eligible for entry into this study (STEP program).
                                                
ff Sentence removed since none of the subjects that transferred into this study were assigned to erlotinib. See Section
10.4, Modification 2.
gg:  Participation of subjects from the SEARCH trial (Study 12917) or from the RESILIENCE trail (Study 2444) was 
added under Amendment 3 See Section 10.3, Modification 5.
hh: These additional objectives were added in Amendment 3. See Section 10.3, Modification 1 and Modification 2.
ii Added clarification for ending the study with Amendment 8. See Section 10.6.6, Modification 5.


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4.2.1
Inclusion Criteria

Patients, who are participating in a previous Bayer/Onyx sponsored study that has reached its 
endpoint (statistical and regulatory or study end), and who are, in the opinion of the 
Investigator, expected to continue to have an overall positive benefit/risk from continuing 
treatment.

Patients who have signed informed consent for this long term extension program.

Women of childbearing potential and men must agree to use adequate contraception prior to 
study entry and for the duration of study participation, including the 30 days period after last 
study drug dosing. The investigator should advise the patient how to achieve an adequate 
contraception.

Women of childbearing potential who have a negative pregnancy test within 7 days of the 
first dose of sorafenib in this long term extension program.

Patient is receiving sorafenib (Nexavar) as a monotherapy in their originating protocol.  
Patients who were being treated with sorafenib (Nexavar) in combination with other 
chemotherapies in the original study, but continued on single agent sorafenib (Nexavar) after 
discontinuation of the combination agent will be eligible.

Patients who are receiving concurrent combination with sorafenib (Nexavar) and TACE
(transarterial chemoembolization) in their originating study will be eligible.jj kk

Patients who are receiving concurrent combination with sorafenib (Nexavar) and 
capecitabine in their originating Study 12444 (RESILIENCE) will be eligible.

Patients who have completed the End of Treatment assessments in their originating study.  
Every effort should be made to conduct the End of Treatment visit such that the patient does 
not have any interruption of sorafenib dosing.
                                                
jj:  The inclusion criterion regarding eligibility of subjects receiving combination sorafenib and TACE in their 
originating studies was added under Amendment 2.  See Section 10.2.
kk Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to erlotinib
from study 12917. See Section 10.4, Modification 2.


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4.2.2
Exclusion Criteria

Any condition that is unstable or that could jeopardize the safety of the patient (please refer to 
the Investigator Brochure and product labeling safety sections).

History of cardiac disease:  congestive heart failure>NYHA Class 2 (Appendix 11.2) or 
uncontrolled hypertension 

Myocardial infarction (MI) within the last 3 months

Symptomatic metastatic brain or meningeal tumors 

Previous or concurrent cancer that is distinct in primary site or histology from the cancer
being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell 
carcinoma, superficial bladder tumors (Ta, Tis & T1) or any cancer curatively treated > 5 
years prior to study entry.

Patients with seizure disorder requiring medication (such as steroid  anti-epileptics)

Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results

Any condition which could jeopardise the safety of the patient and his/her compliance in the 
study
Excluded therapies and medications, previous and concomitant:

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization)ll mm nn
and capecitabine
                                                
ll:  The exclusion criterion regarding concurrent anti-cancer chemotherapy was modified under Amendment 2.  See 
Section 10.2.


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
Concurrent immunotherapy (including monoclonal antibodies), during or within 30 days prior 
to start of study drugoo

Concurrent hormonal therapy, except for bisphosphonates, during or within 30 days prior to 
start of study drugoo

Concomitant Rifampicin and St John’s Wort (Warfarin may be used only with very close 
monitoring.)

Radiotherapy during study or within 3 weeks of start of study drug.  [Palliative radiotherapy 
will be allowed as described in the Prior and Concomitant Therapy Section 4.5.8.]

Concomitant use of potent inhibitors of CYP 3A4 including ketoconazole, itraconazole and 
ritonavir.  Consumption of grapefruit juice should also be avoided.
4.3
Removal of Subjects from Study
Subjects may be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative.

If, in the Investigator's opinion, continuation in the study would be detrimental to the subject's 
well-being.

At the specific request of the Sponsor.

The patient dies.
                                                                                                                                                             
mm Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to 
erlotinib from study 12917. See Section 10.4, Modification 2.
nn: Participation of subjects from the SEARCH trial (Study 12917) or from the RESILIENCE trial (Study 12444) 
was added under Amendment 3.  In Amendment 4, reference to erlotinib is removed, as no subjects was enrolled into 
this study from study 12917 taking the combination of erlotinib and sorafenib. Therefore, capecitabine is not an
excluded therapy. See Section 10.3, Modification 5.
oo:  The exclusion criterion regarding concurrent anti-cancer chemotherapy was modified under Amendment 2.  See 
Section 10.2.


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Also subjects must discontinue treatment for the following reasons: 

Substantial non-compliance. 

Patients with clinical signs or laboratory tests results consistent with pregnancy. Pregnancy 
will be reported by the Investigator on a Pregnancy Monitoring Form (PMF) following the 
same timelines as a Serious Adverse Event.

The patient uses illicit drugs or other substances that may, in the opinion of the Investigator, 
have a reasonable chance of contributing to toxicity or otherwise interfering with results. 

Occurrence of unacceptable toxicity.

When Nexavar is commercially available and reimbursed for the respective indication in the 
country in which the patient lives.

The patient is lost to follow-up. 
In all cases, the reasons for withdrawal must be recorded in the case report form and patient’s 
medical record.  All patients who discontinue due to adverse events or clinical laboratory 
abnormalities should be followed up until they recover or stabilize, and the subsequent outcome 
recorded.
If any patient should die during the trial or within 30 days of the patient’s last dose of sorafenib 
(Nexavar), the Investigator should inform Bayer by completing the SAE Complimentary Form 
and Adverse Event page for the study.
The cause and date of death should also be recorded on the End of Treatment page, as applicable.
4.4
Premature Termination of Study/Closure of Centre
The Sponsor has the right to close this study, and the Investigator/Sponsor has the right to close a 
center, at any time, although this should occur only after consultation between involved parties.  


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The EC/IRB pp must be informed.  Should the study/center be closed prematurely, all study 
materials (except documentation that has to remain stored at site) must be returned to the 
Sponsor.  The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.
4.5
Treatments
4.5.1
Treatments to be Administered
Sorafenib will be supplied as 200 mg tablets.qq rr Patients should continue on the same dose as 
they were receiving in the patient’s originating Bayer/Onyx-sponsored Clinical Trial. 
The patients’ dose may not be increased beyond the dose they were receiving upon entry into this 
program.
If the patient is receiving a reduced dose upon study entry into STEP due to an adverse event 
(AE), it is possible to re-escalate this dose after AE resolution. Anyway the maximum dose 
allowed in the STEP trial is the one the patient had received before AE induced dose reduction in 
the originating study.
Upon completion of the End of Treatment evaluations in the originating study and registration in 
this program, the patient should be dispensed a new bottle of medication specific for this long 
term extension program.  Patients should be dispensed enough medication to last until their next 
scheduled visit.
                                                
pp:  As of Amendment 3, additional text was added to include the head of the center for sites in Japan. See Section 
10.3 Modification 3. Reference to center for sites in Japan was removed with Amendment 8. See Section 10.6.8, 
Modification 8.
qq:  Information on the erlotinib and capecitabine formulations was added under Amendment 3. See Section 10.3, 
Modification 5.
rr Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to erlotinib 
and sorafenib in study 12917 and references to the supply of capecitabine were removed since this drug will not be 
supplied by the sponsor. See Section 10.4, Modifications 2 and 3.


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Every effort should be made to collect all unused medication and empty bottles on the last visit in 
their original protocol as well at every visit that medication is dispensed in this long term 
extension program.
4.5.2
Dose Modificationss
4.5.2.1 Sorafenib monotherapy
If the starting dose is 600 mg bid the modifications of sorafenib (Nexavar) will follow the pre-
defined dose levels:
Dose level 1
600 mg (3 x 200 mg) po q 12 hr
Dose level -1
400 mg (2 x 200 mg) po q 12 hr
Dose level -2
400 mg (2 x 200 mg) po q 24 hr
Dose level -3
400 mg (2 x 200 mg) po q 48 hr
If the starting dose is 400 mg bid the modifications of sorafenib (Nexavar) will follow the pre-
defined dose levels:
Dose level  1
400 mg (2 x 200 mg) po q 12 hr
Dose level -1 
400 mg (2 x 200 mg) po q 24 hr 
Dose level -2 
400 mg (2 x 200 mg) po q 48 hr
If a dose reduction by more than two dose levels in relation to the current pertaining standard 
dose level is required, the patient should be discontinued from the study treatment. Also, at the 
discretion of the investigator, the dose may be re-escalated to a higher dose level up to the present 
standard dose level after the resolution of the adverse event. Resolution of an adverse event is 
                                                
ss:  With the inclusion of subjects from the SEARCH study and The RESILIENCE study, this section was modified 
under Amendment 3 to include information on sorafenib monotherapy, sorafenib/erlotinib combination therapy, and 
sorafenib/capecitabine combination therapy as separate sub-sections.  See Section 10.3, Modification 5.


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defined as the disappearance or the decrease of the AE to a lower toxicity grade, at least ≤ Grade 
2. 
Table 4–1 illustrates dose modifications and delays for hematologic toxicities.
Table 4–1:  Hematologic Criteria for Dose Delay and Dose Modification of Bay 43-9006
Grade
Dose Delay
Dose Modification
Grade 0-2
Treat on time
No Change
Grade 3
Treat on time
DECREASE one dose level b
Grade 4
DELAY a until Grade 2 
DECREASE one dose level b
a
If no recovery after 30 day delay, treatment will be discontinued unless patient is deriving 
clinical benefit
b
If more than 2 dose reductions are required, treatment will be discontinued
Table 4–2 summarizes the recommendations for dose delays and modifications for all non-
hematologic adverse events, except for skin toxicities, which will be detailed separately (Table 4–
3 and Table 4–4).
Table 4–2:  Non-hematologic Criteria for Dose Delay and Dose Modification of Bay 43-9006 
(except skin toxicity)a
Grade
Dose Delay
Dose Modification
Grade 0-2
Treat on time 
No Change
Grade 3
DELAYb until Grade 2 
DECREASE one dose levelc
Grade 4
OFF protocol therapy
OFF protocol therapy
a
Also excludes nausea/vomiting that has not been premedicated, and diarrhea
b
If no recovery after 30 day delay, treatment will be discontinued unless patient is deriving 
clinical benefit
c
If more than 2 dose reductions are required, treatment will be discontinued


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Only for the purpose of dose modifications, patients experiencing Hand-Foot Skin Reactionstt
should have their signs and symptoms graded according to the following system (see Table 4–3). 
Other skin toxicities will be graded according to CTCAE Version 3.0. Please note that Hand-
Foot Skin Reaction will be graded and recorded as an adverse event according to NCI-CTC
Version 3.0 in the CRF.
Table 4–3:  Grading for Hand-Foot Skin Reaction 
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema 
of the hands and/or feet and/or discomfort, which does not disrupt normal 
activities.
Grade 2
Painful erythema and swelling of the hands and/or feet and/or discomfort 
affecting the patient’s activities. 
Grade 3 
Moist desquamation, ulceration, blistering or severe pain of the hands and/or 
feet and/or severe discomfort that causes the patient to be unable to work or 
perform activities of daily living.
According to the grade and incidence of skin toxicity (including rash and hand-foot syndrome) 
for a given patient, the following dose modification schedule will be followed (see Table 4–4).
                                                
tt:  Hand-Foot Syndrome was changed to Hand-Foot Skin Reaction under Amendment 3.  See Section 10.3, 
Modification 6.


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Table 4–4:  Skin Toxicity Criteria for Dose Delay and Dose Modification of Sorafenib
Toxicity Grade
During a Course of 
Therapy
Dose for Next Cycle
Grade 1
Maintain dose level
Maintain dose level
Grade 2
1st appearance
Interrupt until resolved to 
grade 0-1
Maintain dose level
2nd appearance
Interrupt until resolved to 
grade 0-1
Decrease by one dose level
3rd appearance
Interrupt until resolved to 
grade 0-1
Decrease by two dose levels
4th appearance
Discontinue treatment permanently
Grade 3
1st appearance
Interrupt until resolved to 
grade 0-1
Decrease by one dose levela
2nd appearance
Interrupt until resolved to 
grade 0-1
Decrease by two dose levels
3rd appearance
Discontinue treatment permanently
a
For patients who require a dose reduction for grade 3 rash or hand-foot syndrome, the dose of 
study drug may be increased to the starting dose after one full cycle of therapy has been 
administered at the reduced dose without the appearance of rash or hand foot syndrome 
grade 1.
Patients with discomfort due to hand foot syndrome may be treated with topical emollients, low 
potency topical steroids, or urea-containing cream. 
For patients who require a dose reduction for Grade 3 rash or hand-foot syndrome, the dose of 
study drug may be increased to the starting dose after one full cycle of therapy has been 
administered with the reduced dose, without the appearance of rash or hand foot syndrome 
Grade 1. uu, vv, ww, xx, yy, zz, aaa, bbb, ccc, ddd, eee, fff, ggg, hhh, iii, jjj, kkk, lll, mmm, nnn
                                                
uu Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to erlotinib 
from study 12917. See Section 10.4, Modification 2..
vv The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive placebo 
under Amendment 4.  See Section 10.4, Modification 4.
ww The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive 
placebo under Amendment 4.  See Section 10.4, Modification 4.
xx Removed entire Section 4.5.2.2 Sorafenib and capecitabine combination with Amendment 8. See Section 10.6.4, 
Modification 3.
yy The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive placebo
under Amendment 4.  See Section 10.4, Modification 4.


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4.5.2.2
Sorafenib and capecitabine combination
This section extensively described the specific dose modifications for the sorafenib capecitabine 
combination therapy and is not applicable anymore because all patients treated with this 
combination are off the study. The entire section and subsections were removed with Amendment 
8 to avoid confusion for the remaining patients none of whom are receiving sorafenib and 
capecitabine .ooo
4.5.2.3 Sorafenib and TACE combination
This section described the specific dose modifications for the sorafenib TACE combination 
therapy and is not applicable anymore because all patients treated with this combination are off 
                                                                                                                                                             
zz Removed entire Section 4.5.2.2.1 Dose reduction levels with Amendment 8. See Section 10.6.4, Modification 4.
aaa Removed entire Section 4.5.2.2.2 Dose modification for hematologic toxicities with Amendment 8. See Section 
10.6.4, Modification 4.
bbb The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive 
placebo under Amendment 4. See Section 10.4, Modification 4.
ccc Removed entire Section 4.5.2.2.3 Dose modification for non-hematologic toxicities with Amendment 8. See 
Section 10.6.4, Modification 4.
ddd The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive 
placebo under Amendment 4.  See Section 10.4, Modification 4.
eee The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive 
placebo under Amendment 4.  See Section 10.4, Modification 4.
fff The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive placebo
under Amendment 4.  See Section 10.4, Modification 4.
ggg Removed entire Section 4.5.2.2.4 Dose modification and management of sorafenib specific toxicities with 
Amendment 8. See Section 10.6.4, Modification 4.
hhh Removed entire Section 4.5.2.2.5 Dose modification and management of capecitabine specific toxicities with 
Amendment 8. See Section 10.6.4, Modification 4.
iii Removed entire Section 4.5.2.2.6 Dose modification for other non-hematologic toxicities (excluding fatigue, 
dermatologic toxicities, gastrointestinal toxicities, hypertension and toxicities attributable to capecitabine) with 
Amendment 8. See Section 10.6.4, Modification 4.
jjj Removed entire Section 4.5.2.3 Sorafenib and TACE combination with Amendment 8. See Section 10.6.4, 
Modification 4.
kkk Added the CTC version used to grade liver function abnormalities. See Section 10.4, Modification 6.
lll Added the CTC version used to grade liver function abnormalities. See Section 10.4, Modification 6.
mmm Addition of a new section to present the guidance on Sorafenib dose modification in combination with TACE.  
See Section 10.4, Modification 5.
nnn The word placebo was removed to clarify that subjects receiving sorafenib in Study 12444 did not receive 
placebo under Amendment 4.  See Section 10.4, Modification 4.
ooo Added explaining text as to why sorafenib capecitabine combination therapy sections were removed with 
Amendment 8. See Section 10.6.4, Modification 4.


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the study. The entire section was removed with Amendment 8 to avoid confusion for the 
remaining patients none of whom are receiving sorafenib and TACE.ppp
4.5.3
Identity of Investigational Productqqq
4.5.3.1 Sorafenib
BAY 43-9006 will be packed by the Sponsor and will be labeled according to the requirements of 
local law and legislation.  Label text will be approved according to agreed procedures, and the 
master labels will be available in the study file(s).
Label text will be approved according to agreed Bayer procedures, and a copy of the labels will 
be made available to the study site upon request.
Sorafenib (Nexavar) tablets are red in color and are manufactured by Bayer.  The 200 mg tablets 
are packed in bottles containing 140 tablets or in blister packs depending on the climate zone of 
the respective country. 
The active compound of BAY 43-9006 is 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl) -ureid]-
phenoxy}-pyridine-2-carboxylic acid methylamide-4-methylbenzenesulfo-nate, and its molecular 
weight is 637 Daltons.
The drug is poorly soluble in aqueous media.  The tablets need not be protected from light.  The 
formulation is presented as an immediate release dosage form, ie, the active ingredient is 
completely dissolved under in-vitro test conditions within a short period of time.
                                                
ppp Added explaining text as to why sorafenib TACE combination therapy section was removed with Amendment 8. 
See Section 10.6.4, Modification 4.
qqq:  With the inclusion of subjects from the SEARCH study and the RESILIENCE study, this section was modified 
under Amendment 3 to include information on sorafenib, erlotinib, and capecitabine as separate sub-sections.  See 
Section 10.3, Modification 5.


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Supply, packaging, labeling and storage
BAY 43-9006 tablets will be packed in bottles containing 140 tablets per bottle in countries with 
climate zones I/II. In case of blister packaging 10 tablets are packed per blister. Fourteen blister 
strips are packed in one card box, which thus contains 140 tablets in total. rrr
Participating countries and centers will be provided with the study medication according to the 
number of potential patients from other Bayer/Onyx sponsored studies and receipt of the 
registration form by Bayer.  Once the drug has been received, the drug should be kept in a dry, 
safe place, at controlled room temperature of < 25°C.
The study drug must exclusively be used for the patients specified in this protocol and it will only 
be accessible to authorized staff.  
Only the Investigator or a person assigned by him/her will be allowed to supply and administer 
the drug to the patient. The dispensing and return of sorafenib (Nexavar) to a patient will be 
recorded on a Drug Accountability Form maintained either in the Pharmacy or in the patient’s 
files.  In addition, dosing information should be captured on the appropriate page(s) in the CRF.
sss
Capecitabine is commercially approved for breast cancer and readily available in many countries 
including generic sources. Subjects on treatment with both capecitabine and sorafenib at the end 
of the 12444 RESILIENCE trial who are switched to the STEP study will switch to commercial 
supply capecitabine. In addition, subjects will continue to receive sorafenib as clinical supply. ttt
                                                
rrr Reference to study sites in Japan removed with Amendment 8. See Section 10.6.8, Modification 8.
sss Reference to erlotinib removed since at the time of Amendment 4 none of the subjects that transferred into this 
study were assigned to erlotinib and sorafenib in study 12917. See Section 10.4, Modification 2. At a later time, a 
patient in Taiwan, who was taking sorafenib in combination with erlotinib was transferred from SEARCH into the 
STEP trial. This was explained in local Amendment 6, on 25 JUL 2017.
ttt Text changed to clarify that capecitabine will be supplied commercially and not by the sponsor under Amendment 
4.  See Section 10.4, Modification 3.


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4.5.4
Method of Assigning Subjects to Treatment Groups
As the study is an open label allocation, randomization is not required.
4.5.5
Selection of Doses in the Study
Patients will receive sorafenib (Nexavar) 200 mg tablets and should continue receiving the same 
dose they were receiving in their original trial. Patients receiving sorafenibuuu or
sorafenib/capecitabine combination should continue the same doses as in the originating trial.
vvv
4.5.6
Selection and Timing of Dose for Each Subject - amended
The patient should continue receiving the same dose they were receiving in the previous trial.
Dose increase beyond the dose the patient is currently receiving is not acceptable.
Sorafenib (Nexavar) www, and capecitabine may be decreased in the event of toxicity based on the 
Dose Modification criteria outlined in Section 4.5.2.vvv
4.5.7
Blinding
This study is an open label study therefore blinding is not applicable.
4.5.8
Prior and Concomitant Therapy
Any medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator.  This information must be recorded in the patient’s source documents.
                                                
uuu Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to 
erlotinib from study 12917. See Section 10.4, Modification 2.
vvv:  Participation of subjects from the SEARCH trial (Study 12917) or the RESILIENCE trial (Study 12444) was 
added under Amendment 3.  See Section 10.3, Modification 5.
www Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to 
erlotinib from study 12917. See Section 10.4, Modification 2.


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Permissible concomitant medication/therapies:

Patients taking concomitant medications, known to be metabolized by the liver, should be 
closely observed for side effects.  Patients taking narrow therapeutic index medications that 
are hepatically metabolized (liver P450 system) should be monitored proactively for serum/ 
plasma levels of warfarin, phenytoin, quinidine, carbamazepine and phenobarbital. Treatment 
with non-conventional therapies (for example herbs or acupuncture), and vitamin/mineral 
supplements is acceptable provided that the patient continues to be monitored by the patient’s 
physician.  

In general, patients should be closely monitored for side effects of all concomitant 
medications regardless of path of elimination, especially those with narrow therapeutic 
indices, such a digoxin, warfarin, quinidine, phenytoin, phenobarbitol, carbamazepine and 
cyclosporine.

Patients may receive palliative and supportive care for any underlying illness.  Patients who 
receive bisphosphonates prophylactically or for bone metastases may continue while on study 
drug.  

Palliative radiotherapy during the program is permitted.  Study drug may be continued during 
palliative radiotherapy.
Since there is a possibility of decreased sorafenib (Nexavar) efficacy upon chronic co-
administration of CYP3A4 inducers with sorafenib (Nexavar), chronic co-administration of
CYP3A4 inducers with sorafenib (Nexavar) should be avoided to the extent possible.


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Non-permissible concomitant medication/therapies:

Anticancer chemotherapy, except TACE,xxx yyy and capecitabine, zzz immunotherapy or liveaaaa
vaccines during the study.
4.5.9
Treatment Compliance
An adequate record of receipt, distribution and return (or destruction) of all study medication 
supplies must be kept in the form of a Drug Accountability Form provided by the sponsor. In 
addition, information regarding treatment with sorafenib (Nexavar) in this protocol should be 
recorded on the appropriate page in the CRF.
4.6
Study Variables
The primary objective is to enable patients receiving sorafenib (Nexavar) in a completed 
Bayer/Onyx-sponsored Clinical Trial to continue treatment in this extension program.  
4.6.1
Efficacy Variables - amended
Not applicable.bbbb cccc
4.6.2
Safety Variables
All observations pertinent to the safety of the study medication will be recorded in the patient’s 
source documents and be made available at the request of the sponsor.
                                                
xxx  This text regarding concurrent anti-cancer chemotherapy was modified to add TACE under Amendment 4 to be 
consistent with the exclusion criteria modified in Amendment 2.  See Section 10.4, Modification 5.
yyy Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to 
erlotinib from study 12917. See Section 10.4, Modification 2.
zzz: Participation of subjects from the SEARCH trial (Study 12917) or the RESILIENCE trial (Study 12444) was 
added under Amendment 3.  Therefore, erlotinib and capecitabine are not excluded therapies. See Section 10.3, 
Modification 5. 
aaaa:  In Amendment 3, the information regarding vaccines was clarified to refer to live vaccines. See Section 10.3, 
Modification 6.
bbbb:  Overall survival was added as an efficacy variable by Amendment 3. See Section 10.3, Modification 1.
cccc Efficacy variable modified by Amendment 7 to remove overall survival (OS). See Section 10.5.2, Modification 2.


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The following data must be reported in the source documents:dddd

Vital signs (heart rate, blood pressure, temperature)

Concomitant medications
In addition to the above parameters, the following data must be recorded in the CRF provided and
the source documents:

All treatment related adverse events (any grade)

All adverse events NCI-CTCAE Version 3.0 Grade 3 or higher (regardless of attribution). eeee

All Serious Adverse Events, regardless of relationship to study drug

ECOG performance statusj

Laboratory parameters 

Hematology – Hgb, HCT, platelets, RBC, WBC, differential

Blood chemistry – ALT, AST, amylase, lipase

Coagulation – INR as applicable for patients receiving coagulation therapy

Start and stop dates of sorafenib (Nexavar) treatment as well as the dose of sorafenib
(Nexavar)

Reason for termination of study medicationffff
                                                
dddd:  ECOG performance status was moved from the list of data that must be reported in the source documents to 
data the must be recorded in the CRF and the source documents as of Amendment 3. See Section 10.3, Modification 
2.
eeee:  Language specific to the recording of adverse event information in Japan was added under Amendment 3.  See 
Section 10.3, Modification 2. Language specific to the recording of adverse event information in Japan was removed 
with Amendment 8. See Section 10.6.8, Modification 8. 
ffff:  The bullet for Date of death was deleted in Amendment 3. See Section 10.3, Modification 2.


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4.6.3
Assessment Periods - amended
Prior to a site’s participation [and receipt of open label sorafenib (Nexavar)] in this Long Term 
Extension Program, Ethics Committee/IB and Regulatory approval must be received.
Only patients participating in a Bayer/Onyx clinical trial may be included in this Long Term 
Extension Program.
Upon receipt of the medication for the Long Term Extension Program, the patient should be 
scheduled for a final visit for their original study and the Case Report Form for the original study 
completed.  At the same time, medication should be dispensed for the Long Term Extension
Program and requested data transferred from the originating CRF to the CRF for the Long Term 
Extension Program.
Observations and Measurements
Once enrolled in this program, patients will be evaluated according to local routine practice or at 
least every 8 weeks (±7 days) for safety.  Every other visit must be a mandatory on-site visit for 
examination and drug dispensing with the other visit being either in person or as a phone call. It is 
at the discretion of the investigator based on the patient’s current condition and adverse event 
profile to determine if the visit will be performed on site or as a phone visit. Any scheduled phone 
visit is mandatory and it will be at the discretion of the investigator to decide if a phone visit is 
sufficient. If the patient needs a physical examination, the visit will be performed on site. If the 
investigator feels the patient is stable with no new safety concerns nor new AEs in between visits 
a phone call with labs, ECOG and review of AEs would be enoughggggAll observations pertinent 
to the safety of the patient must be recorded in the patient’s source documents.  The following 
must be recorded in the CRF provided:

Assessment of Adverse Events 
                                                
gggg The visit window and safety follow-up have been modified by Amendment 7 to lessen the travel burden on 
patients. See Section 10.5.3, Modification 3.


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o Treatment related event – all CTC grades
o Any CTC Grade 3 or 4 event (regardless of attribution)
o
hhhhAny Serious Adverse Event (regardless of attribution)

Study medication (date dispensed and returned, number of tablets dispensed and returned)

Laboratory Assessments
o Hematology (hemoglobin, hematocrit, RBC, WBC, platelets, differential)
o Blood Chemistry (ALT, AST, amylase, lipase)
o PT-INR (for patients receiving anticoagulation therapy)

Other variablesiiii
o
ECOG performance status
o
Survival status 
End of treatment
In addition to the above parameters, please record the following in the CRF and source 
documents:

The reason for termination 

Date of last dose 
                                                
hhhh:  Language specific to the recording of adverse event information in Japan was added under Amendment 3.  
See Section 10.3, Modification 2. Language specific to the recording of adverse event information in Japan was 
removed with Amendment 8. See Section 10.6.8, Modification 8.
iiii:  The bullet for other variables and the corresponding sub-bullets for ECOG performance status and survival were 
added in Amendment 3. See Section 10.3, Modification 1 and Modification 2.


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
Survival status (dead or alive and date of death or date of last contact)jjjj
Follow-up period
All subjects will be followed until 30 days after the last dose of study drug.kkkk llll
If a patient discontinues due to an adverse event or clinical laboratory abnormality, the patient 
should be followed until the event resolves, the patient stabilized, or 30 days, whichever is 
shorter.  If a patient dies within 30 days of the last dose of study medication, the SAE 
complementary form should be completed and forwarded to Bayer Global Drug Safety.mmmm
4.7
Data Quality
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, in order to 
comply with GCP guidelines.  Each center will be visited by a monitor to ensure compliance with 
the study protocol, GCP and legal aspects.  This will include on-site checking of the specific data
recorded in the case report forms (CRF) for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters, and review of the clinical supplies.
4.8
Documentation
Entries made in the CRF must be either verifiable against source documents, or have been 
directly entered into the CRF, in which case the entry in the CRF will be considered as the source 
data.  The source data parameter to be verified and the identification of the source document must 
be documented.  The study file and all source data should be retained until notification given by 
the sponsor for destruction.
                                                
jjjj:  This bullet for survival status was added in Amendment 3. See Section 10.3, Modification 1.
kkkk:  The text regarding assessment of survival in the follow-up period was added in Amendment 3. See Section
10.3, Modification 1.
llll  This bullet for survival limiting was added in Amendment 7. See Section 10.5.5 Modification 5.
mmmm:  Section 4.6.4, Drug Concentration Measurements, was deleted in Amendment 3. See Section 10.3, 
Modification 6.


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4.9
End of Study
According to Directive EU 2001/20/EC the end of the trial will be notified to the competent 
authorities of the member states concerned based on the following definition. For the member 
states involved, the end of trial will be reached when the last visit of the last patient for all centers 
in the territory of this member state has occurred. This can be reached based on the last patient 
stopping study medication or being switched to any other form of study drug supply. In the event 
that any other mechanism of drug supply is established, the present study will end when all 
patients have transitioned or discontinued from this study for another reason (e.g. consent 
withdrawal, lost to follow-up, death, sponsor decision). Until the transition, patients will continue 
to follow all the procedures and visits required in the current version of the protocol.nnnn As soon 
as the end of trial according to this definition has been reached in all participating centers within 
and outside the community has occurred, the complete end of trial will be reached.
5.
Ethical and legal aspects
5.1
Ethics Committee (EC) or Institutional Review Board (IRB)
Documented approval from appropriate Ethics Committee(s)/IRBs will be obtained for all 
participating centers/countries prior to study start, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the Ethics Committee 
approval must be obtained and also forwarded to the Sponsor.  The Ethics Committeesoooo must 
supply to the Sponsor, upon request, a list of the Ethics Committee members involved in the vote
and a statement to confirm that the Ethics Committee is organized and operates according to GCP 
and applicable laws and regulations.
                                                
nnnn Added clarification on the definition of the end of study with Amendment 8. See Section 10.6.7, Modification 7.
oooo:  Additional text was added  in Amendment 3 to include the head of the center for sites in Japan. See Section 
10.3, Modification 3. Text to include the head of the center for study sites in Japan removed with Amendment 8. See 
Section 10.6.8, Modification 8.


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5.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation
of this study, are designed to ensure that the Sponsor and Investigator abide by Good Clinical 
Practice Guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).  This may 
include an inspection by the Sponsor representatives and/or Regulatory Authority representatives 
at any time.  The Investigator must agree to the inspection of study-related records by the 
Regulatory Authority/Sponsor representatives, and must allow direct access to source documents 
to the Regulatory Authority/Sponsor representatives.  
The study site will be monitored by Bayer Representatives to verify the timely and accurate 
reporting of treatment related Serious Adverse Events, dispensing of Clinical Supplies to 
appropriate patients and accurate maintenance of CRF as well as Study and Regulatory 
Documents.
Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial 
subjects without prior EC/IRB/Sponsor approval/favorable opinion. As soon as possible, the
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the EC/IRB/Sponsor. Any deviations from the protocol must 
be fully explained and documented by the Investigator.
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/notifications, where required, must be in place and 
fully documented prior to study start.


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5.3
Subject Information and Consent
A core information and Informed Consent Form will be provided. Prior to the beginning of the 
study, the Investigator must have the ECs/IRB written approval/favorable opinion of the written 
Informed Consent Form and any other written information to be provided to subjects.  The 
written approval of the EC/IRB together with the approved subject information/Informed Consent 
Forms must be filed in the study files.
Written informed consent must be obtained before any study specific procedure takes place in 
this program.  To ensure continuing administration of medication, patients will be consented and 
registered for this program while still participating in their original trial (see Section 4.6.3).
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files.
5.4
Insurance
All subjects participating in the study will have insurance coverage by the Sponsor, which is in 
line with applicable laws and/or regulations.
5.5
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded on 
any study related documents or forms, and if the subject name appears on any other document 
(eg, pathologist report), it must be obliterated before a copy of the document is supplied to the 
Sponsor.  Study findings stored on a computer will be stored in accordance with local data 
protection laws.  The subjects will be informed in writing that representatives of the Sponsor, 
EC/IRB, or Regulatory Authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.


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If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects’ records to be identified.
6.
Statistical methods and determination of sample size
6.1
Statistical and Analytical Plans- amended
After the end of the studypppp, descriptive analysesqqqq of demography, adverse events (including 
serious), laboratory data, and reasons for termination of treatmentrrrr ssss will be provided in the 
form of a written report.tttt uuuu
6.2
Determination of Sample Size
Not applicable
7.
Adverse events
7.1
Warnings/Precautions
As outlined in the Investigator Brochure and Safety Sections of the Product Labeling.
7.2
Adverse Event Monitoring
Subjects must be carefully monitored for adverse events.  This monitoring also includes specified 
clinical laboratory tests.  Adverse events should be assessed in terms of their seriousness, severity 
                                                
pppp: The timepoint was corrected with Amendment 8. See Section 10.6.9, Modification 9.
qqqq:  Text regarding the presentation of data was modified under Amendment 3. See Section 10.3, Modification 6.
rrrr:  Duration of treatment and overall survival were added in Amendment 3. See Section 10.3, Modification 1 and 
Modification 6.
ssss Statistical and Analytical Plans were modified by Amendment 7 to remove overall survival (OS). See Section 
10.5.2, Modification 2.
tttt:  Date of enrollment will be used for cases in which the originating trial was not randomized.
uuuu:  Information regarding the analysis of survival data was added in Amendment 3. See Section 10.3, 
Modification 1.


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and relationship to study medication.  Adequate medical care will be provided to the subjects for 
any adverse events, and the events will be followed up until resolution or stabilization.vvvv
7.3
Adverse Event Definitions
7.3.1
Adverse Event
An adverse event is any untoward medical occurrence in a subject or clinical investigation subject 
administered with a pharmaceutical product. The adverse event does not necessarily have to have 
a causal relationship with this treatment.  An adverse event can therefore be any unfavorable and
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
medicinal product.
Adverse events associated with the use of a drug in humans, whether or not considered drug 
related, include the following: 

An adverse event occurring in the course of the use of a drug product in professional practice.

An adverse event occurring from an overdose whether accidental or intentional.

An adverse event occurring from drug abuse.

An adverse event occurring from drug withdrawal. 

An adverse event where there is a reasonable possibility that the event occurred purely as a 
result of the subject’s participation in the study (eg, adverse event or serious adverse event 
due to discontinuation of anti-hypertensive drugs during wash-out phase) must also be 
reported as an adverse event even if it is not related to the investigational product.
                                                
vvvv:  Sentence regarding the follow-up of adverse events was added in Amendment 3. See Section 10.3, 
Modification 4.


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The clinical manifestation of any failure of expected pharmacological action is not recorded as an 
adverse event if it is already reflected as a data point captured in the CRF.  If, however, the event 
fulfills any of the criteria for a “serious” adverse event, it must be recorded and reported as such.
If progressive disease leads to signs and symptoms that meet the “serious” criteria (ie,
hospitalization, disability, death or an important medical event), the signs and symptoms should 
be reported as an SAE and not the underlying cause (ie, progressive disease).
7.3.2
Serious Adverse Event
A serious adverse event is any untoward medical occurrence that at any dose: 

Results in death.

Is life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly or birth defect.

Is an important medical event.
Life-threatening: The term “life-threatening” in the definition of “serious” refers to an adverse
event in which the patient was at risk of death at the time of the event. It does not refer to an 
adverse event which hypothetically might have caused death if it were more severe
Hospitalization: Any adverse event leading to hospitalization or prolongation of hospitalization 
will be considered as Serious, UNLESS at least one of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours wwww
OR
                                                
wwww:  The exception regarding Japan was added in Amendment 3. See Section 10.3, Modification 4. The 
exception regarding Japan was removed with Amendment 8. See Section 10.6.8, Modification 8.


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
The admission is pre-planned (ie, elective or scheduled surgery arranged prior to the start of 
the study). 
OR

The admission is not associated with an adverse event (eg, social hospitalization for purposes 
of respite care).
However, it should be noted that invasive treatment during any hospitalization may fulfil the 
criteria of ‘medically important’ and as such may be reportable as a serious adverse event 
dependant on clinical judgement.  In addition where local Regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedent
Disability means a substantial disruption of a person’s ability to conduct normal life’s functions.
Important medical event: Any adverse event may be considered serious because it may 
jeopardize the subject and may require intervention to prevent another serious condition. As 
guidance for determination of important medical events refer to the “WHO Adverse Reaction 
Terminology – Critical Terms List”. These terms either refer to or might be indicative of a 
serious disease state. 
Such reported events warrant special attention because of their possible association with a serious 
disease state and may lead to more decisive action than reports on other terms.
7.3.3
Unexpected Adverse Event
An unexpected adverse event is any adverse drug event, the specificity or severity of which is not
consistent with the current Investigator Brochure (or Package Insert for marketed products).  
Also, reports which add significant information on specificity or severity of a known, already 
documented adverse event constitute unexpected adverse events. The expectedness of AEs will 


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be determined by the Sponsor according to the applicable reference document and according to 
all local regulations.xxxx
7.3.4
Relationship of Adverse Event to Investigational Product
The assessment of the relationship of an adverse event to the administration of study drug is a 
clinical decision based on all available information at the time of the completion of the case 
report form.
An assessment of ‘No’ would include:

The existence of a clear alternative explanation, eg, mechanical bleeding at surgical site.
OR

Non-Plausibility, eg, the subject is struck by an automobile when there is no indication that 
the drug caused disorientation that may have caused the event; cancer developing a few days 
after the first drug administration.
An assessment of ‘Yes’ indicates that there is a reasonable suspicion that the adverse event is 
associated with the use of the investigational drug.
                                                
xxxx:  The sentence regarding expectedness of AEs was added in Amendment 3. See Section 10.3, Modification 4.


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Factors to be considered in assessing the relationship of the adverse event to study drug include: 

The temporal sequence from drug administration: The event should occur after the drug is 
given.  The length of time from drug exposure to event should be evaluated in the clinical 
context of the event.

Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): 
Subject’s response after drug discontinuation (de-challenge) or subjects response after drug 
re-introduction (re-challenge) should be considered in the view of the usual clinical course of 
the event in question.

Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease the 
subject may have.

Concomitant medication or treatment: The other drugs the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them may be suspected
to cause the event in question.

Known response pattern for this class of drug:

The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic properties 
(absorption, distribution, metabolism and excretion) of the test drug(s), coupled with the 
individual subject’s pharmacodynamics should be considered.
7.3.5
Severity of the Serious Adverse Event
The following classification should be used:
The intensity or severity of serious adverse events should be documented using the National 
Cancer Institute-Common Terminology Criteria, Version 3.0 (NCI-CTC v. 3.0). 
Treatment related Serious adverse events (SAEs), as assessed by the investigator, including
laboratory test abnormalities fulfilling the definition of serious, after signing the informed consent 


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and during follow-up period must immediately (within 24 hours of the investigator’s awareness) 
be reported to the person detailed in the study file.  A serious adverse event Form must also be 
completed within 24 hours of the investigator awareness and forwarded to the designated person 
as detailed in the study file. Each serious adverse event must be followed up until resolution or 
stabilization by submission of updated reports to the designated person.
7.3.6
Adverse Event Documentation
All treatment related adverse events or adverse events NCI-CTCAE Version 3.0 Grade 3 or 
higher (regardless of attribution) occurring after the subject has signed the informed consent must 
be fully recorded in the subject’s case record form.
yyyyDocumentation must be supported by an entry in the subject’s file. A laboratory test 
abnormality considered clinically relevant, eg, causing the subject to withdraw from the study, 
requirement treatment or causing apparent clinical manifestations, or judged relevant by the 
investigator, should be reported as an adverse event.  Each event should be described in detail 
along with start and stop dates, severity, relationship to investigational product, action taken and 
outcome.
7.4
Reporting of Serious Adverse Events/Pregnancy
Serious adverse events (SAEs), including laboratory test abnormalities fulfilling the definition of 
serious, after signing the informed consent and during the follow-up period must immediately 
(within 24 hours of the investigator’s awareness) be reported to the person detailed in the study 
file. A serious adverse event form must also be completed within 24 hours of the investigator’s 
awareness and forwarded to the designated person as detailed in the study file.  Each serious 
adverse event must be followed up until resolution or stabilization by submission of updated 
reports to the designated person.  An isolated laboratory abnormality that is assigned Grade 4, 
according to CTC definition, is not reportable as an SAE, unless the investigator assesses that the 
                                                
yyyy:  Language specific to the recording of adverse event information in Japan was added under Amendment 3.  
See Section 10.3, Modification 2. Language specific to the recording of adverse event information in Japan was 
removed under Amendment 8. See Section 10.6.8, Modification 8.


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event meets standard ICH criteria for an SAE.  CTC Grade 4 baseline laboratory abnormalities 
that are part of the disease profile should not be reported as an SAE, specifically when they are 
allowed or not excluded by the protocol inclusion/exclusion criteria.  If an investigator is in doubt 
about the applicable reporting obligations, he/she should consult with the study monitor for the 
Sponsor.
CTC Grade 4 lab abnormalities will be documented in the lab data and will be reviewed on a 
regular basis.
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities.
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to Bayer within the same timelines as a serious adverse event on a 
Pregnancy Monitoring Form. The outcome of a pregnancy should be followed up carefully and 
any abnormal outcome of the mother or the child should be reported. This also applies to 
pregnancies following the administration of the investigational product to the father prior to 
sexual intercourse.
8.
Use of data and publication
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor, who may utilize the data in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.  The 
investigator, whilst free to utilize the data derived from the study for scientific purposes, must 
discuss any publication with the sponsor prior to release and obtain written consent of the sponsor 
on the intended publication.  The sponsor recognizes the right of the investigator to publish the 
results upon completion of the study.  However, the investigator must send a draft manuscript of 
the publication or abstract to the sponsor thirty days in advance of submission in order to obtain 
approval prior to submission of the final version for publication.  This will be reviewed promptly
and approval will not be withheld unreasonably.  In case of a difference of opinion between the 


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sponsor and the investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties.
9.
References
Investigator’s brochure BAY 43-9006/Raf Kinase Inhibitor, Safety Section of the Product 
Information leaflet
10.
Protocol amendments
The original study protocol was dated 05 July 2007 and a local protocol amendment (Amendment 
1) was instituted in Germany on 07 February 2008. The changes made to the protocol under 
Amendment 1 are described in Section 10.1. However, as Amendment 1 was a local amendment 
only, the changes applicable to Germany are not incorporated into the body of this integrated 
protocol.
A global amendment (Amendment 2) was instituted in February 2011. The changes made to the 
protocol under Amendment 2 are described in Section 10.2 and are incorporated into the body of 
this integrated protocol.  
Another global amendment (Amendment 3) was instituted in March 2012. The changes made to 
the protocol under Amendment 3 are described in Section 10.3 and are incorporated into the body 
of this integrated protocol.  
A further global amendment (Amendment 4) was instituted in March 2014. The changes made to 
the protocol under Amendment 4 are described in Section 10.4 and are incorporated into the body 
of this integrated protocol.
In addition, a local protocol amendment (Amendment 5) was instituted in China on 19 JAN 2016. 
The reason for Amendment 5 was the following: A statement was added to allow patients in 
China who reached End of Treatment in their originating Bayer/Onyx sponsored study, but who
continued to receive sorafenib funded by a Bayer-sponsored program, to enter the STEP trial at 


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any time. This change was made so that these patients may continue to receive sorafenib and be 
monitored for safety through the STEP trial.
A further local protocol amendment (Amendment 6) was instituted in Taiwan on 25 JUL 2017. 
The global protocol amendments are described below. The reason for Amendment 6 was the 
following: The rationale for this amendment is the transfer of ongoing Taiwanese patients from 
SEARCH (sorafenib + erlotinib in HCC) into the STEP trial. The amendment allows for 
combination therapy with erlotinib and sorafenib for subjects in the STEP trial.
A global amendment (Amendment 7) was instituted on 15 MAY 2018. The changes made to the 
protocol under Amendment 7 are described in Section 10.5 and are incorporated into the body of 
this integrated protocol.
A global amendment (Amendment 8) was instituted on 26 MAY 2020. The changes made to the
protocol under Amendment 8 are described in Section 10.6 and are incorporated into the body of 
this integrated protocol.
The changes for all global amendments are described below.
10.1
Amendment 1
10.1.1
Overview of Changes
Modification 1: Inclusion and Exclusion Criteria
The inclusion criterion regarding the use of contraception by men and women of childbearing age 
was clarified to state that the investigator should advise the patient regarding what form of 
contraception he/she feels is most appropriate for the patient.
The exclusion criterion regarding the concomitant use of potent inhibitors of CYP 3A4 was 
clarified to state that the consumption of grapefruit should also be avoided during treatment with 
study drug.


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The protocol sections affected by these changes are Section 4.2.1, Inclusion Criteria, and Section 
4.2.2, Exclusion Criteria.
Modification 2: Prior and Concomitant Therapy
The paragraph describing the proactive monitoring of patients using concomitant narrow 
therapeutic index medications that are hepatically metabolized (liver P450 system) was modified 
to include INR (International Normalized Ratio) measurements for warfarin and phenprocoumon 
as part of the recommended monitoring.  
The statement providing examples of concomitant medications with narrow therapeutic indices 
was modified to add phenprocoumon to the list of medications. 
The protocol section affected by these changes is Section 4.5.8, Prior and Concomitant Therapy.
10.1.2
Changes to the Protocol Text
In this section, all affected protocol sections are detailed; the sequence of sections follows the 
structure of the original protocol.  In the display of modifications, the “old text” refers to the 
protocol version preceding this amendment (ie, protocol version 5.2).  Deletions are crossed out
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Section 4.2.1, Inclusion Criteria
Old text:
Women of childbearing potential and men must agree to use adequate contraception prior to 
study entry and for the duration of study participation, including the 30 days period after last 
study drug dosing.  The investigator should advise the patient how to achieve an adequate 
contraception.
New text:
Women of childbearing potential and men must agree to use adequate contraception prior to 
study entry and for the duration of study participation, including the 30 days period after last 
study drug dosing. The investigator should advise the patient how to achieve an adequate 
contraception with methods he feels to be most appropriate for the patient.
Section 4.2.2   Exclusion Criteria
Old text:
Concomitant use of potent inhibitors of CYP 3A4 including ketoconazole, itraconazole and 
ritronavir. Consumption of grapefruit juice should also be avoided.


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New text:
Concomitant use of potent inhibitors of CYP 3A4 including ketoconazole, itraconazole and 
ritronavir. Consumption of grapefruits and grapefruit juice should also be avoided.
Section 4.5.8   Prior and Concomitant Therapy
Old text: 
Patients taking concomitant medications, known to be metabolized by the liver, should be closely 
observed for side effects.  Patients taking narrow therapeutic index medications that are 
hepatically metabolized (liver P450 system) should be monitored proactively for serum/ plasma 
levels of warfarin, phenytoin, quinidine, carbamazepine and phenobarbital.
In general, patients should be closely monitored for side effects of all concomitant medications 
regardless of path of elimination, especially those with narrow therapeutic indices, such a 
digoxin, warfarin, quinidine, phenytoin, phenobarbitol, carbemazepam and cyclosporine.
New text:
Patients taking concomitant medications, known to be metabolized by the liver, should be closely 
observed for side effects.  Patients taking narrow therapeutic index medications that are 
hepatically metabolized (liver P450 system) should be monitored proactively with INR 
(International Normalized Ratio) measurements for warfarin and phenprocoumon; and for serum/ 
plasma levels for phenytoin, quinidine, carbamazepine and phenobarbital.
In general, patients should be closely monitored for side effects of all concomitant medications 
regardless of path of elimination, especially those with narrow therapeutic indices, such as 
digoxin, warfarin, phenprocoumon, quinidine, phenytoin, phenobarbitol, carbamazepine and 
cyclosporine.


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10.2
Amendment 2
10.2.1
Overview of Changes
Modification: Inclusion and Exclusion Criteria
An inclusion criterion was added to allow subjects who received combination treatment with 
sorafenib (Nexavar) and TACE (transarterial chemoembolization) in their originating study to be 
eligible for this extension study.  The exclusion criterion regarding concurrent anti-cancer 
chemotherapy was, therefore, modified to clarify that the exclusion did not apply to subjects
being treated with sorafenib in combination with TACE.
This change was made to allow subjects from the SPACE study to continue to receive sorafenib 
under this extension protocol.  The SPACE study, a randomized, double-blind study of sorafenib 
vs placebo in patients with hepatic cellular carcinoma who are receiving TACE treatment, will be
closed in the near future.  Subjects from this study who are receiving sorafenib and continue to 
benefit from the therapy may now, under this amendment protocol be enrolled in the STEP 
program may continue to receive TACE along with sorafenib.
In addition, this single criterion covering concurrent anti-cancer chemotherapy, concurrent 
immunotherapy, and concurrent hormonal therapy was split into three distinct bullets.  This 
change was made clarity and does not represent a change to study conduct.
The protocol sections affected by these changes are Section 4.2.1, Inclusion Criteria, and Section 
4.2.2, Exclusion Criteria.
10.2.2
Changes to the Protocol Text
In this section, all affected protocol sections are detailed; the sequence of sections follows the
structure of the original protocol.  In the display of modifications, the “old text” refers to the 
protocol version preceding this amendment (ie, protocol version 5.2).  Deletions are crossed out
in the “old text” and additions are underlined in the “new text” (ie, Amendment 2/Version 6.0).


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Section 4.2.1, Inclusion Criteria
Old text:
Patient is receiving sorafenib (Nexavar) as a monotherapy in their originating protocol.  Patients 
who were being treated with sorafenib (Nexavar) in combination with other chemotherapies in 
the original study, but continued on single agent sorafenib (Nexavar) after discontinuation of the 
combination agent will be eligible.
New text:
Patient is receiving sorafenib (Nexavar) as a monotherapy in their originating protocol. Patients 
who were being treated with sorafenib (Nexavar) in combination with other chemotherapies in 
the original study, but continued on single agent sorafenib (Nexavar) after discontinuation of the 
combination agent will be eligible.
Patients who are receiving concurrent combination with sorafenib (Nexavar) and TACE
(transarterial chemoembolization) in their originating study will be eligible.
Section 4.2.2, Exclusion Criteria
Old text:
Concurrent anti-cancer chemotherapy, immunotherapy (including monoclonal antibodies) or 
hormonal therapy, except for bisphosphonates, during or within 30 days prior to start of study 
drug
New text:

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization)

Concurrent immunotherapy (including monoclonal antibodies), during or within 30 days 
prior to start of study drug


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
Concurrent hormonal therapy, except for bisphosphonates, during or within 30 days prior 
to start of study drug 
10.3
Amendment 3
10.3.1
Overview of Changes
Modification 1: Inclusion of an Evaluation of Overall Survival
It is now planned that data from the STEP trial will be transferred to the Integrated Sorafenib 
Database. Data from individual patients from their originating trial are already part of that 
database; therefore collecting survival status for this cohort is felt to be valuable for future 
descriptive data analysis and publication.
The protocol sections affected by this change are Section 2, Study Objectives; Section 4.1, Study 
Design and Plan; Section 4.6.1, Efficacy Variables; Section 4.6.3, Assessment Periods; Section 
6.1, Statistical and Analytical Plans; and Section 11, Study Flow Chart
Modification 2: Evaluation of Safety 
Publication of the safety results of the collected data from STEP is now planned.  Therefore,
including safety as a stated objective is needed. The main objective of this program remains 
unchanged. 
The protocol section affected by this change is Section 2, Study Objectives, 
The inclusion of an assessment of ECOG performance status was added to Section 4.1, Study 
Design and Plan, for consistency with the rest of the protocol.  In addition, for consistency, 
ECOG performance status was added to Section 4.6.3, Assessment Periods under Safety
Variables.


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The CRF was has been modified to collect information on the ECOG performance status in the 
CRF as well as the subject’s source documentation.  Therefore, the ECOG performance status 
must now also be captured in the subject’s CRF.
The protocol section affected by this change is Section 4.6.2, Safety Variables
Date of death was removed from the safety variables as survival status (including date of death 
when applicable) is collected elsewhere
The protocol section affected by this change is Section 4.6.2, Safety Variables.
Finally, in accordance with Japanese regulatory requirements for the recording of adverse event 
data, the protocol was modified to require the recording of ALL adverse events regardless of
NCI-CTCAE grade and regardless of attribution for patients treated at study sites in Japan.
The protocol sections affected by this change are Section 4.6.2, Safety Variables, Section 4.6.3, 
Assessment Periods, and Section 7.3.6, Adverse Event Documentation.
Modification 3: Head of the Center for Sites in Japan
In accordance with local regulatory requirements, specific mention of the head of the center for 
sites in Japan has been added to Section 4.4, Premature Termination of Study/Closure of Centre 
and Section 5.1, Ethics Committee (EC) or Institutional Review Board (IRB).
Modification 4: Adverse Events
In accordance with local regulatory requirements in Japan, specific language has been added to
Section 7.2, Adverse Event Monitoring and Section Section 7.3.3, Unexpected Adverse Event 
In accordance with local Japanese regulatory requirements, Section 7.3.2, Serious Adverse Event, 
was modified to clarify that, in Japan, any adverse event leading to hospitalization or 


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prolongation of hospitalization is to be considered as serious regardless of the length of 
hospitalization or prolongation of hospitalization.
Modification 5:  Inclusion of Subjects From the SEARCH Study (Study 12917) and the 
RESILIENCE Study (Study 12444)
The Sponsor has made the decision to allow patients from the SEARCH study, in which patients 
receive sorafenib in combination with erlotinib, or the RESILIENCE Study, in which patients 
receive sorafenib in combination with capecitabine, to receive continued treatment in the 
Sorafenib Long Term Extension Program (STEP).  Therefore, all necessary information regarding 
the inclusion of these subjects into STEP has been included in the protocol under this amendment 
(Amendment 3).
The protocol sections affected by the inclusion of these subjects are Section 1, Introduction, 
Section 2, Study Objectives, Section 4.1, Study Design and Plan, Section 4.2.1, Inclusion 
Criteria, Section 4.2.2, Exclusion Criteria, Section 4.5.1, Treatments to be Administered, Section
4.5.2, Dose Modification, Section 4.5.3, Identity of Investigational Product(s), Section 4.5.5, 
Selection of Doses in the Study, Section 4.5.8, Prior and Concomitant Therapy, and Section 11, 
Study Flow Chart.
Modification 6:  Minor Changes
Contact names for the Study Manager, Statistician, and Medical Expert were updated on the title 
page of the protocol. 
The information in Section 2 regarding the conditions whereby patients may receive treatment 
under this protocol was modified slightly to clarify that, if switching to commercially available
product, there should be no interruption in the patient’s treatment schedule.


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The text regarding presentation of data as “a summary” was modified in Section 6.1, Statistical 
and Analytical Plans, to clarify that descriptive analysis would be performed.  Duration of 
treatment was added to list of variables for which such analyses would be prepared.
Patients receiving long-term sorafenib may be appropriate candidates for vaccination. However, 
there are no safety data available with live vaccines and, given the propensity for sorafenib to 
cause lymphopenia, it is felt that administering live vaccine to patients receiving sorafenib may 
represent a safety risk.
The protocol section affected by this change is Section 4.5.8, Prior and Concomitant Therapy.
An editorial change was made to delete Section 4.6.4, which is not applicable to this protocol.
In Section 4.5.2, Dose Modification, reference to “Hand-Foot syndrome” was change to “Hand-
Foot Skin Reaction.”
10.3.2
Changes to the Protocol Text
In this section, all affected protocol sections are detailed; the sequence of sections follows the 
structure of the original protocol. In the display of modifications, the “old text” refers to the 
protocol version preceding this amendment (ie, protocol version 6.0).  Deletions are crossed out
in the “old text” and additions are underlined in the “new text” (ie, Amendment 3/ Version 7).
Title Page
Old text:
PPD


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New text:
Section 1, Introduction
Old text:
The only process to provide sorafenib to these patients who have a non-approved/reimbursed 
tumor type is through a clinical trial. The intention of this program is to enable these patients who 
are still benefiting from sorafenib in a completed clinical trial to continue to receive sorafenib.  
New text:
The only process to provide sorafenib to these patients who have a non-approved/reimbursed 
tumor type is through a clinical trial. The intention of this program is to enable these patients who 
are still benefiting from treatment in a completed clinical trial to continue to receive treatment.  
Section 2, Study Objectives
Old text:
The primary purpose of program is to enable patients, currently receiving single agent sorafenib 
(Nexavar) in a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their 
respective study has met its primary endpoint and/or has reached the end as defined in the 
original protocol.  Patients will be able to continue sorafenib (Nexavar®) treatment until the 
treating physician feels the patient is no longer benefiting from the treatment or sorafenib 
PPD


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(Nexavar®) becomes commercially available, and reimbursed for the respective indication as 
applicable in the country in which the patient lives. 
New text:
The primary purpose of program is to enable patients, currently receiving sorafenib (Nexavar) in 
a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their respective study 
has met its primary endpoint and/or has reached the end as defined in the original protocol.  
Patients will be able to continue treatment until (i) the treating physician feels the patient is no 
longer benefiting from the treatment or (ii) the treatment becomes commercially available and 
reimbursed for the respective indication as applicable in the country in which the patient lives and 
the patient can obtain suitable amounts of drug for treatment through standard mechanisms of 
commercial availability (ie, there should be no interruption in the patient’s treatment schedule 
when switching to commercially available product).
Additional objectives include assessment of the safety of Nexavar or Nexavar combination 
treatment and evaluation of overall survival (OS).
Section 4.1, Study Design and Plan
Old text:
This is an open label program that will enable patients receiving sorafenib (Nexavar) in a 
completed Bayer/Onyx sponsored clinical trial to continue single agent sorafenib (Nexavar®) 
treatment. A completed study is one….
The patients will continue receiving single agent sorafenib (Nexavar) at the same dose and 
schedule as in their original Clinical Trial.  
Patients will continue receiving single agent sorafenib (Nexavar) as long as the treating physician 
feels the patient is continuing to benefit from treatment or until sorafenib becomes commercially 


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available and reimbursed for the respective indication in the country in which the patient lives. 
The patient may also continue sorafenib until he/she withdraws consent, is non-compliant, is lost 
to follow up, or if an unacceptable toxicity occurs.
Prior to being dispensed study medication ….  Patients will continue with single agent sorafenib 
(Nexavar) in this program at the same dose and schedule the patient was receiving in their 
original clinical trial.  
Sorafenib (Nexavar) will be provided as 200 mg tablets.  The patient should be evaluated 
according to Good Medical Practices as well as local therapeutic and diagnostic 
standards……..Bimonthly safety evaluations include vital signs (ie, heart rate, blood pressure, 
temperature), ECOG performance status, laboratory evaluations (hematology, ALT, AST, lipase 
and amylase, PT-INR as applicable for anticoagulated patients) and a review of any new or 
ongoing adverse event or concomitant medications as well as study medication taken during the 
visit interval.  All adverse event, and laboratory data as well as End of Treatment information and 
study medication taken must be clearly and accurately recorded in the Case Report Form 
provided.  All other data, including but not limited to, vital signs, ECOG performance status,
concomitant medications and date of death must be recorded in the patient’s source documents 
and may be requested at the discretion of the Sponsor.  
Following the End of Treatment assessments from the original study, the following information 
will be recorded in the long term extension CRF:  demography, date of first dose of sorafenib 
(Nexavar) in originating study, originating study number, ECOG performance status and survival 
status (dead or alive and date of death or date of last contact)  and ongoing adverse events…..
New text:
This is an open label program that will enable patients receiving sorafenib (Nexavar) in a 
completed Bayer/Onyx sponsored clinical trial to continue treatment. A completed study is 
one…..


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The patients will continue receiving single agent sorafenib (Nexavar), sorafenib and erlotinib if
transferred from study 12917 (SEARCH), or sorafenib and capecitabine if transferred from Study 
12444 (RESILIENCE), at the same dose and schedule as in their original Clinical Trial.  
Patients will continue receiving single agent sorafenib (Nexavar; as single agent or combination 
treatment) as long as the treating physician feels the patient is continuing to benefit from 
treatment or until sorafenib (as single agent or combination treatment) becomes commercially 
available and reimbursed for the respective indication in the country in which the patient lives. 
The patient may also continue treatment until he/she withdraws consent, is non-compliant, is lost 
to follow up, or if an unacceptable toxicity occurs.  
Prior to being dispensed study medication …..  Patients will continue with single agent sorafenib 
(Nexavar), sorafenib and erlotinib if transferred from study 12917 (SEARCH), or sorafenib and 
capecitabine if transferred from Study 12444 (RESILIENCE), in this program at the same dose 
and schedule the patient was receiving in their original clinical trial.  
Sorafenib (Nexavar) will be provided as 200 mg tablets. Erlotinib will be provided as 150 mg, 
100 mg, and 25 mg tablets for patients receiving the sorafenib/erlotinib combination and 
transferring from Study 12917 (SEARCH). Capecitabine will be provided as 150 mg and 500 mg 
tablets for patients receiving the sorafenib/capecitabine combination and transferring from Study 
12444 (RESILIENCE).  The patient should be evaluated according to Good Medical Practices as 
well as local therapeutic and diagnostic standards……..Bimonthly safety evaluations include vital 
signs (ie, heart rate, blood pressure, temperature), Eastern Cooperative Oncology Group (ECOG)
performance status, laboratory evaluations (hematology, ALT, AST, lipase and amylase, PT-INR 
as applicable for anticoagulated patients) and a review of any new or ongoing adverse event or 
concomitant medications as well as study medication taken during the visit interval.  All adverse 
events, laboratory data, ECOG performance status and survival status (dead or alive and date of 
death or date of last contact), as well as End of Treatment information and study medication taken
must be clearly and accurately recorded in the Case Report Form provided.  All other data, 


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including but not limited to, vital signs, concomitant medications must be recorded in the 
patient’s source documents and may be requested at the discretion of the Sponsor.  
Following the End of Treatment assessments from the original study, the following information 
will be recorded in the long term extension CRF:  demography, date of first dose of sorafenib 
(Nexavar) in originating study, date of first dose of erlotinib if the patient is transferred from 
SEARCH (study 12917), date of first dose of capecitabine if the patient is transferred from 
RESILIENCE (Study 12444), originating study number, ECOG performance status and survival 
status (dead or alive and date of death or date of last contact) and ongoing adverse events.
Section 4.2.1, Inclusion Criteria
Old text:

Patients, who are participating in a previous Bayer/Onyx sponsored study that has reached its 
endpoint (statistical and regulatory or study end)……

Patients who are receiving concurrent combination with sorafenib (Nexavar) and TACE
(transarterial chemoembolization) in their originating study will be eligible.

Patients who have completed the End of Treatment assessments in their originating study…...  
New text:

Patients, who are participating in a previous Bayer/Onyx sponsored study that has reached its 
endpoint (statistical and regulatory or study end)……

Patients who are receiving concurrent combination with sorafenib (Nexavar) and TACE
(transarterial chemoembolization) in their originating study will be eligible.

Patients who are receiving concurrent combination with sorafenib (Nexavar) and erlotinib in 
their originating study 12917 (SEARCH) will be eligible.


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
Patients who are receiving concurrent combination with sorafenib (Nexavar) and capecitabine
in their originating study 12444 (RESILIENCE) will be eligible.

Patients who have completed the End of Treatment assessments in their originating study…...  
Section 4.2.2, Exclusion Criteria
Old text:
Excluded therapies and medications, previous and concomitant:

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization)…….
New text:
Excluded therapies and medications, previous and concomitant:

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization),
erlotinib, and capecitabine
Section 4.4, Premature Termination of Study/Closure of Centre
Old text:
The Sponsor has the right to close this study, and the Investigator/Sponsor has the right to close a 
center, at any time, although this should occur only after consultation between involved parties.  
The EC/IRB must be informed.……..
New text:
The Sponsor has the right to close this study, and the Investigator/Sponsor has the right to close a 
center, at any time, although this should occur only after consultation between involved parties.  
The EC/IRB (or the head of the center for sites in Japan) must be informed.


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Section 4.5.1, Treatments to be Administered
Old text:
The study drug will be supplied as 200 mg tablets. Patients should continue on the same dose as 
they were receiving in the patient’s originating Bayer/Onyx-sponsored Clinical Trial. 
New text:
Sorafenib will be supplied as 200 mg tablets. Erlotinib will be supplied as 150 mg, 100, and 25 
mg tablets and  capecitabine will be provided as 150 mg and 500 mg tablets. Patients should 
continue on the same dose as they were receiving in the patient’s originating Bayer/Onyx-
sponsored Clinical Trial.
Section 4.5.2, Dose Modification
Old text:
If the starting dose is 600 mg bid the modifications of sorafenib (Nexavar) will follow the pre-
defined dose levels:
Dose level 1
600 mg (3 x 200 mg) po q 12 hr…….
Only for the purpose of dose modifications, patients experiencing Hand-Foot syndrome should 
have their signs and symptoms graded according to the following system (see Table 4-3). Other 
skin toxicities will be graded according to CTCAE Version 3.0.  Please note that Hand Foot 
Syndrome will be graded and recorded as an adverse event according to NCI-CTC Version 3.0 in
the CRF.
Table 4-3:  Grading for Hand-Foot Syndrome 
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema 
of the hands and/or feet and/or discomfort, which does not disrupt normal 
activities……


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New Text:
4.5.2.1  Sorafenib monotherapy
If the starting dose is 600 mg bid the modifications of sorafenib (Nexavar) will follow the pre-
defined dose levels:
Dose level 1
600 mg (3 x 200 mg) po q 12 hr.........
Only for the purpose of dose modifications, patients experiencing Hand-Foot Skin Reaction
should have their signs and symptoms graded according to the following system (see Table 4-3). 
Other skin toxicities will be graded according to CTCAE Version 3.0.  Please note that Hand 
Foot Skin Reaction will be graded and recorded as an adverse event according to NCI-CTC 
Version 3.0 in the CRF.
Table 4-3:  Grading for Hand-Foot Skin Reaction
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema 
of the hands and/or feet and/or discomfort, which does not disrupt normal 
activities……
4.5.2.2  Sorafenib and erlotinib combination
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose
Delays/Dose Modifications table that follows.  Dose modifications will follow predefined dose 
levels: Dose adjustments for hematologic toxicity are based on the blood counts obtained in 
preparation for the day of treatment.


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Table 4-5:  Dose Modification Levels for Sorafenib
Dose
Sorafenib
Starting Dose
400 mg twice daily
-1
400 mg once daily
-2
400 mg every other day
Table 4-6:  Dose Modification Levels for Erlotinib
Dose
Erlotinib
Starting Dose
150 mg once a day
-1
100 mg once a day
-2
50 mg once a day

Except for an event of hypertension, the first agent to dose reduce for the 1st episode of any 
toxicity will be erlotinib

If a subject experiences more than one toxicity, dose reduction should be according to the 
toxicity with the highest grade 

In the case of two or more toxicities of the same grade, the investigator may dose reduce 
according to the toxicity deemed most causally related to study treatment

Subjects for whom one agent is held may continue to receive the other agent if all the 
protocol-defined dose modification steps have been taken and, in the opinion of the treating 
investigator, the subject may continue to benefit from treatment

Subjects with toxicities that are manageable with supportive therapy may not require dose 
reductions (eg, nausea/vomiting may be treated with antiemetics, diarrhea may be treated with 
loperamide rather than by dose reduction). A subject will be withdrawn from the study if 
he/she fails to recover from a treatment-related toxicity to CTCAE Grade 0-1, or tolerable 


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grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) within 
30 days, unless the investigator and sponsor agree that the subject should remain in the study 
because the investigator believes the subject is/may derive benefit from continuing study 
treatment. 
Table 4-7:  Dose Modification Plan for Hematologic Toxicities
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Gr 1
Treat on time
No change in dose
No change in dose
Gr 2
No change
Gr 3*
Treat on time
Re-evaluate weekly
1st episode: no change in dose
1st episode: reduce 
erlotinib to
level -1 (100mg once a day)
2nd episode: reduce sorafenib 
to  level -1 (400mg once daily)
2nd episode: no change to 
above modified dose
3rd episode: no change to above 
modified dose
3rd episode: reduce 
erlotinib to 
level -2 (50mg once a day)
4th episode: reduce sorafenib
to level -2 (400mg every other 
day)
4th episode: no change to 
above modified dose


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Table 4-7:  Dose Modification Plan for Hematologic Toxicities
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Gr 4*
Holda both agents 
until <Gr 2
Re-evaluate weekly
1st episode: no change in dose 
upon continuation of treatment
1st episode: reduce 
erlotinib  to 
level -1 (100mg once a day) 
upon continuation of 
treatment
2nd episode: reduce sorafenib 
to level -1 (400mg once daily) 
upon continuation of treatment
2nd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: no change to above 
modified dose upon 
continuation of treatment
3rd episode: reduce 
erlotinib  to 
level -2 (50mg once a day) 
upon continuation of 
treatment
4th episode: reduce sorafenib
to level -2 (400mg every other 
day) upon continuation of 
treatment
4th episode: no change to 
above modified dose upon 
continuation of treatment
aIf no recovery after 30 day delay, treatment will be discontinued unless subject is deriving clinical 
benefit.
*Intervention/Supportive care regarding Gr 3 or 4 Heme toxicity as per investigator.
If more than 4 dose reductions are required, study treatment will be discontinued.


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Table 4-8:  Dose Modification Plan for non-Hematologic Toxicity except ILD, and 
Hypertension
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Gr 1
Treat on time
No change in dose
No change in dose
Gr 2
No change
Gr 3*
Holda both agents
until <Gr 2
Initiate supportive 
care
Re-evaluate weekly
1st episode: no change in dose 
upon continuation of treatment
1st episode: reduce 
erlotinib to level -1 (100mg 
once a day) upon 
continuation of treatment 
2nd episode: reduce sorafenib
to level -1 (400mg once daily) 
upon continuation of treatment
2nd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: reduce 
erlotinib  to level -2 (50mg 
once a day) upon 
continuation of treatment 
4th episode: reduce sorafenib
to level -2 (400mg every other 
day) upon continuation of 
treatment 
4th episode: no change to 
above modified dose upon 
continuation of treatment
Gr 4*
REMOVE FROM
STUDY
a If no recovery after 30 day delay, treatment will be discontinued unless subject is deriving clinical 
benefit.
If more than 4 dose reductions, study treatment will be discontinued.  Excludes alopecia, 
nausea/vomiting that has not been pre-medicated, and diarrhea not treated with supportive 
care/loperamide.
4.5.2.2.1  Anti-rash and Anti-diarrhea Therapies
Skin rash or dermatosis has been observed in many subjects during treatment with erlotinib.  No 
clinical trials have formally evaluated treatments for rash induced by erlotinib, and there are 
currently no evidence-based recommendations for its management. 


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Subjects who develop a mild rash characterized by pustules or raised, red areas may be treated 
with topical therapy, such as corticosteroids.  If the rash is more severe or there is indication of 
secondary infection, topical clindamycin or tetracycline, or oral minocycline may be used at the 
discretion of the investigator.  (NOTE:  minocycline is known to interfere with anticoagulants and 
oral contraceptives.  Therefore, subjects treated with minocycline who are taking anticoagulants 
and/or oral contraceptives should be monitored accordingly).  Guidance concerning modification 
of study drug dosing is provided in Table 4-8.
Because the pathology of such a rash is not related to acne pathology, retinoids and other acne 
medications, such as benzoyl peroxide, are not recommended, because these agents are more 
likely to exacerbate the rash due to their drying effects on the skin.  
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have shown that 
the frequency and severity of diarrhea rarely hindered the administration of erlotinib and that the 
diarrhea could be managed with loperamide.  The recommended dose of loperamide is 4 mg at 
first onset, followed by 2 mg every 2 to 4 hours until the subject is diarrhea-free for 12 hours.


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Table 4-9:  Dose Modification Plan for Hypertension
Grade
Dose 
Interruption
Dose Reduction
Antihypertensive 
Therapy
Blood Pressure 
Monitoring
Hypertensive NCI 
CTCAE V3
Sorafenib
Erlotinib
Gr 1
Treat on time
Initiate 
supportive 
care
No change in 
dose 
No change in dose 
None
Routine
Asymptomatic, 
transient, (<24hrs) 
increase by >20 
mmHg (diastolic) or 
to >150/100 if 
previously WNL; 
intervention not 
indicated.
Gr 2
Treat on time
Initiate 
supportive
care
No change in 
dose 
No change in dose 
(asymptomatic)
Initiate monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker).
(asymptomatic)
Increase frequency 
and monitor (by health 
professional) every 2 
days until stabilized.
Recurrent or 
persistent (>24 hrs) 
or symptomatic 
increase by 
>20 mmHg 
(diastolic) or to > 
150/100 if previously 
WNL; monotherapy 
may be indicated.
(symptomatic 
/persistent)
OR
Diastolic BP > 110 
mmHg
Add agent(s):
Ca++ channel blocker 
(if not already used)
K+ channel opener 
(angiotensin 
blockers), 
Beta-blocker
Thiazide diuretic
(symptomatic/ 
persistent)
OR
Diastolic BP > 110 
mmHg
Increase frequency 
and monitor (by health 
professional) every 2 
days until stabilized.


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Table 4-9:  Dose Modification Plan for Hypertension
Grade
Dose 
Interruption
Dose Reduction
Antihypertensive 
Therapy
Blood Pressure 
Monitoring
Hypertensive NCI 
CTCAE V3
Sorafenib
Erlotinib
Gr 3
Hold both 
agents until 
≤Gr 2
Initiate 
supportive 
care
Re-evaluate 
weekly
1st episode:  
reduce 
sorafenib to 
level –1 (400 mg 
once daily) upon 
continuation of 
treatment.
1st episode:  no 
change in dose 
upon continuation 
of treatment.
Add agent(s):
Ca++ channel blocker 
(if not already used) 
K+ channel opener 
(angiotensin blockers) 
Beta-blocker 
Thiazide diuretic
Increase frequency 
and monitor (by health 
professional) every 2 
days until stabilized.
Requiring more than 
one drug or more 
intensive therapy
than previously.
2nd episode:  no 
change in dose 
upon 
continuation of 
treatment.
2nd episode: 
reduce erlotinib 
to level –1 (100 
mg once a day) 
upon continuation 
of treatment.
3rd episode: 
reduce 
sorafenib to 
level –2 (400 mg 
every other day) 
upon
continuation of 
treatment. 
3rd episode:  no 
change in dose 
upon continuation 
of treatment.
4th episode:  no 
change in dose 
upon 
continuation of 
treatment.
4th episode:  
reduce erlotinib
to level –2 (50 mg 
once a day) upon 
continuation of 
treatment.
Gr 4
REMOVE 
FROM STUDY
Life-threatening 
consequences (e.g., 
hypertensive crisis)


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4.5.2.2.2  Dose Modification for Hand-Foot Skin Reaction
Subjects experiencing Hand-Foot Skin Reaction should have their signs and symptoms 
graded according to the following system (see Table 4-10). Other skin toxicities will be 
graded according to CTCAE Version 3.0.
At first occurrence of hand foot skin reaction, independent of grade, prompt institution of 
supportive measures such as topical emollients, low potency steroids, or urea-containing 
cream should be administered.
Table 4-10:  Grading for Hand-Foot Skin Reaction
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling or 
erythema of the hands and/or feet and/or discomfort, which does not 
disrupt normal activities.
Grade 2
Painful erythema and swelling of the hands and/or feet and/or discomfort 
affecting the subject’s activities. 
Grade 3 
Moist desquamation, ulceration, blistering or severe pain of the hands 
and/or feet and/or severe discomfort that causes the subject to be unable 
to work or perform activities of daily living.


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Table 4-11:  Dose Modification Plan for Hand Foot Skin Reaction
NCI CTC 
V3.0
Dose 
Interruption
Dose Reduction
HFSR
NCI CTCAE V3.0
Sorafenib
Erlotinib
Gr 1
Treat on
time
No change of 
dose 
No change of 
dose 
Numbness, 
dysesthesia/paresthesia, 
tingling, painless swelling or 
erythema of the hands 
and/or feet and/or 
discomfort, which does not 
disrupt normal activities.
Gr 2
No change
Painful erythema and 
swelling of the hands 
and/or feet and/or 
discomfort affecting the 
subject’s activities.
Gr 3
Holda both 
agents until 
<Gr 2
Initiate 
supportive 
care
Re-evaluate 
weekly
1st episode: no 
change in dose 
upon continuation 
of treatment.
1st episode: 
reduce erlotinib
to level -1 (100 mg 
once a day) upon 
continuation of 
treatment.
Moist desquamation, 
ulceration, blistering or 
severe pain of the hands 
and/or feet and/or severe 
discomfort that causes the 
subject to be unable to 
work or perform activities of 
daily living.
2nd episode: 
reduce sorafenib
to level -1 (400 mg 
once daily) upon 
continuation of 
treatment.
2nd episode: no 
change to above 
modified dose 
upon continuation 
of treatment.
3rd episode: no 
change to above 
modified dose 
upon continuation 
of treatment.
3rd episode: 
reduce erlotinib
to level -2 (50 mg 
once a day) upon 
continuation of 
treatment.
4th episode: 
reduce sorafenib
to level -2 (400 mg 
every other day) 
upon continuation 
of treatment.
4th episode: no 
change to above 
modified dose 
upon continuation 
of treatment.
Gr 4
REMOVE 
FROM 
STUDY
a If no recovery after 30 day delay, treatment will be discontinued unless subject is deriving clinical 
benefit.


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4.5.2.2.3  Dose Modification for Keratitis 
For all grades of suspected keratitis, the erlotinib dose should be held and supportive 
measures instituted.  Subjects with dry eyes should be advised to use an ocular lubricant.  
Subjects who continue to wear contact lenses may have an increased risk of ocular AEs (eg, 
keratitis).  Subjects may continue to wear contacts but should discuss this issue with their 
treating oncologist before entering the study.  In addition, any elective ophthalmological 
surgery while the subject is taking study drug must first be discussed between the investigator 
and the Sponsor.
4.5.2.2.4  Dose Modification for Interstitial Lung Disease
For all grades of suspected interstitial lung disease (ILD), the erlotinib dose should be held 
and supportive measures instituted.  If ILD is confirmed, erlotinib and sorafenib must be 
discontinued permanently.  Acute dyspnea or cough may be signs of ILD.  If a subject 
presents with acute dyspnea or cough, interruption of treatment with erlotinib may be 
considered, at the discretion of the treating physician, until resolution of symptoms or until 
ILD can be ruled out.  If a subject presents with symptoms such as shortness of breath, 
dyspnea, cough, or fever, a chest X-ray or chest CT and, if needed, additional tests to evaluate 
pulmonary function, as clinically indicated, should be considered as part of the work up.  If a 
diagnosis of ILD is confirmed, appropriate treatment measures according to best medical 
practice and local standards should be initiated.
4.5.2.3  Sorafenib and capecitabine combination
Doses of capecitabine or sorafenib/placebo may be reduced/interrupted in the setting of any 
AE that is:

Not controlled by optimal supportive care, or


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
Not tolerated due to symptomatology, disfigurement, or interference with normal 
daily activities, regardless of severity.
Dose modifications will be based on the worst grade of an AE or laboratory abnormality 
during a given cycle.  If multiple AEs are observed, the dose modification should be based on 
the most severe (ie, worst grade) event. 
Dose modifications should take into consideration AEs and dose modifications already 
occurred in study 12444 (RESILIENCE).
Treatment delays of sorafenib/placebo for up to 21 days are acceptable in order to allow for 
resolution of symptoms to NCI-CTCAE v3.0 Grade 1 or less.  For subjects with NCI-CTCAE 
v3.0 Grade 2 or greater toxicities at baseline (screening), resolution of symptoms to baseline 
severity (ie, Grade 2 or greater) is acceptable.
Subjects requiring interruption of study treatment for more than 21 days will be discontinued 
from study treatment.  These subjects will, however, be followed until death or overall 
completion of the trial, whichever comes first. 
Subject requiring further dose reductions beyond 500 mg/m2 BID of capecitabine or 200 mg 
(1 tablet) twice daily every other day of sorafenib will be discontinued from study drug.  In 
the event a subject meets the criteria to discontinue all study drugs (capecitabine plus 
sorafenib), the subject will be followed until death or overall completion of the trial, 
whichever comes first. 
NOTE:

Subjects for whom it is medically appropriate to stop capecitabine administration 
(eg, due to intolerance) must also discontinue sorafenib.  


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
Subjects for whom it is medically appropriate to stop sorafenib administration 
(eg, due to intolerance) may continue to receive capecitabine .
Capecitabine and sorafenib/placebo treatment interruptions are regarded as lost treatment 
days and missed doses should not be replaced; the planned treatment dosing schedule should 
be maintained in the event of a treatment interruption. 
4.5.2.3.1  Dose-reduction levels
Dose-reduction levels of sorafenib and capecitabine for the management of AEs are outlined 
in Table 4-12 and Table 4-13, respectively.
Table 4-12:  Predefined Dose Levels of Sorafenib
Study 
drug:
Sorafenib
Dose Level
0
-1
-2
-3
Applicable 
if sorafenib 
was never 
escalated 
higher than 
600 mg/d 
in study 
12444
200 mg/1 
tablet in 
the 
morning, 
400 mg/2 
tablets in 
the 
evening
200 mg/1 
tablet 
twice 
daily 
200 mg/1 
tablet 
twice 
daily, 
every 
other day 
—
Applicable 
if sorafenib
was 
escalated 
to 800 
mg/d 
following 
cycle 1 in 
study 
12444
400 mg/2 
tablets, 
twice daily
200 mg/1 
tablet in 
the 
morning, 
400 mg/2 
tablets in 
the 
evening
200 mg/1 
tablet 
twice 
daily 
200 mg/1 
tablet 
twice 
daily, 
every 
other day 


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Table 4-13: Predefined Dose Levels of Capecitabine
Study drug:
Capecitabine
Dose Level
0
-1
-2
-3
Applicable if 
capecitabine dose 
was not escalated 
to 1,250 mg/m2
BID daily in study 
12444
1,000 mg/m2
twice daily
750 mg/m2
twice daily 
500 mg/m2
twice daily 
—
Applicable if
capecitabine was 
escalated to 
1,250 mg/m2 BID 
daily in study 
12444
1,250 mg/m2
twice daily
1,000 mg/m2
twice daily 
750 mg/m2
twice daily 
500 mg/m2
twice daily 
4.5.2.3.2  Dose modification for hematologic toxicities
In general, doses of sorafenib should not be reduced for hematologic events, except for Grade 
4 hematologic toxicities.  Any subject experiencing any of the following hematologic 
toxicities should have capecitabine therapy held until the toxicity has resolved to Grade 1 or 
less.

Absolute neutrophil count < 1,000/mm3 (≥ Grade 3) for > 7 days and/or febrile 
neutropenia.

Platelet count < 50,000/mm3 (≥ Grade 3).
At the re-start of capecitabine following these toxicities, the dose of capecitabine should be 
reduced by at least one level (see Table 4-7 and Table 4-8).  Additional dose reductions may 
occur as needed in subsequent cycles.  If a subject requires dose reduction below capecitabine 
500 mg/m2 twice daily or sorafenib/placebo 200 mg twice daily, every other day, study drug 
must be permanently discontinued.


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If the described hematologic toxicity persists for more than 21days, the subject should 
discontinue capecitabine treatment and, therefore, also sorafenib.  
Dose modifications of capecitabine and sorafenib for hematologic toxicities are outlined in 
Table 4-14 and Table 4-15.
Granulocyte colony stimulating factor and erythropoietic growth factors should not be 
administered as prophylaxis may be used.  The dose of capecitabine must be reduced by two 
dose levels with the first episode of febrile neutropenia. 
Table 4-14: Dose Modifications for Hematologic Toxicities: Neutropenia and Anemia
Toxicity
ANC
(x 109/L)
Hemoglobin 
(g/dL)
Capecitabine
Sorafenib
Grade 1
1.5 
< LLN – 10.0 
No change
No change
Grade 2
1.0  to < 1.5 
< 10.0 – 8.0 
No change
No change
Grade 3a
0.5  to < 1.0 
< 8.0
Delay drug until 
toxicity has resolved to 
Grade 2 or less, then 
reduce by one dose 
level
No change
Grade 4a
< 0.5
Life-
threatening 
consequence; 
urgent 
intervention 
indicated
Delay drug until 
toxicity has resolved to 
Grade 2 or less, then 
reduce by two dose 
levels
Delay drug until 
toxicity has resolved to 
Grade 2 or less, then 
reduce by one dose 
level
Febrile 
Neutropenia
—
—
Delay drug until 
toxicity has resolved
(neutropenia to 
Grade 1 or less and 
fever resolved), then 
reduce by two dose 
levels
Delay drug until 
toxicity has resolved 
(neutropenia 
resolved to Grade 1 
or less and fever 
resolved), then 
reduce by one dose 
level
ANC=Absolute neutrophil count
a:  For an ANC of less than 1 x 109/L (≥ Grade 3) for > 7 days, drug should be held until 
toxicity has resolved to Grade 1 or less.


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Table 4-15: Dose Modifications for Hematologic Toxicities: Thrombocytopenia
Toxicity
Platelets    
(x 109/L)
Capecitabine
Sorafenib
Grade 1
≥75 
No change
No change
Grade 2
50 to < 75 
First occurrence, delay drug until toxicity 
has resolved to Grade 1 or less, restart 
at same dose. On subsequent 
occurrences, delay drug until toxicity has 
resolved to Grade 1 or less, then reduce 
by one dose level.
No change
Grade 3
25 to < 50 
Delay drug until toxicity has resolved to 
Grade 1 or less, then reduce by one 
dose level
No change
Grade 4
< 25 
Delay drug until toxicity has resolved to 
Grade 1 or less, then reduce by two 
dose levels
Delay drug until toxicity
has resolved to Grade 1 
or less, then reduce by 
one dose level
4.5.2.3.3  Dose modification for non-hematologic toxicities
Dose modification for toxicities common to both sorafenib and capecitabine
Dermatologic toxicities (eg, HFSR, rash), gastrointestinal toxicities (eg, diarrhea), and fatigue 
are common to both sorafenib and capecitabine.  Therefore, because it may not be possible to 
identify the causative agent should these events present in this trial, a pragmatic approach to 
dose adjustments has been taken to ensure subject safety. 
Hand Foot Skin Reaction
Subjects experiencing HFSR should have their signs and symptoms graded according to
Table 4-16.
Subjects with discomfort due to HFSR should be treated with topical emollients, low-potency 
topical steroids, or urea-containing creams. 


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Table 4-16:  Grading for Hand-Foot Skin Reaction
Grade 1
Grade 2
Grade 3
Palmar-plantar 
erythrodysesthesia 
syndrome
Minimal skin 
changes or 
dermatitis 
(eg, erythema, 
edema, or 
hyperkeratosis
) without pain
Skin changes 
(eg, peeling, 
blisters  
bleeding, 
edema, or 
hyperkeratosi
s) with pain; 
limiting 
instrumental 
activities of 
daily living 
(ADL)
Severe skin 
changes (eg, 
peeling, 
blisters, 
bleeding, 
edema, or 
hyperkeratosis
) with pain; 
limiting self-
care ADL
Further 
description / 
examples of 
skin changes
Numbness, 
dysesthesia/pa
resthesia, 
tingling,
painless 
swelling, or 
erythema of 
the hands 
and/or feet
Painful 
erythema and 
swelling of 
the hands 
and/or feet
Moist 
desquamation, 
ulceration, 
blistering, or 
severe pain of 
the hands 
and/or feet
Effect on 
activities
Does not 
disrupt normal 
activities
Limiting 
instrumental 
activities of 
daily life 
(eg, preparin
g meals, 
shopping for 
groceries or 
clothes, using 
the 
telephone, 
managing 
money)
Limiting self-
care activities 
of daily life 
(eg, bathing,
dressing and 
undressing, 
feeding self, 
using the 
toilet, taking
medications) 
and not 
bedridden
a:  Palmar-plantar erythrodysesthesia syndrome is a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of hands or the soles of the feet.
The dose-modification schedule outlined below and in Table 4-17 should be followed as 
appropriate based on (i) the grade of the toxicity(ies), (ii) the incidences of skin toxicity 
(including rash and HFSR), gastrointestinal toxicity, and fatigue, and (iii) the cycle of 
treatment. 


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All dose modifications will follow the predefined dose levels presented in Table 4-12 and 
Table 4-13 (Section 4.5.2.3.1). 
General guidelines for dose modification for toxicities common to both
sorafenib and capecitabine
Grade 1:
If any dermatologic toxicities, gastrointestinal 
toxicities or fatigue occur at grade 1, maintain doses 
of capecitabine and sorafenib/placebo.  No dose 
modification is required for any occurrence of Grade 
1 fatigue, dermatologic toxicity or gastrointestinal 
toxicity.  The investigator should use symptomatic 
treatment to alleviate the toxicity.
Grade 2 or 
Grade 3:
If dermatologic toxicities, gastrointestinal toxicities, 
or fatigue occur at Grade 2 or Grade 3, both drugs
(ie, capecitabine and sorafenib) should be held until 
the toxicity resolves to Grade 1 or less. 
The algorithm in Table 4-10 should be followed for 
dose modifications when re-starting study treatment.  
This algorithm should also be used for each 
recurrence of these toxicities to determine which 
drug (ie, capecitabine or sorafenib) should be 
reduced.  Actions to be taken at each occurrence are 
outlined below.
At the first occurrence of Grade 2 or Grade 3 
fatigue, dermatologic toxicity, and/or 
gastrointestinal toxicity, the dose of capecitabine 
should be reduced by one dose level when restarting 


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study treatment (see Table 4-6).  Sorafenib should 
be restarted at the same dose as prior to the onset of 
the event(s).
At the second occurrence of Grade 2 or Grade 3
fatigue, dermatologic toxicity, and/or 
gastrointestinal toxicity, the dose of
sorafenib/placebo should be reduced by one dose 
level when restarting study treatment (see Table 4-
5).  Capecitabine should be restarted at the same 
dose as prior to the onset of the event(s).
As a general rule, at any subsequent occurrence of 
Grade 2 or Grade 3 fatigue, dermatologic toxicity, 
and/or gastrointestinal toxicity, if the last dose 
modification was made for sorafenib/placebo, 
sorafenib/placebo should be restarted at the same 
dose as prior to the onset of the event(s), and the 
dose of capecitabine should be reduced by one dose 
level.  If, on the other hand, the last dose 
modification was made for capecitabine, 
capecitabine should be restarted at the same dose as 
prior to the onset of the event(s), and the dose 
sorafenib/placebo should be reduce by one dose 
level.  
Subjects who continue to experience toxicity and 
require a dose reduction below the lowest dose level 
of capecitabine (500 mg/m2 twice daily) or 


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sorafenib/ placebo (200 mg/1 placebo tablet twice 
daily every other day) must discontinue study drug.
Grade 4: 
Grade 4 toxicities require both study drugs to be 
discontinued permanently.


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Table 4-17:  Recommended Dose Modifications for Fatigue, Dermatologic Toxicities and/or GI Toxicities
Grade 1
No interruption of study drugs or dose reductions of study drugs are required for Grade-1 adverse events.
Grade 2 or Grade 3 - FIRST occurrence including occurrences in study 12444
If dose at onset of event is:
Then:
When event resolves, resume treatment at:
Sorafenib
200 mg/1 tablet in the am
and 400 mg/ 2 tablets in the 
pm 
ORa
400 mg/ 2 tablets twice daily 
Hold both 
sorafenib and 
capecitabine until 
the AE has 
resolved to 
Grade 1 or less 
then resume 
treatment as 
directed.b
Sorafenib
Same dose 
as prior to 
event
200 mg/1 tablet in the am 
and 400 mg/ 2 tablets in 
the pm 
ORa
400 mg/2 tablets twice daily 
Capecitab
ine
1,000 mg/m2 twice daily 
ORa
1,250 mg/m2 twice daily
Capecitabine
Reduce dose
750 mg/m2 twice daily
ORa
1,000 mg/m2 twice daily
Grade 2 or Grade 3 - SECOND occurrence including occurrences in study 12444
If dose at onset of event is:
Then:
When event resolves, resume treatment at:
Sorafenib
200 mg/1 tablet in the am 
and 400 mg/ 2 tablets in the 
pm, daily
ORa
400 mg/ 2 tablets twice daily
Hold both 
sorafenib and 
capecitabine 
until the AE has 
resolved to 
Grade 1 or less 
then resume 
treatment as 
directed.b
Sorafenib
Reduce dose
200 mg/1 tablet twice daily
ORa
200 mg/1 tablet in the am 
and 400 mg/ 2 tablets in the 
pm, daily
Capecitab
ine
750 mg/m2 twice daily
ORa
1,000 mg/m2 twice daily
Capecitabine
Same dose 
as prior to 
event
750 mg/m2 twice daily
ORa
1,000 mg/m2 twice daily
a:  The dose at which study drug is resumed is based on the dose being administered at the onset of the AE and must follow the predefined dose levels as 
specified in Table 4-12 (sorafenib) and Table 4-13(capecitabine).
b:  Interruption in administration of either study drug for more than 21 days requires permanent discontinuation of that study drug.


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Table 6-10:  Recommended Dose Modifications for Fatigue, Dermatologic Toxicities and/or GI Toxicities (continued)
Grade 2 or Grade 3 – THIRD and all SUBSEQUENT occurrences including occurrences in 12444
If dose at onset of event is:
Then:
When event resolves, resume treatment at:
Sorafenib
200 mg/ 1 tablet twice daily
ORa
200 mg/ 1 tablet in the am 
and 400 mg/ 2 tablets in the 
pm, daily
Hold both 
sorafenib 
and 
capecitabine 
until the AE 
has resolved 
to Grade 1 
or less then 
resume 
treatment as 
directed.b
Sorafenib
Same dose 
as prior to 
event
200 mg/ 1 tablet twice 
daily
ORa
200 mg/ 1 tablet in the am 
and 400 mg/ 2 tablets in 
the pm, daily
Capecitabi
ne
750 mg/m2 twice daily
ORa
1,000 mg/m2 twice daily
Capecitabine
Reduce dose
500 mg/m2 twice daily
ORa
750 mg/m2 twice daily
Sorafenib
200 mg/ 1 tablet twice daily
ORa
200 mg/ 1 tablet in the am 
and 400 mg/ 2 tablets in the 
pm, daily
Hold both 
sorafenib 
and 
capecitabine 
until the AE 
has resolved 
to Grade 1 
or less then 
resume 
treatment as 
directed.b
Sorafenib
Reduce dose
200 mg/ 1 tablet twice 
daily, every other day
ORa
200 mg/ 1 tablet twice 
daily
Capecitabi
ne
500 mg/m2 twice daily
ORa
750 mg/m2 twice daily
Capecitabine
Same dose 
as prior to 
event
500 mg/m2 twice daily
ORa
750 mg/m2 twice daily
Sorafenib
200 mg/ 1 tablet twice daily
Hold both 
sorafenib 
and 
capecitabine 
until the AE 
has resolved 
to Grade 1 
or less then 
resume 
treatment as 
Sorafenib
Same dose 
as prior to 
event
200 mg/ 1 tablet twice 
daily 
Capecitabi
ne
750 mg/m2 twice daily
Capecitabine
Reduce dose 
500 mg/m2 twice daily


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directed.b
Sorafenib
200 mg/ 1 tablet twice daily, 
every other day 
Hold both 
sorafenib 
and 
capecitabine 
until the AE 
has resolved 
to Grade 1 
or less then 
resume 
treatment as 
directed.b
Sorafenib
Same dose 
as prior to 
event
200 mg/ 1 tablet twice 
daily, every other day
Capecitabi
ne
750 mg/m2 twice daily
Capecitabine
Reduce dose 
500 mg/m2 twice daily
a:  The dose at which study drug is resumed is based on the dose being administered at the onset of the AE and must follow the predefined dose 
levels as specified in Table 4-12 (sorafenib) and Table 4-13 (capecitabine).
b:  Interruption in administration of either study drug for more than 21 days requires permanent discontinuation of that study drug.
Table 6-10:  Recommended Dose Modifications for Fatigue, Dermatologic Toxicities and/or GI Toxicities (continued)
Sorafenib
200 mg/ 1 tablet twice daily, 
every other day
Discontinue both 
drugs 
permanently
—
Capecitabi
ne
500 mg/m2 twice daily
Grade 4 toxicities require both study drugs to be discontinued permanently.


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4.5.2.3.4  Dose modification and management of sorafenib-specific toxicities
Sorafenib dose modifications or delays will not impact capecitabine therapy.  Subjects who 
require a delay or dose modification of sorafenib/placebo should continue to receive 
capecitabine as scheduled.
Dose modification and management of sorafenib-specific toxicities should follow Section 
4.5.2.1 (Sorafenib monotherapy)
4.5.2.3.5  Dose modification and management of capecitabine-specific toxicities 
If the following toxicities occur, they will be deemed to be primarily related to capecitabine.  
Such toxicities, therefore, warrant specific dose modifications for capecitabine only as 
described here and in Table 4-18. 
Subjects who require a delay or dose modification of capecitabine should continue to receive 
sorafenib as scheduled.
1) Stomatitis (Grade 2 or higher)
If Grade 2 or 3 stomatitis occurs, administration of capecitabine should be immediately 
interrupted until the event resolves to Grade 1 or less.  The subject should be treated 
symptomatically.  Subsequent doses of capecitabine should be administered in accordance 
with the algorithm in Table 4-18.
2) Cardiac toxicity
Subjects with cardiac toxicity greater than Grade 2, which is attributable to capecitabine, will 
be permanently discontinued from capecitabine therapy and withdrawn from study treatment.


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3) Dihydropyrimidine dehydrogenase deficiency
If a subject develops clinical manifestations consistent with suspected DHPD deficiency, 
including Grade 3 or 4 neutropenia, mucositis, diarrhea, and/or encephalopathy, within the 
first or second cycle of study treatment, the subject should be tested for DHPD levels or 
genetic polymorphisms if such testing is locally available.  If DHPD deficiency is confirmed, 
the subject should be permanently discontinued from capecitabine and withdrawn from the 
trial.  If such testing is not available and DHPD deficiency is suspected, the subject should be 
permanently discontinued from capecitabine and withdrawn from study treatment.
Table 4-18: Dose Modification for Stomatitis Associated With Capecitabine
Grade 2
Grade 3
Grade 4
First occurrence
Interrupt treatment until 
resolved to Grade 0-1, then 
continue at same dose with 
prophylaxis where possible.
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 75% of 
the original dose.
Discontinue 
permanently.
Second 
occurrence
Interrupt treatment until 
resolved to Grade 0-1, then 
continue at 75% of the 
original dose.
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 50% of 
the original dose.
—
Third 
occurrence
Interrupt treatment until 
resolved to Grade 0-1, then 
continue at 50% of the 
original dose.
Discontinue permanently.
—
Fourth 
occurrence
Discontinue permanently.
—
—
Note: For Grade-1 toxicity, maintain current dose of capecitabine.  No dose interruption or 
modification is required.
Occurrences should include events in study 12444


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4.5.2.3.6  Dose modification for other non-hematologic toxicities (excluding fatigue, 
dermatologic toxicities, gastrointestinal toxicities, hypertension and toxicities 
attributable to capecitabine)
For other non-hematologic toxicities (excluding fatigue, dermatologic toxicities, 
gastrointestinal toxicities, hypertension and toxicities attributable to capecitabine), dose 
modifications are to be handled as outlined in Table 4-19. For the toxicities alopecia, altered 
taste, and nail changes, which are considered unlikely to become serious or life threatening, 
treatment can be continued at the same dose without reduction or interruption.


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Table 4-19:  Dose Modification for Other Non-Hematologic Toxicities (Excluding Fatigue, Dermatologic Toxicities, 
Gastrointestinal Toxicities, Hypertension and Toxicities Attributable to Capecitabine)
Toxicity 
Grade
Occurrence
Sorafenib
Capecitabine
Dose 
Interruption
Dose 
Reduction
Dose 
Interruption
Dose 
Reduction
Grade 1
Any
None
None
None
None
Grade 2
First
None
None
Delay until 
resolved to 
Grade 1 or 
less
Resume at 
full dose
Subsequent
None
None
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Grade 3
Any
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Grade 4
Any
Discontinue 
study drug
—
Discontinue 
study drug
—
a:  If recovery is not achieved after 21 days of interruption, study drug should be discontinued. 
b:  Subjects who continue to experience toxicity and require a dose reduction below the lowest dose level of capecitabine 
(500 mg/m2 twice daily) or sorafenib/placebo (200 mg/1 placebo tablet twice daily, every other day) must discontinue study drug.
Occurrences should include events in study 12444


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Section 4.5.3, Identity of Investigational Product(s)
Old text:
Section 4.5.3  Identity of Investigational Product(s)
BAY 43-9006 will be packed by the Sponsor and will be labeled according to the 
requirements of local law and legislation.…….
New text:
Section 4.5.3  Identity of Investigational Product(s)
4.5.3.1  Sorafenib
BAY 43-9006 will be packed by the Sponsor and will be labeled according to the 
requirements of local law and legislation.…….
4.5.3.2  Erlotinib
Erlotinib tablets are manufactured by Schwartz Pharma Manufacturing, Inc. for OSI 
Pharmaceuticals, Inc. 
The tablet formulation consists of erlotinib and the excipients lactose monohydrate, 
hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, 
sodium starch glycolate, sodium lauryl sulfate, and titanium dioxide.  The 25 mg, 100 mg, 
and 150 mg strengths are supplied as round white, film-coated, bi-convex tablets with no 
imprint. The active compound of erlotinib is N-(3-ethynylphenyl)-6, 7-bis(2-methoxyethoxy)-
4-quinazolinamine and its molecular weight is 429.90 Daltons.
Supply, packaging, labeling and storage


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The erlotinib tablets will be supplied in high-density, polyethylene bottles of 30 tablets each.  
The bottles will have a tamper-evident seal and a child-resistant cap.  Each bottle of erlotinib
will have a 1-panel standard label or booklet label affixed.  For the 100 mg and 150 mg 
erlotinib doses, two bottles will be further packaged into a subject pack with a 2-panel 
standard label or booklet label affixed.  For the 50 mg erlotinib dose, four bottles of erlotinib 
25 mg tablets will be further packaged into a subject pack with a 2-panel standard label or 
booklet label affixed.  One panel of the label will be permanently attached to the subject pack 
while the other portion will be a tear-off section that will be appended to the dispensing 
documentation. This label will contain the study ID, sponsor ID, contents, directions for use,
storage requirements, batch, and investigational use statement as well as spaces to record the 
subject number and date dispensed. The label will also include any other text as required by 
local law and legislation. Each subject pack label will also have a unique pack number.  The 
labels on the bottles within the pack will have the same pack number.  The labels will not 
contain any unblinding information. Erlotinib must be stored at room temperature and not 
above 25°C (77°F).
Once the study medication has been received, it must be stored in a dry, secure location (ie, 
locked cabinet) accessible only to authorized staff.  
The study drug must be used exclusively for the investigation specified in this protocol.  The 
investigative site must acknowledge receipt of drug supplies.  Generally, acknowledgement 
for this study will be done using the IVRS/IWRS system.  The confirmation of receipt sent by 
the IVRS/IWRS system must be printed and filed appropriately in the investigative site file.  
Occasionally, the IVRS/IWRS may not be available.  The site will be instructed on using the 
Dispatch Order Form for acknowledgment in that situation.  The CRA will instruct the site on 
how to sign the Dispatch Order Form and return it to the shipping unit.
Only the investigator or a person(s) assigned will be allowed to dispense the study 
medications to the subject.  To have complete control over the distribution and use of study 


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drugs, drug accountability must be performed at every subject visit.  Empty bottles/blisters 
must be returned to the investigator along with all unused medication.  Drug accountability 
will be performed throughout the study.  Destruction of all unused material (ie, empty bottles, 
unused tablets, etc) must be documented and performed per standard operating procedures.  
One copy of the destruction certificate must be kept in the investigator’s file and the other 
copy must be sent to the Bayer representative.  
4.5.3.3  Capecitabine
The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine 
and its molecular weight is 359.35 daltons. Capecitabine is available in 150-mg and 500-mg, 
film-coated tablets and is supplied as biconvex, oblong tablets. The 150-mg tablet is light 
peach in color and the 500-mg tablet is peach colored. Each tablet contains the following 
inactive ingredients: anhydrous lactose, croscarmellose sodium, hydroxypropyl 
methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The film 
coating contains hydroxylpropyl methylcellulose, talc, titanium dioxide, and synthetic yellow 
and red iron oxides.
Sponsor-supplied capecitabine 150-mg and 500-mg tablets will be supplied in child-resistant 
blister packs (wallets) of 20 tablets each.  Each blister pack of capecitabine will have a 2-
panel standard label or booklet label affixed.  One portion of the label will be permanently 
attached to the subject pack while the other portion will be a tear-off section that will be 
appended to the dispensing documentation.  This label will contain the trial ID, sponsor ID, 
contents, directions for use, storage requirements, batch, and investigational use statement as 
well as spaces to record the subject number and date dispensed.  The label will also include 
any other text as required by local law and legislation.  The capecitabine must be stored in its 
original, immediate package at a temperature not above 30°C (86°F).  


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Alternatively, capecitabine may be supplied locally according to institutional procedures or 
may be supplied by the sponsor to the site in locally available commercial packaging labeled 
for the study.  
Section 4.5.5, Selection of Doses in the Study
Old text:
Patients will receive sorafenib (Nexavar) 200 mg tablets and should continue receiving the 
same dose they were receiving in their original trial
New text:
Patients will receive sorafenib (Nexavar) 200 mg tablets and should continue receiving the 
same dose they were receiving in their original trial.  Patients receiving sorafenib/erlotinib or 
sorafenib/capecitabine combination should continue the same doses as in the originating trial.
Section 4.5.6, Selection and Timing of Dose for each Subject
Old text:
Sorafenib (Nexavar) may be decreased in the event of toxicity based on the Dose 
Modification criteria outlined in Section 4.5.2.vvv
New text:
Sorafenib (Nexavar), erlotinib, and capecitabine may be decreased in the event of toxicity 
based on the Dose Modification criteria outlined in Section 4.5.2.vvv
Section 4.5.8, Prior and Concomitant Therapy
Old text:


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Non-permissible concomitant medication/therapies:

Anticancer chemotherapy, immunotherapy or vaccines during the study.
New text:
Non-permissible concomitant medication/therapies:

Anticancer chemotherapy, except erlotinib and capecitabine, immunotherapy or live
vaccines during the study.
Section 4.6.1, Efficacy Variables
Old text:
Not applicable
New text:
Overall Survival (OS)
Section 4.6.2, Safety Variables
Old text:
Primary objective
All observations pertinent to the safety of the study medication will be recorded in the 
patient’s source documents and available at the request of the sponsor.
The following data must be reported in the source documents:

ECOG performance status

Vital signs (heart rate, blood pressure, temperature)


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
………
In addition to the above parameters, the following data must be recorded in the CRF provided 
and the source documents:

All treatment related adverse events (any grade)

All adverse events NCI-CTCAE Version 3.0 Grade 3 or higher (regardless of attribution). 

All Serious Adverse Events, regardless of relationship to study drug

Laboratory parameters ………..

Reason for termination of study medication

Date of death, as applicable
New text:
All observations pertinent to the safety of the study medication will be recorded in the 
patient’s source documents and available at the request of the sponsor.
The following data must be reported in the source documents:

Vital signs (heart rate, blood pressure, temperature)

…………
In addition to the above parameters, the following data must be recorded in the CRF provided 
and the source documents:

All treatment related adverse events (any grade)

All adverse events NCI-CTCAE Version 3.0 Grade 3 or higher (regardless of attribution).  
Study Sites in Japan: In accordance with Japanese regulatory requirements ALL adverse 
events regardless of NCI-CTCAE grade and regardless of attribution are to be recorded.


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
All Serious Adverse Events, regardless of relationship to study drug

ECOG performance status

Laboratory parameters …………

Reason for termination of study medication
Section 4.6.3, Assessment Periods
Old text:
Observations and Measurements
Once enrolled in this program………

Assessment of Adverse Events 
o Treatment related event – all CTC grades
oAny CTC Grade 3 or 4 event (regardless of attribution)
o Any Serious Adverse Event (regardless of attribution)

Study medication (date dispensed and returned, number of tablets dispensed and returned)

Laboratory Assessments ………
End of treatment
In addition to the above parameters, please record the following in the CRF and source 
documents:

The reason for termination 

Date of last dose 

Date of death, if applicable


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Follow up period
If a patient discontinues due to an adverse event or clinical laboratory abnormality, the patient 
should be followed until the event resolves, the patient stabilized, or 30 days, whichever is 
shorter………..
New text:
Observations and Measurements
Once enrolled in this program………

Assessment of Adverse Events 
o Treatment related event – all CTC grades
oAny CTC Grade 3 or 4 event (regardless of attribution)
Study Sites in Japan: In accordance with Japanese regulatory requirements ALL 
adverse events regardless of NCI-CTCAE grade and regardless of attribution are to be 
recorded.
o Any Serious Adverse Event (regardless of attribution)

Study medication (date dispensed and returned, number of tablets dispensed and returned)

Laboratory Assessments ………

Other variables
o
ECOG performance status
o
Survival status 


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End of treatment
In addition to the above parameters, please record the following in the CRF and source 
documents:

The reason for termination 

Date of last dose 

Survival status (dead or alive and date of death or date of last contact)
Follow up period
All subjects will be followed for survival. Assessment of survival status will be performed 
approximately every 3 months in the follow-up period.
If a patient discontinues due to an adverse event or clinical laboratory abnormality, the patient 
should be followed until the event resolves, the patient stabilized, or 30 days, whichever is 
shorter……..
Section 4.6.4, Drug Concentration Measurements
Old text:
Section 4.6.4, Drug Concentration Measurements
Not applicable
New text: 
There is no new text; this section was deleted
Section 5.1, Ethics Committee (EC) or Institutional Review Board (IRB)
Old text:


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……...  When necessary, an extension, amendment or renewal of the Ethics Committee 
approval must be obtained and also forwarded to the Sponsor.  The Ethics Committees supply 
to the Sponsor, upon request, a list of the Ethics Committee members involved in the vote and 
a statement to confirm that the Ethics Committee is organized and operates according to GCP 
and applicable laws and regulations.
New text:
……  When necessary, an extension, amendment or renewal of the Ethics Committee 
approval must be obtained and also forwarded to the Sponsor.  The Ethics Committees or the 
head of the center for sites in Japan must supply to the Sponsor, upon request, a list of the 
Ethics Committee members involved in the vote and a statement to confirm that the Ethics 
Committee is organized and operates according to GCP and applicable laws and regulations.
Section 6.1, Statistical and Analytical Plans
Old text:
At the time that the last patient last visit occurs, a summary of demography, adverse events 
(including serious), laboratory data and reasons for termination of treatment will be provided 
in the form of a written report. Later on information on overall survival may be provided.
New text:
At the time that the last patient last visit occurs, descriptive analyses of demography, adverse 
events (including serious), laboratory data, reasons for termination of treatment, duration of 
treatment, and overall survival will be provided in the form of a written report. 
Overall survival (OS) will be measured from the date of randomization/date of enrollmentgg
in the originating trial until the date of death due to any cause. If a subject is still alive at the 


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date of database cutoff, the subject will be censored at the date of the last contact (last time 
the subject was known to be alive). Subgroup analyses may be performed, if necessary.
gg: Date of enrollment will be used for cases in which the originating trial was not randomized.
Section 7.2, Adverse Event Monitoring
Old text:
….Adverse events should be assessed in terms of their seriousness, severity and relationship 
to study medication. 
New text:
………  Adverse events should be assessed in terms of their seriousness, severity and 
relationship to study medication. Adequate medical care will be provided to the subjects for 
any adverse events, and the events will be followed up until resolution or stabilization.
Section 7.3.2, Serious Adverse Event 
Old text:
Hospitalization:  Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the following 
exceptions is met:

The admission results in a hospital stay of less than 12 hours
OR……


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New text:
Hospitalization:  Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the following 
exceptions is met:

The admission results in a hospital stay of less than 12 hours (because of local 
regulatory requirements, this exception is not applicable to Japan).
OR……
Section 7.3.3, Unexpected Adverse Event 
Old text:
……Also, reports which add significant information on specificity or severity of a known, 
already documented adverse event constitute unexpected adverse events.
New text:
……  Also, reports which add significant information on specificity or severity of a known, 
already documented adverse event constitute unexpected adverse events. The expectedness of 
AEs will be determined by the Sponsor according to the applicable reference document and 
according to all local regulations.
Section 7.3.6, Adverse Event Documentation
Old text:
All treatment related adverse events or adverse events NCI-CTCAE Version 3.0 Grade 3 or 
higher (regardless of attribution) occurring after the subject has signed the informed consent 
must be fully recorded in the subject’s case record form.


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Documentation must be supported by an entry in the subject’s file……….
New text:
All treatment related adverse events or adverse events NCI-CTCAE Version 3.0 Grade 3 or 
higher (regardless of attribution) occurring after the subject has signed the informed consent 
must be fully recorded in the subject’s case record form.
Study Sites in Japan: In accordance with Japanese regulatory requirements ALL adverse 
events regardless of NCI-CTCAE grade and regardless of attribution are to be recorded.
Documentation must be supported by an entry in the subject’s file………..
Section 11, Appendices 
Old text:
Activity
Visit 1
Minimum 
Every
8 weeks
End of 
Treatment
Demography a, b ………….
X
ECOG performance
X
X
X
Adverse events a  ……………………
…
…
…
Laboratory evaluations a  …………………..
…
…
…
Dispense/return sorafenib a
X
X
X
Reason for termination of treatment a
X
Date of death, as applicable a
X
Concomitant medications
X
X
X
a
Record these data in the CRF and source documents.
b
Includes …...
c
For anticoagulated patients only
New text:
Activity
Visit 1
Minimum 
Every
8 weeks
End of 
Treatment
Demography a, b ……………
X
ECOG performance a
X
X
X
Survival status (dead or alive, date of death or 
X
Xd


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date of last contact, as applicable)
Adverse events a  ……………………
…
…
…
Laboratory evaluations a  …………………..
…
…
…
Dispense/return sorafenib (and erlotinib or 
capecitabine if applicable)a
X
X
X
Reason for termination of treatment a
X
Concomitant medications
X
X
X
a
Record these data in the CRF and source documents.
b
Includes …...
c
For anticoagulated patients only
d
For patients in long term follow up, survival status is assessed at a minimum of every 3 months


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10.4
Amendment 4
10.4.1
Overview of Changes
Modification 1 Change of responsibility for the Study Manager and Medical Expert. 
Contact names for the Study Manager and Medical Expert were updated on the title page of 
the protocol.  A line was also added for the signature of the Global Clinical Lead.
The protocol section affected by this change is the title page.
Modification 2 Removal of all references to erlotinib.
All references to erlotinib were removed since none of the subjects that transferred into this 
study were assigned to erlotinib+sorafenib in study 12917 (SEARCH).  Where entire sections 
were removed, this also changed the section numbering in subsequent sections and tables.
The protocol sections affected by this change are Section 4.1 Study design and Plan, Section 
4.2.1 Inclusion Criteria, Section 4.2.2 Exclusion Criteria, Section 4.5.1 Treatments to be 
Administered, Section 4.5.2.2 Sorafenib and erlotinib combination therapy, Section 4.5.2.2.1
Anti-rash and Anti-diarrhea Therapies, Section 4.5.2.2.2 Dose Modification for Hand-Foot 
Skin Reaction, Section 4.5.2.2.3 Dose Modification for Keratitis, Section 4.5.2.2.4 Dose 
Modification for Interstitial Lung Disease, Section 4.5.3.2 Erlotinib, Section 4.5.5 Selection 
of Doses in the Study, Section 4.5.6 Selection and Timing of Dose for Each Subject and 
Section 4.5.8 Prior and Concomitant Therapy.
Modification 3 Clarification regarding the supply of capecitabine for subjects from 
Study 12444 changing from clinical supply by the sponsor to commercial supply.
The protocol current language suggest that for those subjects who will be transferred from the 
RESILIENCE study (12444) and taking a combination of capecitabine and sorafenib, both 
sorafenib and capecitabine will be provided by the sponsor. However, capecitabine is 


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commercially approved for breast cancer and readily available in many countries including 
generic sources, the study team proposes to modify the protocol to reflect that capecitabine 
will NOT be provided by the sponsor but should be sourced from commercial sources for 
those subjects who are on combination treatment. Only sorafenib will be provided by the 
sponsor.
The protocol sections affected by this change are Section 4.1 Study design and Plan, Section 
4.5.1 and Treatments to be Administered and Section 4.5.3.3 Capecitabine.
Modification 4 Removal of references to placebo in association with sorafenib 
administration in Study 12444 (RESILIENCE).
In Study 12444 (RESILIENCE), subjects received either capecitabine and sorafenib or 
capecitabine and placebo.  In this protocol, the text as written can be misinterpreted to 
indicate that subjects from Study 12444  received both sorafenib and placebo and none of the
subjects received sorafenib and placebo in Study 12444.  This modification removes the word 
placebo when referring to subjects in Study 12444 who received sorafenib.
The protocol sections affected by this change are Section 4.5.2.2 Sorafenib and capecitabine 
combination, Section 4.5.2.2.2 Dose modification for hematologic toxicities, 
Section 4.5.2.2.3 Dose modification for non-hematologic toxicities, Section 4.5.2.2.4 Dose 
modification and management of sorafenib-specific toxicities and Section 4.5.2.2.6 Dose 
modification for other non-hematologic toxicities (excluding fatigue, dermatologic toxicities, 
gastrointestinal toxicities, hypertension and toxicities attributable to capecitabine).
Modification 5 Addition of TACE to the permissible anticancer chemotherapies in 
Section 4.5.8 Prior and Concomitant Therapy and addition of guidance on Sorafenib 
dose modification in combination with TACE in Section 4.5.2.3.
One of the changes implemented during Amendment 2 (16 Mar 2011) was to modify the 
exclusion criteria to allow patients who were receiving TACE and sorafenib in a Bayer 


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sponsored study to participate in the STEP study. This is reflected in protocol Section 4.2.2
(Exclusion criteria) and in Section 10.2.2 that describes the changes and rationale for the 
amendment. However, Section 4.5.8(Prior and Concomitant Therapy) was not modified to 
allow the concomitant use of TACE and sorafenib and is not in line with the intent of 
Amendment 2 and the related text in Section 4.2.2. 
The lack of changing Section 4.5.8to be in line with the other sections of the protocol was an 
unintentional oversight. The study team issued an administrative letter on 11 Dec 2013 to 
clarify that since the implementation of Amendment 2, concomitant TACE and sorafenib is 
permissible as per the protocol (Section 4.2.2 and 10.2.2). This discrepancy in Section 4.5.8
is now being corrected in this amendment to reflect that TACE is permissible.
Meanwhile, the guidance on Sorafenib dose modification in combination with TACE is added 
as the Section 4.5.2.3.
The protocol section affected by this change are Section 4.5.2.3 Sorafenib and TACE 
combination and Section 4.5.8 Prior and Concomitant Therapy (Non-permissible concomitant 
medication/therapies).
Modification 6 Clarification of which CTC version was used for the grading of liver 
function abnormalities.
Since there are differences between CTC versions in the definitions of severity grades for
liver function test abnormalities, it was decided to specify the version of CTC used as a 
reference for the grading.
The protocol section affected by this change is Section 4.5.2.3 Sorafenib, Table 4-13 and 
Table 4-14.


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10.4.2
Changes to the Protocol Text
In this section, all affected protocol sections are detailed; the sequence of sections follows the 
structure of the original protocol.  In the display of modifications, the “old text” refers to the 
protocol version preceding this amendment (ie, protocol version 7.0).  Some section numbers 
and table numbers changed from those in the preceding protocol due to the removal of some 
section detailed in this section.  Deletions are crossed out in the “old text” and additions are 
underlined in the “new text” (ie, Amendment 4/ Version 8.0).
Title Page
Old text:
Date
Date
Date
New Text:
Date
Date
Date
PPD
PPD


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Section 4.1, Study Design and Plan
Old text: 
The patients in this open-label program will continue receiving single-agent sorafenib 
(Nexavar), sorafenib and erlotinib combination if transferred from study 12917 (SEARCH),
or sorafenib and capecitabine combination if transferred from Study 12444 (RESILIENCE) 
at the same dose and schedule as in their original Clinical Trial.
Prior to being dispensed study medication for this long term extension program, patients will 
be required to complete their End of Treatment visit in their originating study.  Once the End 
of Treatment visit in the originating study is complete, patients will be required to provide 
informed consent for this long term extension program.  Patients will continue with single 
agent sorafenib (Nexavar), if transferred from Study 12917 (SEARCH), or sorafenib and 
capecitabine if transferred from Study 12444 (RESILIENCE) in this program at the same 
dose and schedule the patient was receiving in their original clinical trial.
Sorafenib (Nexavar) will be provided as 200 mg tablets. Erlotinib will be provided as 
150 mg, 100 mg, and 25 mg tablets for patients receiving the sorafenib/erlotinib 
combination and transferring from Study 12917 (SEARCH). Capecitabine will be provided
as 150 mg and 500mg tablets for patients receiving the sorafenib/capecitabine combination 
and transferring from Study 12444 (RESILIENCE).


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New text:
The patients in this open-label program will continue receiving single-agent sorafenib 
(Nexavar) or sorafenib and capecitabine combination if transferred from Study 12444 
(RESILIENCE) at the same dose and schedule as in their original Clinical Trial.
Prior to being dispensed study medication for this long term extension program, patients will 
be required to complete their End of Treatment visit in their originating study.  Once the End 
of Treatment visit in the originating study is complete, patients will be required to provide 
informed consent for this long term extension program.  Patients will continue with single 
agent sorafenib (Nexavar) or sorafenib and capecitabine if transferred from Study 12444 
(RESILIENCE) in this program at the same dose and schedule the patient was receiving in 
their original clinical trial.  
Sorafenib (Nexavar) will be provided as 200 mg tablets. Capecitabine is available in many 
countries including generic sources and will be commercially supplied as 150 mg and 
500mg tablets for patients receiving the sorafenib/capecitabine combination and 
transferring from Study 12444 (RESILIENCE).
Section 4.2.1, Inclusion Criteria
Old text:

Patients who are receiving concurrent combination with sorafenib (Nexavar) and 
erlotinib in their originating Study 12917 (SEARCH) will be eligible.
New text:
None


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Section 4.2.2, Exclusion Criteria
Old text:
Excluded therapies and medications, previous and concomitant

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization), 
erlotinib, and capecitabine
New text:
Excluded therapies and medications, previous and concomitant

Concurrent anti-cancer chemotherapy, except TACE (transarterial chemoembolization) 
and capecitabine
Section 4.5.1, Treatments to be Administered
Old text:
Sorafenib will be supplied as 200 mg tablets. Erlotinib will be supplied as 150 mg, 100, 
and 25 mg tablets, and capecitabine will be provided as 150 mg and 500 mg tablets.  
Patients should continue on the same dose as they were receiving in the patient’s originating 
Bayer/Onyx-sponsored Clinical Trial.
New text:
Sorafenib will be supplied as 200 mg tablets. Patients should continue on the same dose 
as they were receiving in the patient’s originating Bayer/Onyx-sponsored Clinical Trial.


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Section 4.5.2.2, Sorafenib and erlotinib combination therapy
Old text:
4.5.2.2 Sorafenib and erlotinib combination therapy
Doses will be delayed or reduced for clinically significant hematologic and non-
hematologic toxicities that are related to protocol therapy according to the guidelines 
shown in Table 4 5andTable 4 6. Dose modifications will follow predefined dose levels.  
Dose adjustments for hematologic toxicity are based on the blood counts obtained in 
preparation for the day of treatment.
Table 4-5:  Dose Modification Levels for Sorafenib
Dose
Sorafenib
Starting Dose
400 mg twice daily
-1
400 mg once daily
-2
400 mg every other day
Table 4-6:  Dose Modification Levels for Erlotinib
Dose
Erlotinib
Starting Dose
150 mg once a day
-1
100 mg once a day
-2
50 mg once a day

Except for an event of hypertension, the first agent to dose reduce for the 1st episode of
any toxicity will be erlotinib


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
If a subject experiences more than one toxicity, dose reduction should be according to 
the toxicity with the highest grade 

In the case of two or more toxicities of the same grade, the investigator may dose 
reduce according to the toxicity deemed most causally related to study treatment

Subjects for whom one agent is held may continue to receive the other agent if all the 
protocol-defined dose modification steps have been taken and, in the opinion of the 
treating investigator, the subject may continue to benefit from treatment

Subjects with toxicities that are manageable with supportive therapy may not require 
dose reductions (eg, nausea/vomiting may be treated with antiemetics; diarrhea may be 
treated with loperamide rather than by dose reduction). A subject will be withdrawn 
from the study if he/she fails to recover from a treatment-related toxicity to CTCAE 
Grade 0-1, or tolerable grade 2 (or within 1 grade of starting values for pre-existing 
laboratory abnormalities) within 30 days, unless the investigator and sponsor agree that 
the subject should remain in the study because the investigator believes the subject 
is/may derive benefit from continuing study treatment. 
Table 4-7:  Dose Modification Plan for Hematologic Toxicities
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Gr 1
Treat on time
No change in dose
No change in dose
Gr 2
No change
Gr 3*
Treat on time
Re-evaluate weekly
1st episode: no change in 
dose
1st episode: reduce 
erlotinib to 
level -1 (100 mg once a 
day)
2nd episode: reduce 
sorafenib to  level -1 (400 mg 
once daily)
2nd episode: no change to 
above modified dose
3rd episode: no change to 
3rd episode: reduce 


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Table 4-7:  Dose Modification Plan for Hematologic Toxicities
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
above modified dose
erlotinib to 
level -2 (50 mg once a day)
4th episode: reduce sorafenib
to level -2 (400 mg every other 
day)
4th episode: no change to 
above modified dose
Gr 4*
Holda both agents 
until <Gr 2
Re-evaluate weekly
1st episode: no change in 
dose upon continuation of 
treatment
1st episode: reduce 
erlotinib  to 
level -1 (100 mg once a 
day) upon continuation of 
treatment
2nd episode: reduce 
sorafenib to level -1 (400 mg 
once daily) upon continuation 
of treatment
2nd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: reduce 
erlotinib to level -2 (50 mg 
once a day) upon 
continuation of treatment
4th episode: reduce sorafenib
to level -2 (400 mg every other 
day) upon continuation of 
treatment
4th episode: no change to 
above modified dose upon 
continuation of treatment
aIf no recovery after 30 day delay, treatment will be discontinued unless subject is deriving 
clinical benefit.
*Intervention/Supportive care regarding Gr 3 or 4 Heme toxicity as per investigator.
If more than 4 dose reductions are required, study treatment will be discontinued.
Table 4-8:  Dose Modification Plan for non-Hematologic Toxicity except ILD, and Hypertension
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Gr 1
Treat on time
No change in dose
No change in dose
Gr 2
No change
Gr 3*
Holda both agents 
until <Gr 2
1st episode: no change in 
dose upon continuation of 
1st episode: reduce 
erlotinib to level -1 


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Table 4-8:  Dose Modification Plan for non-Hematologic Toxicity except ILD, and Hypertension
NCI CTC 
V3.0
Dose Interruption
Dose Reduction
Sorafenib
Erlotinib
Initiate supportive 
care
Re-evaluate weekly
treatment
(100 mg once a day) upon 
continuation of treatment 
2nd episode: reduce 
sorafenib to level -1 (400 mg 
once daily) upon continuation 
of treatment
2nd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: no change to 
above modified dose upon 
continuation of treatment
3rd episode: reduce 
erlotinib to level -2 (50 mg 
once a day) upon 
continuation of treatment 
4th episode: reduce sorafenib
to level -2 (400 mg every other 
day) upon continuation of 
treatment 
4th episode: no change to 
above modified dose upon 
continuation of treatment
Gr 4*
REMOVE FROM 
STUDY
a If no recovery after 30 day delay, treatment will be discontinued unless subject is deriving 
clinical benefit.
If more than 4 dose reductions, study treatment will be discontinued.  Excludes alopecia, 
nausea/vomiting that has not been pre-medicated, and diarrhea not treated with supportive 
care/loperamide.
New text (change in section numbering):
Section 4.5.2.2 Sorafenib and capecitabine combination
Section 4.5.2.2.1, Anti-rash and Anti-diarrhea Therapies
Old text:
4.5.2.2.1 Anti-rash and Anti-diarrhea Therapies


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Skin rash or dermatosis has been observed in many subjects during treatment with 
erlotinib.  No clinical trials have formally evaluated treatments for rash induced by 
erlotinib, and there are currently no evidence-based recommendations for its management. 
Subjects who develop a mild rash characterized by pustules or raised, red areas may be 
treated with topical therapy, such as corticosteroids.  If the rash is more severe or there is 
indication of secondary infection, topical clindamycin or tetracycline, or oral minocycline
may be used at the discretion of the investigator.  (NOTE:  minocycline is known to 
interfere with anticoagulants and oral contraceptives.  Therefore, subjects treated with 
minocycline who are taking anticoagulants and/or oral contraceptives should be monitored 
accordingly).  Guidance concerning modification of study drug dosing is provided inTable 
4-8.
Because the pathology of such a rash is not related to acne pathology, retinoids and other
acne medications, such as benzoyl peroxide, are not recommended, because these agents 
are more likely to exacerbate the rash due to their drying effects on the skin.  
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have 
shown that the frequency and severity of diarrhea rarely hindered the administration of
erlotinib and that the diarrhea could be managed with loperamide.  The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until the subject is 
diarrhea-free for 12 hours.


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Table 4-9:  Dose Modification Plan for Hypertension
Grade
Dose 
Interruption
Dose Reduction
Antihypertensive 
Therapy
Blood Pressure 
Monitoring
Hypertensive NCI 
CTCAE V3
Sorafenib
Erlotinib
Gr 1
Treat on time
Initiate 
supportive 
care
No change in 
dose 
No change in 
dose 
None
Routine
Asymptomatic, 
transient, (< 24hrs) 
increase by 
> 20 mm Hg 
(diastolic) or to 
> 150/100 if 
previously WNL; 
intervention not 
indicated.
Gr 2
Treat on time
Initiate 
supportive 
care
No change in 
dose 
No change in 
dose 
(asymptomatic)
Initiate monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker).
(asymptomatic)
Increase frequency 
and monitor (by 
health professional) 
every 2 days until 
stabilized.
Recurrent or 
persistent 
(> 24 hrs) or 
symptomatic 
increase by 
> 20 mm Hg 
(diastolic) or to 
> 150/100 if 
previously WNL; 
monotherapy may 
be indicated.
(symptomatic 
/persistent)
OR
Diastolic BP 
> 110 mm Hg
Add agent(s): 
Ca++ channel 
blocker (if not 
already used)
K+ channel opener 
(angiotensin 
blockers), 
Beta-blocker
Thiazide diuretic
(symptomatic/ 
persistent)
OR
Diastolic BP 
> 110 mm Hg
Increase frequency 
and monitor (by
health professional) 
every 2 days until 
stabilized.


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Table 4-9:  Dose Modification Plan for Hypertension
Grade
Dose 
Interruption
Dose Reduction
Antihypertensive 
Therapy
Blood Pressure 
Monitoring
Hypertensive NCI 
CTCAE V3
Sorafenib
Erlotinib
Gr 3
Hold both 
agents until 
≤Gr 2
Initiate 
supportive 
care
Re-evaluate 
weekly
1st episode:  
reduce sorafenib 
to level –1 
(400 mg once 
daily) upon 
continuation of 
treatment.
1st episode:  no 
change in dose 
upon 
continuation of 
treatment.
Add agent(s): 
Ca++ channel 
blocker 
(if not already used) 
K+ channel opener 
(angiotensin 
blockers) 
Beta-blocker 
Thiazide diuretic
Increase frequency 
and monitor (by 
health professional) 
every 2 days until 
stabilized.
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.
2nd episode:  no 
change in dose 
upon continuation 
of treatment.
2nd episode: 
reduce erlotinib 
to level –1 
(100 mg once a
day) upon 
continuation of 
treatment.
3rd episode: 
reduce sorafenib 
to level –2 
(400 mg every 
other day) upon 
continuation of 
treatment. 
3rd episode:  no 
change in dose 
upon 
continuation of 
treatment.
4th episode:  no 
change in dose 
upon continuation 
of treatment.
4th episode:  
reduce erlotinib
to level –2 (50 mg 
once a day) upon 
continuation of 
treatment.
Gr 4
REMOVE 
FROM 
STUDY
Life-threatening 
consequences (eg, 
hypertensive 
crisis)


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New text (change in section numbering):
Section 4.5.2.2.1 Dose-reduction levels
Section 4.5.2.2.2, Dose Modification for Hand-Foot Skin Reaction
Old text:
4.5.2.2.2 Dose Modification for Hand-Foot Skin Reaction
Subjects experiencing Hand-Foot Skin Reaction should have their signs and symptoms 
graded according to the following system (seeTable 4-10). Other skin toxicities will be 
graded according to CTCAE Version 3.0.
At first occurrence of hand foot skin reaction, independent of grade, prompt institution of 
supportive measures such as topical emollients, low potency steroids, or urea-containing 
cream should be administered.
Table 4-10:  Grading for Hand-Foot Skin Reaction
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling or 
erythema of the hands and/or feet and/or discomfort, which does not 
disrupt normal activities.
Grade 2
Painful erythema and swelling of the hands and/or feet and/or 
discomfort affecting the subject’s activities. 
Grade 3 
Moist desquamation, ulceration, blistering or severe pain of the 
hands and/or feet and/or severe discomfort that causes the subject 
to be unable to work or perform activities of daily living.


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Table 4-11:  Dose Modification Plan for Hand Foot Skin Reaction
NCI CTC 
V3.0
Dose 
Interruption
Dose Reduction
HFSR
NCI CTCAE V3.0
Sorafenib
Erlotinib
Gr 1
Treat on time
No change of 
dose 
No change of 
dose 
Numbness, 
dysesthesia/paresthesia, 
tingling, painless swelling 
or erythema of the hands 
and/or feet and/or 
discomfort, which does 
not disrupt normal 
activities.
Gr 2
No change
Painful erythema and 
swelling of the hands 
and/or feet and/or 
discomfort affecting the 
subject’s activities.
Gr 3
Holda both 
agents until 
< Gr 2
Initiate 
supportive 
care
Re-evaluate 
weekly
1st episode: no 
change in dose 
upon 
continuation of 
treatment.
1st episode: 
reduce erlotinib
to level -1 
(100 mg once a 
day) upon 
continuation of 
treatment.
Moist desquamation, 
ulceration, blistering or 
severe pain of the hands 
and/or feet and/or severe 
discomfort that causes 
the subject to be unable 
to work or perform 
activities of daily living.
2nd episode: 
reduce sorafenib
to level -1 
(400 mg once 
daily) upon 
continuation of 
treatment.
2nd episode: no 
change to above 
modified dose 
upon 
continuation of 
treatment.
3rd episode: no 
change to above 
modified dose 
upon 
continuation of 
treatment.
3rd episode: 
reduce erlotinib
to level -2 (50 mg 
once a day) upon 
continuation of
treatment.
4th episode: 
reduce sorafenib
to level -2 (400 
mg every other 
day) upon 
continuation of 
treatment.
4th episode: no 
change to above 
modified dose 
upon 
continuation of 
treatment.
Gr 4
REMOVE 
FROM 
STUDY
a If no recovery after 30 day delay, treatment will be discontinued unless subject is deriving 
clinical benefit.


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New text (change in section numbering):
Section 4.5.2.2.2 Dose modification for hematologic toxicities
Section 4.5.2.2.3, Dose Modification for Keratitis
Old text:
4.5.2.2.3 Dose Modification for Keratitis
For all grades of suspected keratitis, the erlotinib dose should be held and supportive 
measures instituted.  Subjects with dry eyes should be advised to use an ocular lubricant.  
Subjects who continue to wear contact lenses may have an increased risk of ocular AEs 
(eg, keratitis).  Subjects may continue to wear contacts but should discuss this issue with 
their treating oncologist before entering the study.  In addition, any elective 
ophthalmological surgery while the subject is taking study drug must first be discussed 
between the investigator and the Sponsor.
New text (change in section numbering):
Section 4.5.2.2.3 Dose modification for non-hematologic toxicities
Section 4.5.2.2.4, Dose Modification for Interstitial Lung Disease
Old text:
4.5.2.2.4 Dose Modification for Interstitial Lung Disease


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For all grades of suspected interstitial lung disease (ILD), the erlotinib dose should be held 
and supportive measures instituted.  If ILD is confirmed, erlotinib and sorafenib must be 
discontinued permanently.  Acute dyspnea or cough may be signs of ILD.  If a subject 
presents with acute dyspnea or cough, interruption of treatment with erlotinib may be 
considered, at the discretion of the treating physician, until resolution of symptoms or until 
ILD can be ruled out.  If a subject presents with symptoms such as shortness of breath, 
dyspnea, cough, or fever, a chest X-ray or chest CT and, if needed, additional tests to 
evaluate pulmonary function, as clinically indicated, should be considered as part of the 
work up.  If a diagnosis of ILD is confirmed, appropriate treatment measures according to 
best medical practice and local standards should be initiated.
New text (change in section numbering):
Section 4.5.2.2.2 Dose modification and management of sorafenib-specific toxicities
Section 4.5.2.3, Sorafenib and capecitabine combination
Old text:
Doses of capecitabine or sorafenib/placebo may be reduced/interrupted in the setting of any 
AE that is:

Not controlled by optimal supportive care, or

Not tolerated due to symptomatology, disfigurement, or interference with normal daily 
activities, regardless of severity.


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New text:
Section 4.5.2.2 Sorafenib and capecitabine combination
Doses of capecitabine or sorafenib may be reduced/interrupted in the setting of any AE that 
is:

Not controlled by optimal supportive care, or

Not tolerated due to symptomatology, disfigurement, or interference with normal daily 
activities, regardless of severity.
Section 4.5.2.3, Sorafenib and TACE combination (new section)
New text:
Doses of sorafenib maybe be delayed or reduced for clinically significant hematologic and 
non-hematologic toxicities that are related to Sorafenib and TACE combination. 
Dose modifications should take into consideration AEs and dose modifications already 
occurred in Study 12918 (SPACE).
Sorafenib dose modification in combination with TACE should follow the sorafenib 
monotherapy section guidelines (section 4.5.2.1) except dose modification for liver function 
test abnormalities. The following tables (Table 4–13 and Table 4–14) illustrate dose 
reductions and interruptions of Sorafenib if ALT or AST increase to CTC Grade 3 or 4 
within 72 hours post-TACE along with the instruction for dose re-escalation following dose 
reduction for TACE related liver function test abnormalities. 


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Table 4-13: Criteria for Dose Reduction and Dose Interruption of Sorafenib if ALT or 
AST Increase to CTC Grade 3 or 4 within 72 hours Post TACE
Criteria for Dose Interruption and Dose Modification of Sorafenib if ALT/AST increased to CTC 
Grade 3 within 72 hours post TACE
DURATION of ALT/AST elevation
ACTION
DOSE MODIFICATION
1
Grade 3  within 72 h post TACE
Continue study drug
No
2
Grade 3  persists >1 weeks post TACE
Continue study drug
YES: 
Decrease one dose 
level a
3
Grade 3  persists >2 weeks post TACE
Continue study drug
YES: 
Decrease dose further b
4
Grade 3  persists >3 weeks post TACE c STOP     study drug
YES: 
OFF Protocol Therapy
Criteria for Dose Interruption and Dose Modification of Sorafenib if ALT/AST increased to CTC
Grade 4 within 72 hours post TACE
DURATION of abnormal ALT/AST or 
bilirubin
ACTION
DOSE MODIFICATION
5
Grade 4 AST or ALT for up to 1 week 
following TACE and bilirubin ≤2x pre-
TACE value
Continue study drug, 
check ALT/AST, 
bilirubin every 1-2 days
No change 
6
Grade 4 AST or ALT at any time within 
1 week following TACE and bilirubin 
>2x pre-TACE value
STOP study drug until 
a.) bilirubin decreased 
to ≤2x pre-TACE value, 
and
b.) ALT and AST 
decreased to grade 3 
(check ALT/AST, 
bilirubin every 1-2 days
)
Once bilirubin <2x pre-
TACE value and ALT 
and AST decreased to 
grade 3 or less within 1 
week of TACE, continue 
study drug at 
DECREASED dose (one 
level) a and follow grade 
3 table above (criteria 3)
7
Grade 4 AST or ALT persists >1 week 
and bilirubin remains at ≤ 2 x pre-
TACE value
Continue study drug
DECREASE one dose 
level a and follow grade 
3 table above (criteria 3)
8
Grade 4 AST or ALT persists > 1 week 
or bilirubin has not decreased to ≤2x 
pre-TACE value after 1 week 
STOP study drug
OFF Protocol Therapy
a   to 400 mg daily, if pre-TACE dose was full dose (or to 400mg every other day, if pre-TACE dose was 400 mg daily)
b   to 400 mg every other day (or discontinue, if pre-TACE dose was 400 mg daily)
c   if more than 2 dose reductions are required, patient is off protocol therapy


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Table 4–14: Post-TACE Sorafenib Dose Re-Escalation Scheme
CAUSE FOR DOSE 
REDUCTION
RE-ESCALATE to 
400 mg every other 
day, if
RE-ESCALATE to 
400 mg every day, 
if
RE-ESCALATE to 
400 mg twice daily, 
if
1
Grade 3  ALT or AST 
persisted >1 week 
post-TACE
N/A
N/A
Grade 2 (or less) 
ALT and AST for at 
least 2 weeks under 
400 mg daily
2
Grade 3  ALT or AST 
persisted >2 weeks 
post-TACE
N/A
Grade 2 (or less) 
ALT and AST for at 
least 2 weeks under 
400 mg every other 
day
Grade 2 (or less) 
ALT and AST for at 
least 2 additional 
weeks
under 400 mg daily
3
Grade 4  ALT or AST 
persisted >1 week 
and bilirubin 
remained at <2x pre-
TACE value
N/A
N/A
Grade 2 (or less) 
ALT and AST, and 
bilirubin ≤2x pre-
TACE value for at 
least 2 weeks under 
400 mg daily
Note: Liver function test abnormalities will be graded using the CTCAE v. 3.0
The rationale for additional criteria for ALT/AST increase within 72 hours following 
TACE is as follows:
Transarterial Chemoembolization (TACE) induces necrosis of tumor cells and to some 
degree affects normal liver tissue near the tumor tissue targeted by the TACE procedure.  A 
common observation after TACE is a transient, reversible rise of liver enzymes peaking at 
24-36 hours. One previous study confirmed AST and ALT levels increased 1–3 days after 
embolization and normalized to near pre-embolization values 1-month post procedure.
Therefore, ALT/AST increases within 72 hours after TACE should be handled with 
different dose modification guidelines, reflecting the duration of Grade 3/4 ALT/AST 
increases as well as bilirubin levels.
Note: Liver function test abnormalities will be graded using the CTCAE v. 3.0


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Section 4.5.2.3.2, Dose modification for hematologic toxicities
Old text:
At the re-start of capecitabine following these toxicities, the dose of capecitabine should be 
reduced by at least one level (see Table 4-14 and Table 4-15).  Additional dose reductions 
may occur as needed in subsequent cycles.  If a subject requires dose reduction below 
capecitabine 500 mg/m2 twice daily or sorafenib/placebo 200 mg twice daily, every other 
day, study drug must be permanently discontinued.
New text:
Section 4.5.2.2.2 Dose modification for hematologic toxicities
At the re-start of capecitabine following these toxicities, the dose of capecitabine should be 
reduced by at least one level (see Table 4-14 and Table 4-15).  Additional dose reductions 
may occur as needed in subsequent cycles.  If a subject requires dose reduction below 
capecitabine 500 mg/m2 twice daily or sorafenib 200 mg twice daily, every other day, study 
drug must be permanently discontinued.
Section 4.5.2.3.3, Dose modification for non-hematologic toxicities
Old text:
General guidelines for dose modification for toxicities common to both 
sorafenib and capecitabine
Grade 1:
If any dermatologic toxicities, gastrointestinal toxicities 
or fatigue occur at grade 1, maintain doses of 


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capecitabine and sorafenib/placebo.  No dose 
modification is required for any occurrence of Grade 1 
fatigue, dermatologic toxicity or gastrointestinal toxicity.  
The investigator should use symptomatic treatment to 
alleviate the toxicity.
Grade 2 or Grade 3:
If dermatologic toxicities, gastrointestinal toxicities, or 
fatigue occur at Grade 2 or Grade 3, both drugs 
(ie, capecitabine and sorafenib) should be held until the 
toxicity resolves to Grade 1 or less. 
The algorithm in Table 4-17 should be followed for dose 
modifications when re-starting study treatment.  This 
algorithm should also be used for each recurrence of 
these toxicities to determine which drug (ie, capecitabine 
or sorafenib) should be reduced.  Actions to be taken at 
each occurrence are outlined below.
At the first occurrence of Grade 2 or Grade 3 fatigue, 
dermatologic toxicity, and/or gastrointestinal toxicity, the 
dose of capecitabine should be reduced by one dose level 
when restarting study treatment (see Table 4-13).  
Sorafenib should be restarted at the same dose as prior to 
the onset of the event(s).
At the second occurrence of Grade 2 or Grade 3 fatigue, 
dermatologic toxicity, and/or gastrointestinal toxicity, the 
dose of sorafenib/placebo should be reduced by one dose 
level when restarting study treatment (see Table 4-12).  


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Capecitabine should be restarted at the same dose as 
prior to the onset of the event(s).
As a general rule, at any subsequent occurrence of Grade 
2 or Grade 3 fatigue, dermatologic toxicity, and/or 
gastrointestinal toxicity, if the last dose modification was 
made for sorafenib/placebo, sorafenib/placebo should be 
restarted at the same dose as prior to the onset of the 
event(s), and the dose of capecitabine should be reduced 
by one dose level.  If, on the other hand, the last dose 
modification was made for capecitabine, capecitabine 
should be restarted at the same dose as prior to the onset 
of the event(s), and the dose sorafenib/placebo should be 
reduce by one dose level.  
Subjects who continue to experience toxicity and require 
a dose reduction below the lowest dose level of 
capecitabine (500 mg/m2 twice daily) or 
sorafenib/placebo (200 mg/1 placebo tablet twice daily 
every other day) must discontinue study drug.
Grade 4: 
Grade 4 toxicities require both study drugs to be 
discontinued permanently.
New text:
Section 4.5.2.2.3 Dose modification for non-hematologic toxicities
General guidelines for dose modification for toxicities common to both 


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sorafenib and capecitabine
Grade 1:
If any dermatologic toxicities, gastrointestinal toxicities 
or fatigue occur at grade 1, maintain doses of 
capecitabine and sorafenib.  No dose modification is 
required for any occurrence of Grade 1 fatigue, 
dermatologic toxicity or gastrointestinal toxicity.  The 
investigator should use symptomatic treatment to alleviate 
the toxicity.
Grade 2 or Grade 3:
If dermatologic toxicities, gastrointestinal toxicities, or 
fatigue occur at Grade 2 or Grade 3, both drugs 
(ie, capecitabine and sorafenib) should be held until the 
toxicity resolves to Grade 1 or less. 
The algorithm in Table 4-17 should be followed for dose 
modifications when re-starting study treatment.  This 
algorithm should also be used for each recurrence of 
these toxicities to determine which drug (ie, capecitabine 
or sorafenib) should be reduced.  Actions to be taken at 
each occurrence are outlined below.
At the first occurrence of Grade 2 or Grade 3 fatigue, 
dermatologic toxicity, and/or gastrointestinal toxicity, the 
dose of capecitabine should be reduced by one dose level 
when restarting study treatment (see Table 4-13).  
Sorafenib should be restarted at the same dose as prior to 
the onset of the event(s).
At the second occurrence of Grade 2 or Grade 3 fatigue, 


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dermatologic toxicity, and/or gastrointestinal toxicity, the 
dose of sorafenib should be reduced by one dose level 
when restarting study treatment (see Table 4-12).  
Capecitabine should be restarted at the same dose as 
prior to the onset of the event(s).
As a general rule, at any subsequent occurrence of Grade 
2 or Grade 3 fatigue, dermatologic toxicity, and/or 
gastrointestinal toxicity, if the last dose modification was 
made for sorafenib, sorafenib should be restarted at the 
same dose as prior to the onset of the event(s), and the 
dose of capecitabine should be reduced by one dose level.  
If, on the other hand, the last dose modification was 
made for capecitabine, capecitabine should be restarted 
at the same dose as prior to the onset of the event(s), and 
the dose sorafenib should be reduce by one dose level.  
Subjects who continue to experience toxicity and require 
a dose reduction below the lowest dose level of 
capecitabine (500 mg/m2 twice daily) or sorafenib 
(200 mg tablet twice daily every other day) must 
discontinue study drug.
Grade 4: 
Grade 4 toxicities require both study drugs to be 
discontinued permanently.
Section 4.5.2.3.4, Dose modification and management of sorafenib-specific toxicities
Old text:


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Sorafenib dose modifications or delays will not impact capecitabine therapy.  Subjects who 
require a delay or dose modification of sorafenib/placebo should continue to receive 
capecitabine as scheduled.
New text:
Section 4.5.2.2.4 Dose modification and management of sorafenib-specific toxicities
Sorafenib dose modifications or delays will not impact capecitabine therapy.  Subjects who 
require a delay or dose modification of sorafenib should continue to receive capecitabine 
as scheduled.
Section 4.5.2.3.6, Dose modification for other non-hematologic toxicities (excluding 
fatigue, dermatologic toxicities, gastrointestinal toxicities, hypertension and toxicities 
attributable to capecitabine)


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Old text:
Table 4-19:  Dose Modification for Other Non-Hematologic Toxicities (Excluding Fatigue, Dermatologic Toxicities, 
Gastrointestinal Toxicities, Hypertension and Toxicities Attributable to Capecitabine)
Toxicity 
Grade
Occurrence
Sorafenib
Capecitabine
Dose 
Interruption
Dose 
Reduction
Dose 
Interruption
Dose 
Reduction
Grade 1
Any
None
None
None
None
Grade 2
First
None
None
Delay until 
resolved to 
Grade 1 or 
less
Resume 
at full 
dose
Subsequent
None
None
Delay until 
resolved to 
Grade 1 or 
less
Reduce
dose by 
one dose 
levela,b
Grade 3
Any
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Grade 4
Any
Discontinue 
study drug
—
Discontinue 
study drug
—
a:  If recovery is not achieved after 21 days of interruption, study drug should be discontinued. 
b:  Subjects who continue to experience toxicity and require a dose reduction below the lowest dose level of 
capecitabine (500 mg/m2 twice daily) or sorafenib/placebo (200 mg/1 placebo tablet twice daily, every other day) must 
discontinue study drug.


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Table 4-19:  Dose Modification for Other Non-Hematologic Toxicities (Excluding Fatigue, Dermatologic Toxicities, 
Gastrointestinal Toxicities, Hypertension and Toxicities Attributable to Capecitabine)
Toxicity 
Grade
Occurrence
Sorafenib
Capecitabine
Dose 
Interruption
Dose 
Reduction
Dose 
Interruption
Dose 
Reduction
Occurrences should include events in Study 12444
New text:
Section 4.5.2.2.6 Dose modification for other non-hematologic toxicities (excluding fatigue, dermatologic toxicities, 
gastrointestinal toxicities, hypertension and toxicities attributable to capecitabine)
Table 4-12:  Dose Modification for Other Non-Hematologic Toxicities (Excluding Fatigue, Dermatologic Toxicities, 
Gastrointestinal Toxicities, Hypertension and Toxicities Attributable to Capecitabine)


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Toxicity 
Grade
Occurrence
Sorafenib
Capecitabine
Dose 
Interruption
Dose 
Reduction
Dose 
Interruption
Dose 
Reduction
Grade 1
Any
None
None
None
None
Grade 2
First
None
None
Delay until 
resolved to 
Grade 1 or 
less
Resume 
at full 
dose
Subsequent
None
None
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Grade 3
Any
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Delay until 
resolved to 
Grade 1 or 
less
Reduce 
dose by 
one dose 
levela,b
Grade 4
Any
Discontinue 
study drug
—
Discontinue 
study drug
—
a:  If recovery is not achieved after 21 days of interruption, study drug should be discontinued. 
b:  Subjects who continue to experience toxicity and require a dose reduction below the lowest dose level of 
capecitabine (500 mg/m2 twice daily) or sorafenib (200 mg tablet twice daily, every other day) must discontinue study 
drug.
Occurrences should include events in Study 12444


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Section 4.5.3.2, Erlotinib
Old text:
4.5.3.2 Erlotinib
Erlotinib tablets are manufactured by Schwartz Pharma Manufacturing, Inc. for OSI 
Pharmaceuticals, Inc. 
The tablet formulation consists of erlotinib and the excipients lactose monohydrate, 
hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, 
sodium starch glycolate, sodium lauryl sulfate, and titanium dioxide.  The 25 mg, 100 mg, 
and 150 mg strengths are supplied as round white, film-coated, bi-convex tablets with no
imprint. The active compound of erlotinib is N-(3-ethynylphenyl)-6, 7-bis(2-
methoxyethoxy)-4-quinazolinamine and its molecular weight is 429.90 Daltons.
Supply, packaging, labeling and storage
The erlotinib tablets will be supplied in high-density, polyethylene bottles of 30 tablets each.  
The bottles will have a tamper-evident seal and a child-resistant cap.  Each bottle of
erlotinib will have a 1-panel standard label or booklet label affixed.  For the 100 mg and 
150 mg erlotinib doses, two bottles will be further packaged into a subject pack with a 2-
panel standard label or booklet label affixed.  For the 50 mg erlotinib dose, four bottles of 
erlotinib 25 mg tablets will be further packaged into a subject pack with a 2-panel standard 
label or booklet label affixed.  One panel of the label will be permanently attached to the 
subject pack while the other portion will be a tear-off section that will be appended to the 
dispensing documentation. This label will contain the study ID, sponsor ID, contents, 
directions for use, storage requirements, batch, and investigational use statement as well as 
spaces to record the subject number and date dispensed. The label will also include any 


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other text as required by local law and legislation. Each subject pack label will also have a 
unique pack number.  The labels on the bottles within the pack will have the same pack 
number.  The labels will not contain any unblinding information. Erlotinib must be stored 
at room temperature and not above 25°C (77°F).
Once the study medication has been received, it must be stored in a dry, secure location (ie, 
locked cabinet) accessible only to authorized staff.  
The study drug must be used exclusively for the investigation specified in this protocol.  
The investigative site must acknowledge receipt of drug supplies.  Generally, 
acknowledgement for this study will be done using the IVRS/IWRS system.  The 
confirmation of receipt sent by the IVRS/IWRS system must be printed and filed 
appropriately in the investigative site file.  Occasionally, the IVRS/IWRS may not be 
available.  The site will be instructed on using the Dispatch Order Form for 
acknowledgment in that situation.  The CRA will instruct the site on how to sign the 
Dispatch Order Form and return it to the shipping unit.
Only the investigator or a person(s) assigned will be allowed to dispense the study 
medications to the subject.  To have complete control over the distribution and use of study 
drugs, drug accountability must be performed at every subject visit.  Empty bottles/blisters 
must be returned to the investigator along with all unused medication.  Drug accountability 
will be performed throughout the study.  Destruction of all unused material (ie, empty 
bottles, unused tablets, etc) must be documented and performed per standard operating 
procedures.  One copy of the destruction certificate must be kept in the investigator’s file 
and the other copy must be sent to the Bayer representative.
New text:
None


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Section 4.5.3.3, Capecitabine
Old text:
4.5.3.3 Capecitabine
Sponsor-supplied capecitabine 150-mg and 500-mg tablets will be supplied in child-
resistant blister packs (wallets) of 20 tablets each.  Each blister pack of capecitabine will 
have a 2-panel standard label or booklet label affixed.  One portion of the label will be 
permanently attached to the subject pack while the other portion will be a tear-off section 
that will be appended to the dispensing documentation.  This label will contain the trial ID, 
sponsor ID, contents, directions for use, storage requirements, batch, and investigational 
use statement as well as spaces to record the subject number and date dispensed.  The label 
will also include any other text as required by local law and legislation.  The capecitabine 
must be stored in its original, immediate package at a temperature not above 30°C (86°F).  
Alternatively, capecitabine may be supplied locally according to institutional procedures or 
may be supplied by the sponsor to the site in locally available commercial packaging 
labeled for the study
New text:
Capecitabine is commercially approved for breast cancer and readily available in many 
countries including generic sources. Subjects on treatment with both capecitabine and 
sorafenib at the end of the 12444 RESILIENCE trial who are switched to the STEP study 
will switch to commercial supply capecitabine. In addition, subjects will continue to receive 
sorafenib as clinical supply.


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Section 4.5.5, Selection of Doses in the Study
Old text:
Patients will receive sorafenib (Nexavar) 200 mg tablets and should continue receiving the 
same dose they were receiving in their original trial. Patients receiving sorafenib/erlotinib or 
sorafenib/capecitabine combination should continue the same doses as in the originating 
trial.
New text:
Patients will receive sorafenib (Nexavar) 200 mg tablets and should continue receiving the 
same dose they were receiving in their original trial. Patients receiving sorafenib or 
sorafenib/capecitabine combination should continue the same doses as in the originating 
trial.
Section 4.5.6, Selection and Timing of Dose for Each Subject
Old text:
The patient should continuing receiving the same dose they were receiving in the previous 
trial.  Dose increase beyond the dose the patient is currently receiving is not acceptable.
Sorafenib (Nexavar), erlotinib, and capecitabine may be decreased in the event of toxicity 
based on the Dose Modification criteria outlined in Section 4.5.2.
New text:
The patient should continuing receiving the same dose they were receiving in the previous 
trial.  Dose increase beyond the dose the patient is currently receiving is not acceptable.


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Sorafenib (Nexavar) and capecitabine may be decreased in the event of toxicity based on the 
Dose Modification criteria outlined in Section 4.5.2.
Section 4.5.8, Prior and Concomitant Therapy
Old text:
Non-permissible concomitant medication/therapies:

Anticancer chemotherapy, except erlotinib and capecitabine, immunotherapy or live
vaccines during the study.
New text:
Non-permissible concomitant medication/therapies:

Anticancer chemotherapy, except TACE and capecitabine, immunotherapy or live
vaccines during the study.


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Section 11.1, Study Flow Chart
Old text:
Activity
Visit 1
Minimum 
Every
8 weeks
End of 
Treatment
Demography a, b
X
Pregnancy Test
X
Vital signs
X
X
X
ECOG performancea
X
X
X
Survival status (dead or alive, date of death or 
date of last contact, as applicable)
X
Xd
Adverse events a
All treatment related
All Grade 3 or higher regardless of 
attribution
All serious adverse events
X
X
X
X
X
X
X
X
X
Laboratory evaluations a
Hematology (Hgb, RBC, WBC, 
platelets, differential)
CBC (ALT, AST, amylase, lipase)
PT-INR c
X
X
X
X
X
X
X
X
X
Dispense/return sorafenib (and erlotinib or
capecitabine if applicable)a
X
X
X
Reason for termination of treatment a
X
Concomitant medications
X
X
X
a
Record these data in the CRF and source documents.
b
Includes originating study number, patient number and date of first sorafenib dose in originating 
study.
c
For anticoagulated patients only
d
For patients in long term follow up, survival status is assessed at a minimum of every 3 months


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New text:
Activity
Visit 1
Minimum 
Every
8 weeks
End of 
Treatment
Demography a, b
X
Pregnancy Test
X
Vital signs
X
X
X
ECOG performancea
X
X
X
Survival status (dead or alive, date of death or 
date of last contact, as applicable)
X
Xd
Adverse events a
All treatment related
All Grade 3 or higher regardless of 
attribution
All serious adverse events
X
X
X
X
X
X
X
X
X
Laboratory evaluations a
Hematology (Hgb, RBC, WBC, 
platelets, differential)
CBC (ALT, AST, amylase, lipase)
PT-INR c
X
X
X
X
X
X
X
X
X
Dispense/return sorafenib (and capecitabine if 
applicable)a
X
X
X
Reason for termination of treatment a
X
Concomitant medications
X
X
X
a
Record these data in the CRF and source documents.
b
Includes originating study number, patient number and date of first sorafenib dose in originating 
study.
c
For anticoagulated patients only
d
For patients in long term follow up, survival status is assessed at a minimum of every 3 months


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10.5
Amendment 7
Date of amendment: 15 MAY 2018, v6.0.
10.5.1
Modification 1: Change of responsibility for Sponsor’s Medical Expert, 
Study Manager, Statistician, Global Clinical Lead and Principal 
Investigator
Description of modification to the title page:
On the title page of the protocol, Sponsor’s address was updated, Sponsor’s address (US 
territory) was added. Also, the contact names for the Study Manager, Statistician and Global 
Clinical Lead were updated. In addition, the Principal Investigator’s contact name and 
address were updated.
Rationale:
Personnel change in study team and Principal Investigator.
List of affected section:
Section Title page – amended.
10.5.2
Modification 2: Overall survival (OS) evaluation removed from the study 
objectives
Description of modification to the study plan:
The overall survival (OS) evaluation has been removed from the study objectives.
Rationale:
Given that the primary study objective is to enable patients receiving sorafenib (Nexavar) in a 
completed Bayer/Onyx sponsored clinical trial to continue treatment, the data on OS is not  
being utilized for any analyses. Therefore, to minimize burden to patients and sites, OS data 
collection at follow up will no longer be performed and OS will be removed as a study 
objective.
List of effected sections:
Sections 2, 4.6.1, 6.1
10.5.3
Modification 3: Safety visits
Description of modification to the study design and plan:
The patients should be evaluated by a study physician for safety at least once every 8 weeks
and more frequently as needed. The protocol allows for a ±7 day window when scheduling 
any visit. Physicians can choose to continue to see the patients every 8 weeks in a face to face 
visit. At least every other visit must be a mandatory on site visit for examination and drug 


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dispensing, with the other visit being either in person or as a phone call. It is at the discretion 
of the investigator based on the patient’s current condition and adverse event profile to 
determine if the next visit will be performed on site or as a phone visit. Any scheduled phone 
visit is mandatory and it will be at the discretion of the investigator to decide if that phone 
visit is sufficient. If the patient needs a physical examination, the visit will be performed on 
site. If the investigator feels the patient is stable with no new safety concerns nor new AEs in 
between visits, a phone call with labs, ECOG and review of AEs would be enough.
Rationale:
To lessen the travel burden on patients and enable better compliance at site while ensuring 
patient’s safety. It is at the discretion of the Investigator and based on the patient’s current 
condition to determine if the visit will be performed on site or as a phone call.
The protocol allows for a ±7 day window when scheduling any visit.
List of affected sections:
Sections 4.1, 4.6.3, 11.1
10.5.4
Modification 4: Laboratory evaluations
Description of modification to the study design and plan:
The laboratory evaluations were modified.
Rationale:
To ensure that the laboratory evaluations were not missed.
List of affected section:
Section 4.1
10.5.5
Modification 5: Follow-up period changed
Description of modification to the study objectives:
FU period was changed from until survival to until 30 days after last dose of study drug. 
Overall survival is removed from the objective. 
Rationale:
This would allow some sites with only patients in survival follow-up for years to close, and to 
minimize burden to patients and to enable better compliance at sites.
List of affected sections:
Sections 4.6.3, 11.1


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10.5.6
Modification 6: Editorial changes, corrections and clarifications
Description of modification to the study plan / Rationale:
The minor editorial changes are not shown by footnotes in the body text.

Cover page added

Minor text revisions and corrections
List of affected sections:
Sections 1, 2, 3, 4, 4.5.6, 5, 6, 7, 8, 9, 10, 11
10.6
Amendment 8
Date of amendment: 26 MAY 2020, v7.0.
10.6.1
Modification 1: Change of responsibility for Sponsor’s Medical Expert, 
Study Manager, Statistician, Medical Expert, and Global Clinical Lead
Description of modification:
Change of study team members on the title page of the protocol; the Sponsor’s Medical 
Expert’s role is now filled by the Clinical Development Leader (CDL), and the respective 
contact information was updated. Further, contact names for the Study Manager, and 
Statistician were updated. In addition, the signature of the Global Clinical Lead was removed 
as this role is now filled by the CDL.
Rationale:
The role name and personnel change in study team.
List of affected section:
Section Title page – amended.
10.6.2
Modification 2: Added new eSignature text
Description of modification:
New eSignature text added.
Rationale:
New eSignature process implemented at Bayer.
List of affected section:
Section Title page – amended.


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10.6.3
Modification 3: Added Post-Trial Access Program
Description of modification:
For completeness added that, at least in theory, Sorafenib study patients can continue to 
receive the treatment (study drug) not only through a subsequent clinical but also through a 
Post-Trial Access Program or any other mechanism (e.g. local access program).
Rationale:
To provide the investigator with information on further potential post-study drug supply
mechanisms for sorafenib that are without costs to the patients.
List of affected sections:
Sections 1.
10.6.4
Modification 4: Removal of the instructions for dose modifications for 
the combination of sorafenib with capecitabine and TACE
Description of modification:
In Section 4.5.2.2, its subsections and Section 4.5.2.3 the instructions for dose modifications 
for the combination of sorafenib with capecitabine and TACE were removed.
In addition, explaining text as to why sorafenib combination therapy sections were removed 
was added to Section 4.5.2.2 and 4.5.2.3.
Rationale:
As of Amendment 8 there are no patients receiving combination therapy with capecitabine or 
TACE. The sections were removed to avoid confusion for the remaining patients none of 
whom are receiving capecitabine or TACE.
List of affected sections:
Sections 4.5.2.2, its subsections and 4.5.2.3.
10.6.5
Modification 5: Added clarification for continuation on study drug
Description of modification:
Added further options that can lead to the end of study treatment in the STEP study These are
the transfer to a Post-Trial-Access Program, another study or any other mechanism (e.g. local 
access program) in accordance with local legal without costs to the patient with respect to 
sorafenib.
Rationale:


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To allow physicians to stop the study treatment not only if the patient is no longer benefitting 
from the treatment or the treatment becomes commercially available/is reimbursed, but also if 
there is one of the following options available: a Post-Trial-Access Program, another study or 
any other mechanism (e.g. local access program) in accordance with local legal and 
compliance rules with no cost to the patient with respect to sorafenib.
List of affected section:
Section 2 and 4.1.
10.6.6
Modification 6: Added clarification for ending the study
Description of modification:
Added option to end this study when all patients have transitioned or discontinued from the 
study.
Rationale:
To clarify when the STEP study will end if an alternative mechanism of continued drug 
supply is established. 
List of affected section:
Section 4.1.
10.6.7
Modification 7: Added clarification on last patient last visit date
Description of modification:
Added clarification on the definition of the end of study.
Rationale:
To define under what circumstances LPLV for this study will be achieved, which includes 
patients stopping study drug or being switched to receive treatment through an alternative 
mechanism of sorafenib supply. 
List of affected sections:
Sections 4.9.
10.6.8
Modification 8: Removed reference to Study Sites in Japan
Description of modification:
Removed reference regarding Japanese regulatory requirements for Japanese study sites.
Rationale:
There are no patients on treatment from any Japanese study sites.


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List of affected sections:
Sections 4.4, 4.5.3.1, 4.6.2, 4.6.3, 5.1, 7.3.2 and 7.3.6.
10.6.9
Modification 9: Corrected timepoint
Description of modification:
The timepoint of the performance of the analyses was corrected, last patient last visit was 
changed to “after the end of the study”.
Rationale:
For further clarity.
List of affected section:
Section 6.1.
10.6.10 Modification 9: Editorial changes, corrections and clarifications
Description of modification:
The minor editorial changes are not shown by footnotes in the body text. In addition to the 
changes summarized above, minor changes were made to correct typographical errors, and 
add clarity.
List of affected sections:
Sections Cover page of the integrated protocol, Glossary and Abbreviations, 1, 2, 4.1, 4.2, 
4.2.2, 4.5.3.1, 10.


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11.
Appendices
11.1
Study Flow Chart
Activityzzzz
Visit 1
Minimum Every
8 weeks
(±7 days)aaaaa
End of 
Treatment
Demography a, b
X
Pregnancy Test
X
Vital signs
X
X
X
ECOG performancea
X
X
X
Survival status (dead or alive, date of death or 
date of last contact, as applicable)bbbbb
X
Xd
Adverse events a
All treatment related
All Grade 3 or higher regardless of 
attribution
All serious adverse events
X
X
X
X
X
X
X
X
X
Laboratory evaluations a
Hematology (Hgb, RBC, WBC, 
platelets, differential)
CBC (ALT, AST, amylase, lipase)
PT-INR c
X
X
X
X
X
X
X
X
X
Dispense/return sorafenib (and
ccccc
capecitabine if applicable ddddd)a
X
X
X
Reason for termination of treatment a
X
Concomitant medications
X
X
X
a
Record these data in the CRF and source documents.
b
Includes originating study number, patient number and date of first sorafenib dose in originating 
study.
c
For anticoagulated patients only
d
The long term follow up period is until 30 days after last dose of study drug.eeeee fffff
                                                
zzzz:  The text row regarding date of death was deleted in Amendment 3. See Section 10.3, Modification 6.
aaaaa The visit window has been modified by Amendment 7. See Section 10.5.3, Modification 3.
bbbbb: The text row concerning survival was added in Amendment 3. See Section 10.3, Modification 1.
ccccc Reference to erlotinib removed since none of the subjects that transferred into this study were assigned to 
erlotinib from study 12917. See Section 10.4, Modification 2.
ddddd: Participation of subjects from the SEARCH trial (Study 12917) or the RESILIENCE trial (Study 12444) 
was added under Amendment 3.  See Section 10.3, Modification 5
eeeee:  The table footnote regarding assessment of survival was added in Amendment 3. See Section 10.3,
Modification 1.
fffff The table footnote was revised to change the FU period to until 30 days after last dose of study drug in 
Amendment 7. See Section 10.5.5, Modification 5.


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11.2
New York Heart Association Criteria
Functional Capacity
Class I:  Patients with cardiac disease but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
Class II:  Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitations, dyspnea, or anginal pain.
Class III:  Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitations, dyspnea, or anginal pain.
Class IV:  Patients with cardiac disease resulting in ability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort is 
increased.


Integrated Clinical Study Protocol Amendment 8
BAY 43-9006 / 12311
26 MAY 2020
Version 7.0
Page: 147 of 147
11.3
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light housework, office work). 
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5
Death

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
Sorafenib Long Term Extension Program (STEP) 
NCT Number: 
NCT00625378 
Document Date: 
22 JUN 2021 
 
 


Statistical Analysis Plan
BAY 43-9006/12311
Page: 1 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
Title page
Sorafenib Long Term Extension Program (STEP)
Bayer study drug
Sorafenib/Nexavar®  BAY 43-9006
Study purpose:
The primary purpose of program is to enable patients, currently 
receiving sorafenib (Nexavar) in a Bayer/Onyx sponsored clinical 
trial, to continue sorafenib treatment after their respective study has 
met its primary endpoint and/or has reached the end as defined in the 
original protocol.
Clinical study 
phase:
IIIb
Date:
22 JUN 2021
Study No.:
12311
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
BAY 43-9006/12311
Page: 2 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
Table of Contents
Title page................................................................................................................................... 1
Table of Tables ......................................................................................................................... 2
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
4.1
General Principles............................................................................................................ 4
4.2
Handling of Dropouts ...................................................................................................... 5
4.3
Handling of Missing Data................................................................................................ 5
4.4
Interim Analyses and Data Monitoring ........................................................................... 5
4.5
Data Rules........................................................................................................................ 5
4.6
Blind Review ................................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 6
5.1
Assignment of analysis sets ............................................................................................. 6
6.
Statistical Methodology .................................................................................................... 6
6.1
Population characteristics ................................................................................................ 6
6.2
Efficacy............................................................................................................................ 7
6.3
Pharmacokinetics/pharmacodynamics............................................................................. 7
6.4
Safety ............................................................................................................................... 7
7.
Document history and changes in the planned statistical analysis............................... 8
8.
References .......................................................................................................................... 8
Table of Tables
Table 1–1: Patient numbers of study 12311 by feeder trial ....................................................... 3


Statistical Analysis Plan
BAY 43-9006/12311
Page: 3 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
Abbreviations
AE
Adverse event
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
ECOG
Eastern Cooperative Oncology Group
GMS
Global Medical Standards
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
SAE
Serious adverse event
SAP
Statistical Analysis Plan
STEP
Sorafenib Long-Term Extension Program
TAS
Therapeutic Area Standards
1.
Introduction
Experience has shown that in nearly all clinical trials with sorafenib (Nexavar®) there are 
patients who are continuing to receive sorafenib after the study has met its primary endpoint. 
The only process to provide sorafenib to these patients who have a non-approved/reimbursed 
tumor type is through a clinical trial. The intention of this program is to enable patients who 
are still benefiting from treatment in a completed clinical trial to continue to receive 
treatment.
This SAP is based on the integrated clinical study protocol amendment 8, version 7.0, dated 
26 MAY 2020, and describes the final statistical analysis methods for the STEP study.
All feeder trials, providing patients to this study are listed in below table.
Table 1–1: Patient numbers of study 12311 by feeder trial
Feeder trial number
Number of Patients,  n (%)
100375
3      (1.5)
100554
24      (11.7)
100557
1      (0.5)
10874
1      (0.5)
10916
1      (0.5)
11213
18      (8.7)
11538
3      (1.5)
11546
1      (0.5)
11559
1      (0.5)
11718
1      (0.5)
11721
6      (2.9)
11848
12      (5.8)
11849
1      (0.5)
11868
5      (2.4)
11941
65      (31.6)
11961
7      (3.4)
11988
3      (1.5)
12007
4      (1.9)
12347
2      (1)
12782
4      (1.9)
12913
7      (3.4)
12917
7      (3.4)
12918
4      (1.9)
13266
5      (2.4)
14295
7      (3.4)
14898
13      (6.3)
Total
206      (100)


Statistical Analysis Plan
BAY 43-9006/12311
Page: 4 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
2.
Study Objectives
The primary purpose of this program is to enable patients, currently receiving sorafenib 
(Nexavar) in a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their 
respective study has met its primary endpoint and/or has reached the end as defined in the 
original protocol.
Patients will be able to continue treatment until (i) the treating physician feels the patient is no 
longer benefiting from the treatment or (ii) the treatment becomes commercially available and 
reimbursed for the respective indication as applicable in the country in which the patient lives 
and the patient can obtain suitable amounts of drug for treatment through standard 
mechanisms of commercial availability (i.e., there should be no interruption in the patient’s 
treatment schedule when switching to commercially available product) or (iii) the patient can 
join a Post-Trial-Access Program, another study or can receive sorafenib through any other 
mechanism (e.g. local access program) in accordance with local legal and compliance rules, 
with no cost to the patient with respect to sorafenib.
An additional objective is the assessment of the safety of Nexavar or Nexavar combination 
treatment.
3.
Study Design
This is an open label program that will enable patients receiving sorafenib (Nexavar) in a 
completed Bayer/Onyx sponsored clinical trial to continue treatment. A completed study is 
one that has passed the official statistical and regulatory endpoints and/or has reached its end, 
as outlined in that protocol. The patients in this open-label program will continue receiving 
sorafenib treatment at the same dose and schedule as in their original Clinical Trial.
Patients will continue receiving treatment, as long as the treating physician feels the patient is 
continuing to benefit from treatment or until treatment becomes commercially available and 
reimbursed for the respective indication in the country in which the patient lives or until being 
switched to any other form of drug supply with no interruption in the patient’s treatment 
schedule.  The patient may also continue treatment until he/she withdraws consent, is non-
compliant, is lost to follow up, or if an unacceptable toxicity occurs.
Further details can be found in the protocol.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA).
The creation of tables will follow the Bayer Therapeutic Area Standards (TAS) for Oncology 
and the Global Medical Standards (GMS).


Statistical Analysis Plan
BAY 43-9006/12311
Page: 5 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, mean, standard deviation, minimum, quartiles, median, and maximum will 
be calculated for metric data. Frequency tables will be generated for categorical data.
The analysis is limited to the data coming from this study.
Tables will be created by treatment group (sorafenib monotherapy, sorafenib+erlotinib). For 
the disposition data, baseline data and ECOG data, the total will also be displayed. Safety data 
(adverse events, laboratory data) will not be combined across the treatment groups. Since 
there is only one patient with sorafenib+erlotinib treatment, safety data from the patient with 
sorafenib+erlotinib will only be listed.
4.2
Handling of Dropouts
Not applicable.
4.3
Handling of Missing Data
Missing data will not be imputed for statistical analysis.
4.4
Interim Analyses and Data Monitoring
Not applicable.
4.5
Data Rules
Baseline value for laboratory measurements and ECOG performance status are the last non-
missing values documented before or on the day of first study medication administration in 
the STEP study.
In this study, adverse events (AEs) ongoing from previous study could also be documented in 
addition to newly occurring AEs. Since the STEP data are not combined with data from the 
feeder trials, the start and stop dates of sorafenib treatment in the feeder trial are not available 
and it cannot be derived if the ongoing AEs are treatment-emergent or not. The ongoing AEs 
will therefore be analyzed separately and not termed ‘treatment-emergent’. AEs in STEP are 
considered as treatment-emergent, if they start or worsen from enrolment date in STEP and up 
to 30 days after the last sorafenib dose. New non-treatment emergent AEs are those that start 
later than 30 days after last sorafenib treatment. 
The investigator should document the AE start date and additionally tick if an AE was 
ongoing from previous study or not. The assignment if an AE is ongoing or new will be 
primarily based on the AE start date and will be done according to the following rules:
-
Any AE documented on or after enrolment date in STEP will be considered as new.
-
Any AE with start date before STEP enrolment date will be considered as ongoing.
-
In case the AE start is partially missing (i.e. day and/or month are missing), the date 
will be imputed as specified below.
-
If the AE start date is completely missing, the answer to the question ‘Ongoing from 
previous study’will be used – ‘yes’ indicates the AE is ongoing, ‘No’ indicates the AE 
is new.
The following imputation will be used for partially missing AE start date, whenever it is 
necessary to assign the AE to the ‘ongoing’ or ‘new’ category:


Statistical Analysis Plan
BAY 43-9006/12311
Page: 6 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
-
If only the day is missing, the first of the month will be used, except if the start 
month/year are equal to enrolment month/year, then the start day of enrolment will be 
used.
-
If day and month are missing, then 1st of July will be used, except if the start year is 
equal to the enrolment year, then the start day/month of enrolment will be used.
4.6
Blind Review
The results of the final data assessment will be documented in the validity findings and 
assignment to analysis sets. Any changes to the statistical analysis prompted by the results of 
the  review of study data will be documented in an amendment and, if applicable, in a 
supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of the study data and documented in the validity findings and analysis sets (see 
Section 4.6).
Full analysis set (FAS) = All enrolled subjects
All subjects who signed informed consent for STEP are contained in the FAS. This analysis 
set will be used for disposition tables and subject data listings.
Safety analysis set (SAF)
The population for safety analysis will be comprised of all subjects who received at least one 
dose of study medication. The SAF will be used for the analyses of the population 
characteristics and baseline variables, treatment duration, ECOG performance status, and all 
safety parameters.
6.
Statistical Methodology
6.1
Population characteristics
The number and percentage of subjects enrolled will be displayed by feeder trial. The number 
and percentage of subjects enrolled as well as the reason for termination of treatment will be 
summarized.
Baseline characteristics and demographics (age, sex, race, diagnosis of cancer, and ECOG 
performance status) will be summarized for the time point entering this study 12311; as 
documented in 12311. Age will also be categorized as 15-17, 18–64, 65-74, 75-84, ≥85 years, 
as applicable.


Statistical Analysis Plan
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Reference Number: RD-SOP-1119
Supplement Version: 10
6.2
Efficacy
Not applicable.
6.3
Pharmacokinetics/pharmacodynamics
Not applicable.
6.4
Safety
Descriptive statistics will be calculated for the treatment duration. Duration of study treatment 
within STEP will be calculated in days as the date of the last dose of any study treatment –
date of the first dose of any study treatment + 1. Duration in months will be presented in 
months, calculated by dividing days by 30.4. In addition to the descriptive statistics 
referenced in section 4.1, the sum of all treatment durations will also be calculated.
Adverse Events (AEs) will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). AE grading will be documented using 
version 3.0 of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE).
In STEP, AEs ongoing from previous study as well as new AEs occurring during STEP were 
collected. AEs will be classified as ‘ongoing AE’, ‘new treatment-emergent AE’ or ‘new non 
treatment-emergent AEs after 30 days after last sorafenib dose’ (see Section 4.5). Tables will 
be created for ongoing AE, new treatment-emergent AE, and the combination of both. New 
non treatment-emergent AEs after 30 days after last sorafenib dose will only be listed.
AEs will be summarized by counts and incidence proportions, and grouped by MedDRA 
system organ class, MedDRA preferred term, and worst CTCAE grade, for the following:

New TEAEs in STEP:
o
TEAE
o
Drug-related TEAE
o
TEAE leading to dose reduction
o
Drug-related TEAE leading to dose reduction
o
TEAE leading to dose interruption
o
Drug-related TEAE leading to dose interruption
o
TEAE leading to drug discontinuation
o
Drug-related TEAE leading to drug discontinuation
o
TESAE
o
Drug-related TESAE
o
TEAEs leading to death
o
Drug-related TEAEs leading to death

Ongoing AEs from feeder studies: 


Statistical Analysis Plan
BAY 43-9006/12311
Page: 8 of 8
Reference Number: RD-SOP-1119
Supplement Version: 10
o
AEs
o
Drug-related AEs
o
SAEs
o
Drug-related SAEs

All AEs in STEP (ongoing AEs from feeder studies + new TEAEs in STEP)
o
AEs
o
Drug-related AEs
o
SAEs
o
Drug-related SAEs
The numbers of deaths and the primary cause of death (as reported by the investigator) will be 
tabulated and listed. 
Hematology and blood chemistry values will be summarized according to their worst CTCAE 
grade, where applicable. Hematology and blood chemistry values will be graded based on the 
applicable laboratory threshold values outlined in NCI CTCAE version 3.0.
Individual time courses of ECOG performance status will be displayed graphically. 
Frequencies of the ECOG performance status categories will be summarized for baseline and 
per 6-month time interval, using the last value per 6-month time interval.
7.
Document history and changes in the planned statistical analysis
Not applicable.
8.
References
Not applicable.