Clinical trial NCT03890731
Conditions: Solid Cancer
Keywords: Metastatic colorectal cancer (mCRC) Renal cell cancer Gastro-intestinal stromal tumor Hepatocellular carcinoma
Sponsor: Bayer
Start date: 2019-04-02; Completion date: 2023-02-28
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to enable participants, currently receiving regorafenib in a Bayer-sponsored clinical trial, to continue treatment after their respective study has been closed. Patients participating in this study will be observed to collect information on how safe the drugs are and how this treatment is tolerated.

Detailed description:
The primary objectives of the study are a) to allow patients from Bayer-sponsored trials to continue regorafenib treatment after their respective study has been completed, and b) to further assess the safety of regorafenib. Secondary objective is the documentation of drug tolerability.

Arms: arm 1: Adult patients from completed Bayer-sponsored regorafenib trials who are benefitting from regorafenib treatment.
Interventions: intervention 1: BAY73-4506 (Regorafenib, Stivarga)
Intervention descriptions: intervention 1: Regorafenib is administered orally as 20 or 40 mg tablets at the dose that each patient received during the last cycle of the feeder trial. The dose may be either 60, 80, 120 or 160 mg once daily for 3 weeks of every 4-week cycle (3 weeks on, 1 week off).

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A single arm, open-label, multicenter Phase 2 study of regorafenib 
in participants who have been treated in a previous Bayer-
sponsored regorafenib study (monotherapy or combination 
treatment) that has reached the primary completion endpoint or the 
main data analysis, or has been stopped prematurely. 
NCT Number: 
NCT03890731 
Document Date: 
20 NOV 2018 
 


CONFIDENTIAL
Clinical Study Protocol 
BAY 73-4506 / 20328
Amendment 1
Title Page
Protocol title:
A single arm, open-label, multicenter Phase 2 study of 
regorafenib in participants who have been treated in a previous 
Bayer-sponsored regorafenib study (monotherapy or combination 
treatment) that has reached the primary completion endpoint or 
the main data analysis, or has been stopped prematurely.
Protocol number:
20328
Compound Number:
BAY 73-4506
Study phase:
Phase 2
Short title:
Regorafenib rollover study.
Sponsor Name and 
Legal Registered 
Address:
Sponsor (Non-US): Bayer AG, D-51368 Leverkusen, Germany
Sponsor (US territory): Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, Whippany, New Jersey 
07981-0915, USA
Regulatory Agency 
Identifier Number(s):
EudraCT  2018-003650-24
Approval Date:
20 NOV 2018
The information provided in this document is strictly confidential and is intended solely for the performance 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) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.


CONFIDENTrAL 
Sponsor Signatory 
 
Clinical Study Protocol 
BAY 73-4506 I 20328 
Amendment I 
Da
Medical Monitor Name and Contact Information will be provided separately. 
Page 2 of43 
PPD
PPD
PPD


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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 1
20 NOV 2018
Original Protocol
27 SEP 2018
Amendment 1 (20 NOV 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Synopsis, 3, 
9, 9.1, 
9.4.1, 9.4.2
Safety was upgraded to a 
second primary objective and a 
respective endpoint was added to 
the protocol. A respective 
endpoint was also added for the 
secondary objective tolerability.
These updates were done to ensure 
compliance with posting requirements 
on CT.gov following a review of the 
initial Protocol Registration Form.
11
List of 4 initial feeder studies in 
Section 11 was removed.
The feeder protocol titles were removed 
from the section “References” to avoid 
any future amendments to enable 
participants of other than the currently 
considered regorafenib studies to enter 
this roll-over study.


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Clinical Study Protocol 
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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Protocol Amendment Summary of Changes Table............................................................... 3
Table of Tables ......................................................................................................................... 6
Table of Figures........................................................................................................................ 6
1.
Protocol Summary ............................................................................................................ 7
1.1
Synopsis........................................................................................................................... 7
1.2
Schema............................................................................................................................. 8
1.3
Schedule of Activities (SoA) ........................................................................................... 9
2.
Introduction..................................................................................................................... 11
2.1
Study Rationale.............................................................................................................. 11
2.2
Background.................................................................................................................... 11
2.3
Benefit/Risk Assessment ............................................................................................... 11
3.
Objectives and Endpoints............................................................................................... 12
4.
Study Design .................................................................................................................... 12
4.1
Overall Design ............................................................................................................... 12
4.2
Scientific rationale for Study Design............................................................................. 13
4.3
Justification for Dose..................................................................................................... 14
4.4
End of Study Definition................................................................................................. 14
5.
Study Population............................................................................................................. 14
5.1
Inclusion Criteria ........................................................................................................... 14
5.2
Exclusion Criteria .......................................................................................................... 15
5.3
Lifestyle Considerations ................................................................................................ 16
5.4
Screen Failures............................................................................................................... 16
6.
Study Intervention .......................................................................................................... 16
6.1
Study Intervention(s) Administered............................................................................... 17
6.2
Preparation/Handling/Storage/Accountability............................................................... 17
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 17
6.4
Study Intervention Compliance ..................................................................................... 17
6.5
Concomitant Therapy .................................................................................................... 17
6.5.1
Drug-drug interactions relevant for regorafenib......................................................... 18
6.5.2
Permitted concomitant therapies ................................................................................ 19
6.5.3
Prohibited prior and concomitant therapies................................................................ 20
6.5.4
Documentation of prior and new concomitant therapies............................................ 21
6.6
Dose Modification ......................................................................................................... 21
6.7
Intervention after the End of the Study.......................................................................... 25
7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal.......................................................................................... 25
7.1
Discontinuation of Study Intervention........................................................................... 25
7.1.1
Temporary Discontinuation........................................................................................ 26
7.1.2
Rechallenge ................................................................................................................ 26
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 26
7.3
Lost to Follow up........................................................................................................... 26


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8.
Study Assessments and Procedures............................................................................... 27
8.1
Efficacy Assessments .................................................................................................... 27
8.2
Safety Assessments........................................................................................................ 27
8.3
Adverse Events and Serious Adverse Events ................................................................ 27
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 28
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 28
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 28
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 28
8.3.5
Pregnancy ................................................................................................................... 29
8.4
Treatment of Overdose .................................................................................................. 29
8.5
Pharmacokinetics........................................................................................................... 30
8.6
Pharmacodynamics ........................................................................................................ 30
8.7
Genetics ......................................................................................................................... 30
8.8
Biomarkers..................................................................................................................... 30
8.9
Medical Resource Utilization and Health Economics ................................................... 30
9.
Statistical Considerations ............................................................................................... 30
9.1
Statistical Hypotheses.................................................................................................... 30
9.2
Sample Size Determination ........................................................................................... 30
9.3
Populations for Analyses ............................................................................................... 30
9.4
Statistical Analyses........................................................................................................ 31
9.4.1
Efficacy Analyses....................................................................................................... 31
9.4.2
Safety Analyses .......................................................................................................... 31
9.4.3
Other Analyses ........................................................................................................... 31
9.5
Interim Analyses............................................................................................................ 31
10. Supporting Documentation and Operational Considerations .................................... 31
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 31
10.1.1
Regulatory and Ethical Considerations ...................................................................... 31
10.1.2
Financial Disclosure ................................................................................................... 32
10.1.3
Informed Consent Process.......................................................................................... 32
10.1.4
Data Protection ........................................................................................................... 32
10.1.5
Dissemination of Clinical Study Data ........................................................................ 33
10.1.6
Data Quality Assurance.............................................................................................. 33
10.1.7
Source Documents...................................................................................................... 34
10.1.8
Study and Site Closure ............................................................................................... 34
10.1.9
Publication Policy....................................................................................................... 34
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 34
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 34
10.3.1
Definition of AE......................................................................................................... 34
10.3.2
Definition of SAE....................................................................................................... 35
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 36
10.3.4
Reporting of SAEs...................................................................................................... 38
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 40
10.5
Appendix 5: Abbreviations............................................................................................ 42
10.6
Appendix 6 CYP3A4 inducers and inhibitors ............................................................... 43
11. References ........................................................................................................................ 43


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Table of Tables
Table 1–1: Schedule of activities ............................................................................................... 9
Table 6–1:  Dose modification levels for regorafenib.............................................................. 21
Table 6–2:  Dose Modification/Delay for Toxicities Related to Study Drug (Except Hand Foot 
Skin Reaction, Hypertension, and ALT and/or AST increases)a,c......................... 22
Table 6–3:  Dose modifications for HFSR related to regorafenib (dose expansion phase) 
(“Palmar-plantar erythrodysesthesia syndrome”) ................................................. 23
Table 6–4:  Recommended dose modification and measures for hypertension....................... 24
Table 6–5:  Dose modification/interruption for ALT/AST increases related to regorafenib... 25
Table 10–1:  An overview of CYP3A4 inducers and strong CYP3A4 inhibitors.................... 43
Table of Figures
Figure 1–1:  Study schema......................................................................................................... 8


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: A single arm, open-label, multicenter Phase 2 study of regorafenib in 
participants who have been treated in a previous Bayer-sponsored regorafenib study 
(monotherapy or combination treatment) that has reached the primary completion endpoint, or 
main data analysis, or has been stopped prematurely.
Short Title: Regorafenib rollover study
Rationale: The primary purpose of the study is to enable participants, currently receiving 
regorafenib in a Bayer-sponsored clinical trial, to continue treatment after their respective 
study has reached the primary completion endpoint, main data analysis, or has been stopped 
prematurely, and the respective data have been cleaned.  Participants will be able to continue 
treatment until the treating physician feels the participant is no longer benefiting from 
treatment.
Objectives 
Objectives
Primary

The primary purpose of the program is to enable participants, currently receiving 
regorafenib in a Bayer-sponsored clinical trial and assessed by the principal 
investigator (PI) to be benefitting, to continue regorafenib treatment after their 
respective study has reached the primary completion endpoint, or main data analysis, 
or has been stopped prematurely.

And the documentation of safety 
Secondary

Documentation of tolerability
Overall Design:
This is an open-label study that will enable participants currently receiving regorafenib in a 
completed Bayer-sponsored regorafenib clinical trial to continue treatment.  A completed 
study is defined as one that has reached the primary completion endpoint, or main data 
analysis, or has been stopped prematurely, and the respective data have been cleaned.
Disclosure Statement: This is an open-label study that will enable participants currently 
receiving regorafenib in a completed Bayer-sponsored regorafenib clinical trial to continue 
treatment.
Number of Participants:
Participants who are currently receiving treatment in on-going regorafenib studies may be 
eligible to enroll in the study. There may be periods when there are no active participants in 
this study but it will remain open for enrollment.


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Intervention Groups and Duration:
The start of the treatment period is defined by the first administration of regorafenib in the 
rollover study. Participants will be treated in 28-day cycles (ie, 3 weeks on, 1 week off) with 
once daily oral administration of regorafenib.  Participants will continue regorafenib treatment 
until any of the discontinuation criteria specified in Section 7.2 occur. 
After permanent discontinuation from the study, an end of treatment (EoT) visit will be 
performed within 14 days after the last dose of regorafenib was administered. Following 
completion of the EoT evaluation, a phone call to monitor safety will take place 30-35 days 
after the last dose of regorafenib was administered.
Data Monitoring Committee: No
1.2
Schema
The design of the study is represented in Figure 1–1.
Figure 1–1:  Study schema


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1.3
Schedule of Activities (SoA)
Table 1–1: Schedule of activities
Procedure
Screeninga
Intervention Periodb [Cycles 
consisting of 4 weeks]
End of study 
treatment
(up to 14 days 
after last 
dose) 
Safety 
Follow-up 
(30-35 days 
after last 
dose, 
phone call)
Notes
Cycle 1 Day 1c
Cycle 4 Day 1 
+ every 3 months
(+/- 1 week) 
Informed consent
X
Inclusion and exclusion 
criteria
X
Including pregnancy test done by 
treating physician.
Demography
X
Tumor type
X
Medical history 
X
Medical important events, e.g. 
Grade 3/4 (S)AEs, since the start of 
treatment in the feeder study should 
be reported as medical history in 
this rollover study.
Study treatment
→→→→→→→
Recheck clinical status before 1st 
dose of study medication.
Regorafenib dosing as per feeder 
study protocol. 
Drug dispensing
X
X
Drug accountability
X
X
X
AE review
X
X
X
X
X
To be documented only: 

AEs leading to dose 
reduction, interruption/delay 
and discontinuation

Any ongoing Grade 3 and 4 
AEs, or Grade 2 AEs that 
affect vital organs (e.g. heart, 
liver) per feeder study 
protocol CTCAE version. 
These events need to be re-
graded by the investigator 


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according to CTCAE Ver 5.0.  

Any new CTCAE Ver 5.0 
Grade 3 and 4 AEs, or Grade 
2 AEs that affect vital organs 
(e.g. heart, liver) 
SAE review
X
X
X
X
X
To be documented any ongoing or 
new SAEs
Concomitant 
medication review
X
X
X
X
X
Abbreviations:  AE - adverse event; CTCAE - Common terminology criteria for adverse events; SAE - serious adverse event.
a  During the screening period the participant will be on treatment under the umbrella of the feeder study. At the end of treatment visit of the feeder study,   eligibility criteria 
will be reviewed and the participants should sign informed consent for the rollover study.  
b  Safety assessments should be done according to local standard of care and regorafenib label information by the treating physician.
c  The treating investigator should ensure a seamless transition without a change in the treatment schedule.  Any treatment interruption should not exceed 28 consecutive 
days including 1 week break.


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2.
Introduction
Experience has shown that in nearly all clinical trials with regorafenib (Stivarga®) there are 
participants who are continuing to receive regorafenib after the study has been completed. A 
completed study is defined as one that has reached the primary completion endpoint, main 
data analysis, or has been stopped prematurely, and the respective data have been cleaned. 
The intention of this rollover study is to enable these participants who are still benefiting from 
treatment to continue to receive regorafenib treatment.
2.1
Study Rationale
The primary purpose of the study is to enable participants, currently receiving regorafenib in a 
Bayer sponsored clinical trial, to continue treatment after their respective study has been 
completed. A completed study is defined as one that has reached the primary completion 
endpoint, main data analysis, or has been stopped prematurely, and the respective data have 
been cleaned.  Participants will be able to continue treatment until the treating physician feels 
the participant is no longer benefiting from treatment.
2.2
Background
Approved indications of regorafenib include pre-treated metastatic colorectal cancer (CRC), 
hepatocellular carcinoma (HCC), and gastro-intestinal stromal tumors (GIST). Regorafenib is 
currently being studied in multiple solid tumors. This rollover study encompasses Phase 1-4 
Bayer-sponsored clinical trials that have reached the primary completion endpoint, or main 
data analysis, or have been stopped prematurely, and the respective data have been cleaned,
and are only kept open to ensure treatment of participants who are still benefiting from 
regorafenib treatment.
2.3
Benefit/Risk Assessment
Only participants who have been treated in a previous Bayer-sponsored regorafenib study and 
are still benefiting from treatment will be allowed to be enrolled in this study. They will 
continue treatment on the dose level that has been well tolerated before. 
The site’s principal investigator of the regorafenib study to which the subject is initially 
assigned, is expected to assess the overall benefit/risk for each participant. When the 
investigator deems there is a positive benefit/risk assessment the participant can be included 
in this rollover study.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of regorafenib may be found in the Investigator’s Brochure (IB).


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

The primary purpose of the program is to 
enable participants, currently receiving 
regorafenib in a Bayer sponsored clinical 
trial and assessed by the PI to be 
benefitting, to continue regorafenib 
treatment after their respective study has 
met its primary completion date, or main 
data analysis, or has been stopped 
prematurely.

And the documentation of safety 

Frequency and severity of SAEs 
and protocol-specified AEs 
Secondary

Documentation of tolerability

Frequency of dose modifications 
4.
Study Design
This is an open-label study that will enable participants currently receiving regorafenib in a 
completed Bayer-sponsored regorafenib clinical trial to continue treatment.  A completed 
study is defined as one that has reached the primary completion endpoint, main data analysis, 
or has been stopped prematurely, and the respective data have been cleaned.  
4.1
Overall Design
The participants in this open-label program will continue receiving regorafenib monotherapy 
at the dose level previously assigned under the following conditions:

as long as the interval of drug interruption does not exceed 4 weeks

as long as the treating physician feels the participant is continuing to benefit from 
treatment 

until he/she withdraws consent 

until he/she is non-compliant 

until he/she is lost to follow up 

until an unacceptable toxicity or death occurs

until patient starts a new anti-cancer treatment

until the development of a second malignancy


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
participants with a beta human chorionic gonadotropin (beta-hCG) test consistent with 
pregnancy. Pregnancy will be reported along the same timelines as a serious adverse 
event (SAE). 
Prior to receiving study medication for this rollover study, participants will be required to 
complete at least their EoT visit in their feeder study.  During this visit, criteria for the start of 
a subsequent cycle of therapy, as determined by the guidelines of the feeder protocol 
(eligibility criteria) will be reviewed and the participants should sign informed consent for the 
rollover study. 
Participants should continue taking study medication dispensed under the umbrella of the 
feeder studies until first treatment in this rollover study. The participant needs to complete 
the last treatment cycle in the feeder study and will start treatment in the rollover study at 
Cycle 1 Day1. The treating investigator should ensure a seamless transition without a change 
in the treatment schedule.  Any treatment interruption should not exceed 28 consecutive days 
including 1 week break. 
Local standards of medical care should be applied to all participants. Details must be recorded 
in the patient’s source documents and may be requested at the discretion of the Sponsor. 
The investigator will continuously assess the benefit/risk of regorafenib treatment when the 
participant is seen in the clinic for his standard of care visits and will ensure that participants 
that achieve any of the withdrawal conditions above discontinue treatment. 
Safety assessments should be done according to local standard of care and regorafenib label 
information by the treating physician.
Following the EoT assessments from the feeder study, the following information will be 
recorded in the rollover study eCRF: 

demography including study number, tumor type, and participant’s identification 
number of the feeder study 

medical history: medical important events, e.g. Grade 3/4 (S)AEs, since the start of 
treatment in the feeder study should be reported as  medical history in this rollover 
study 

any ongoing or new SAEs 

any AEs leading to dose reduction, interruption/delay and discontinuation of 
regorafenib

any on-going Grade 3 / 4 AEs, or Grade 2 AEs that affect vital organs (e.g. heart, 
liver) per feeder study CTCAE version. These events need to be re-graded by the 
investigator according to CTCAE Ver 5.0.

new CTCAE Ver 5.0 Grade 3 and 4 AEs, or Grade 2 AEs that affect vital organs (e.g. 
heart, liver)

concomitant medications 
4.2
Scientific rationale for Study Design
Not applicable for this rollover study.


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4.3
Justification for Dose
Not applicable for this rollover study.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has discontinued treatment 
and/or has completed the Safety Follow-up visit.
The end of the study is defined as the date when the last participant has completed the study 
and the sponsor has decided to close enrollment.
5.
Study Population
Participants who remain ongoing in a Bayer-sponsored Clinical Trial that has reached the 
primary completion date for data analysis and, in the opinion of the Investigator, are still 
benefiting from regorafenib treatment, will be eligible for entry into this study. The feeder 
studies must have completed all submissions and related regulatory requirements, e.g. 90 day 
safety update as required for US submissions.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be age-eligible in the feeder study at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2. Participant is currently participating in any Bayer-sponsored regorafenib study and is 
receiving study treatment.
3.
Participant is currently benefiting from treatment with regorafenib monotherapy and 
meets criteria to initiate a subsequent cycle of therapy, as determined by the guidelines 
of the feeder protocol.
4.
Any ongoing adverse events that require temporary treatment interruption must be 
resolved to baseline grade or assessed as stable and not requiring further treatment 
interruption by the investigator.
Sex
5. Male or female
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. This applies for the 
time between signing of the informed consent form and 2 months after the last 
administration of the study intervention.
Male participants:
In addition to the above methods, male trial participants and male partners of female 
trial participants must also use condoms during sex as an extra measure of protection 
against pregnancy.


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Female participants:
The investigator or a designated associate is requested to advise sexually active 
participants on how to achieve highly effective birth control using one or more of 
the following methods:

Hormonal contraception associated with inhibition of ovulation containing both 
estrogen and progestogen (oral, intravaginal or transdermal)

Hormonal contraception associated with inhibition of ovulation containing only 
progestogen (oral, injectable or implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner (provided that partner is the sole sexual partner of the 
woman of childbearing potential who is the trial participant and that the 
vasectomized partner has received medical assessment of surgical success)
Women not considered to be of childbearing potential include those who biologically 
sterile, permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral 
salpingectomy) or postmenopausal. Postmenopausal women are defined as no menses 
for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
Informed Consent
6. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Ineligibility, for medical reasons, to start the next cycle in the respective feeder study
2. Patients with a beta-hCG test consistent with pregnancy.
Prior/Concomitant Therapy
3. Participants are using one or more of the prohibited medications listed in the 
respective feeder study protocol. A comprehensive list can be found in Section 6.5. 
Prior/Concurrent Clinical Study Experience
4. Participant has been previously permanently discontinued from regorafenib treatment.
Diagnostic assessments
Not Applicable for this study.
Other Exclusions
5. Participant is unable to comply with the requirements of the study. 


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5.3
Lifestyle Considerations
Not Applicable for this study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
6.
Study Intervention
The following investigational products will be used in the study:

Regorafenib, 20 mg tablets 

Regorafenib, 40 mg tablets 
Participants will be treated with the regorafenib dose taken during the last cycle of the feeder 
study. They will receive either 60, 80, 120, or 160 mg orally (p.o.) every day (qd) for 3 weeks 
of every 4 week cycle (i.e. 3 weeks on, 1 week off).
Study drug should be taken within 2 hours after a light meal with approximately 240 mL 
(8 fluid ounces) of water, preferably in the morning. If necessary, the study drug may be taken 
at different times of the day, but there should be consistency with respect to dosing intervals 
(the recommendation is to have at least a 20 hour interval between doses). 
If a dose of study drug will be missed, the missed dose should be skipped (vomited tablets 
cannot be made up), and the next dose should be taken at the regular time. The subsequent 
dose of study drug should not be doubled. The investigator should be informed if the dose of 
regorafenib taken exceeded the scheduled dose.
Regorafenib will be provided by the sponsor as tablets.  
The regorafenib 40 mg tablet is coated, not divisible, gray-orange-red, oval (length 16 mm, 
width 7, thickness 4.9-5.6) and 472 mg each in total weight. The 40 mg tablets are embossed 
with “40” on one side of the tablet, and “BAYER” on the other side. The packaging 
configuration is 30 tablets regorafenib 40mg and a 3 g desiccant capsule per bottle of 
regorafenib 40 mg.
The regorafenib 20 mg tablet is coated, not divisible, gray-orange-red, round, biconvex 
(diameter 9mm, thickness 3.5-4.0mm) and 238 mg each in total weight. The 20 mg tablets are 
not coded.
The packaging configuration is 65 tablets regorafenib 20 mg and a 3 g desiccant capsule per 
bottle of regorafenib 20 mg.
Regorafenib tablets are in an immediate-release dosage form with rapid dissolution 
characteristics under the in vitro test conditions.


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6.1
Study Intervention(s) Administered
Participants will be treated with the regorafenib dose taken during the last cycle of the feeder 
study.
6.2
Preparation/Handling/Storage/Accountability
Regorafenib tablets will be packed in high density polyethylene (HDPE) bottles with a white 
child resistant closure and induction seal. Each bottle includes a desiccant cartridge inside.
Once the drug has been received it has to be kept in a secure, dry location. The tablets have to 
be stored in the original bottle according to the labelled storage advice. The tablets have to be 
stored in the original pack provided in order to protect from moisture and swallowed 
immediately after they have been taken out.  The bottle has to be kept tightly closed after first 
opening and the desiccant has to remain in the bottle. Once the bottle is opened, the tablets 
have to be discarded after 7 weeks. 
Unused tablets must be returned to the trial site by the patient. Beyond that, no special 
precautions are required, when handling the study drug. 
The bottles will have a label affixed containing study identification, product identification, 
and quantity of tablets. 
The study drug must be exclusively used for the purpose specified in this protocol, and it will 
only be accessible to authorized staff.  The investigator or designee must confirm the receipt 
of the drug by signing the drug acknowledgment form.
The study drug will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For the study drug, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance group. 
A complete record of batch numbers and expiry dates of all study drug as well as the labels 
will be maintained in the sponsor study file.
For more information about study drug, please refer to the Investigator’s Brochure.
6.3
Measures to Minimize Bias: Randomization and Blinding
Not applicable. This is an open-label study.
6.4
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance will 
be assessed by counting returned tablets/capsules. Deviation(s) from the prescribed dosage 
regimen should be recorded in the eCRF.
6.5
Concomitant Therapy
All medication which is considered necessary for the subject’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. All concomitant medications (including start/stop dates, dose frequency, 


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route of administration and indication) must be recorded in the subject’s source 
documentation, as well as in the appropriate pages of the CRF. 
6.5.1
Drug-drug interactions relevant for regorafenib
6.5.1.1
Inhibitors / inducers of CYP3A4
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a 
single dose of regorafenib (160 mg on Day 5) resulted in an increase in mean exposure (AUC) 
of regorafenib of approximately 33%, and a decrease in mean exposure of the active 
metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is 
recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity 
(Appendix 10.6) as their influence on the steady-state exposure of regorafenib and its 
metabolites has not been studied.
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single 
dose of regorafenib (160 mg on Day 7) resulted in a reduction in AUC of regorafenib of 
approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, 
and no change in exposure of active metabolite M-2. Other CYP3A4 inducers 
(Appendix 10.6) may also increase metabolism of regorafenib. Inducers of CYP3A4 should 
be avoided, or selection of an alternate concomitant medicinal product, with no or 
minimal potential to induce CYP3A4 should be considered.
Appendix 10.6 provides an overview of the most commonly used strong CYP3A4 inhibitors 
and CYP3A4 inducers) that should be avoided during the study.
6.5.1.2
UGT1A1 and UGT1A9 substrates 
In vitro data indicate that regorafenib as well as its active metabolites M-2 inhibit 
glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at 
concentrations which are achieved in vivo at steady state. 
Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted 
in an increase of approximately 44% in mean exposure (AUC) of SN-38, a substrate of 
UGT1A1 and an active metabolite of irinotecan. An increase in mean exposure (AUC) of 
irinotecan of approximately 28% was also observed. This indicates that co-administration of 
regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. The 
clinical significance is unknown and is dependent on the substrate.
6.5.1.3
Breast cancer resistance protein and P-glycoprotein substrates
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of 
rosuvastatin (5 mg), a breast cancer resistance protein (BCRP) substrate, resulted in a 3.9-fold 
increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax. This 
indicates that co-administration of regorafenib may increase the plasma concentrations of 
other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, 
it is recommended to monitor patients closely for signs and symptoms of increased 
exposure to BCRP substrates. 
6.5.1.4
CYP isoform-selective substrates
A cytochrome P450 enzyme (CYP) probe substrate study in cancer patients was conducted to 
evaluate the effect of regorafenib on the pharmacokinetics of CYP2C9 substrate warfarin 
(10 mg), CYP2C19 substrate omeprazole (40 mg), CYP3A4 substrate midazolam (2 mg) and 


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CYP2C8 substrate rosiglitazone (4 mg) and to provide information about potential changes in 
exposure of these substrates when administered with regorafenib.
Overall, the PK data suggest that regorafenib may be given concomitantly with substrates
of CYP3A4, CYP2C8, CYP2C9, and CYP2C19 without the expectation of a clinically 
meaningful drug interaction.
6.5.1.5
Antibiotics
The concentration-time profile indicates that regorafenib and its metabolites may undergo 
enterohepatic circulation. Co-administration with neomycin, a poorly absorbed antimicrobial 
agent used for eradicating the gastrointestinal microflora (which may interfere with the 
enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure. There was 
an approximately 80% decrease in the exposure of the active metabolites M-2 and M-5. 
Effects of other antibiotics have not been studied. The clinical significance of the neomycin 
effect and potential interactions with other antibiotics is unknown, but may result in a 
decreased efficacy of regorafenib.
6.5.1.6
Bile salt-sequestering agents
Bile salt-sequestering agents may interact with regorafenib by forming insoluble complexes 
which may impact absorption (or reabsorption), thus resulting in potentially decreased 
exposure. The clinical significance of these potential interactions is unknown, but may 
result in a decreased efficacy of regorafenib.
6.5.2
Permitted concomitant therapies
All concomitant medications (including start / stop dates, total daily dose, and indication) 
must be recorded in the patient’s source documentation and in the eCRF.

Treatment with non-conventional therapies (e.g. herbs or acupuncture) and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the investigator. However, St John’s Wort (herbal 
preparation based on the plant species hypericum) is not permitted.

Patients who are therapeutically treated with an agent such as warfarin or heparin or 
novel oral anticoagulants (NOACs) such as dabigatran or rivaroxaban will be allowed 
to participate provided that no prior evidence of underlying abnormality in coagulation 
parameters exists. Close monitoring of at least weekly evaluations for patients on 
warfarin will be performed until INR is stable based on a measurement that is pre-dose 
as defined by the local standard of care.

P-glycoprotein substrates: clinical data indicate that regorafenib has no effect on 
digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein 
substrates, such as digoxin, without a clinically meaningful drug interaction (see 
Section 6.5.1.3).

Patients may receive palliative or supportive care for any underlying illness (e.g., 
Megestrol acetate (Megace®) as supportive care). 

Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients on this trial. The use of anti-
diarrheal or anti-emetics according to standard practice is strongly encouraged.

Bisphosphonates and/or RANKL inhibitor therapies (such as denosumab) for bone 
metastases may be continued if treatment with an agent from one of these two classes 


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was initiated prior to signing informed consent. Bisphosphonates and/or RANKL 
inhibitor therapies cannot be initiated after informed consent has been signed, unless 
in the opinion of the investigator, the patient does not have PD.

Radiotherapy:
o
Palliative radiotherapy during the study is allowed for local pain control after 
individual benefit-risk assessment provided that:
In the opinion of the investigator, the patient does not have PD,
No more than 25% of the patient’s bone marrow is irradiated,
The radiation field does not encompass a lung field (to reduce the risk for 
ILD caused by irradiation pneumonitis). 
o
Regorafenib may only be continued during palliative radiotherapy after an 
individual benefit-risk assessment. The investigator should consult the sponsor.
Note: administration of palliative radiation therapy to a symptomatic solitary lesion or to 
the brain will be considered clinical progression 

Analgesics.

Nutritional support.
Major surgery for any reason different than symptom management or tumor control should 
only be performed during the study period if, in the opinion of the investigator and after 
careful individual benefit / risk assessment (taking into account the potential wound healing 
complications that have been described with all anti-VEGF drugs), the surgery will be 
beneficial for the patient. It is recommended to stop regorafenib treatment two weeks before 
surgery. The decision to resume regorafenib after surgery should be based on clinical 
judgment of adequate wound healing. Patients should be placed back on study therapy within 
4 weeks of the scheduled interruption of regorafenib. 
Note: 

if treatment interruption of regorafenib will be >28 consecutive days - including the 
1 week drug holiday - patient must be discontinued from regorafenib. 
Patients may receive other medications that the investigator deems to be medically necessary.
6.5.3
Prohibited prior and concomitant therapies
Patients are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial:

Disease-specific anti-neoplastic therapies, including kinase inhibitors, 
immunotherapy, chemotherapy, or experimental therapies other than regorafenib are 
not allowed. 

Surgery for symptom management or tumor control.

Strong CYP 3A4 inhibitors / inducers. Strong CYP3A4 inhibitors or CYP3A4 
inducers (See Appendix 10.6) are not allowed. 

Any drug that targets angiogenesis, especially VEGF and VEGFR.


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
Tyrosine-kinase inhibitors (TKIs)

Antiviral treatment for HCV 

Bone marrow transplant or stem cell rescue.

Prior and concomitant palliative radiation therapy is allowed if the target lesion(s) are 
not included within the radiation field and no more than 25% of the bone marrow is 
irradiated.

Use of biologic response modifiers, such as granulocyte colony stimulating factor (G-
CSF), within the 3 weeks prior to the randomization date. 
o
G-CSF and other hematopoietic growth factors may be used during the study in the 
management of acute toxicity such as febrile neutropenia when clinically indicated 
or at the discretion of the investigator; however they may not be substituted for a 
required dose reduction. 
o
Patients taking chronic erythropoietin are permitted.

Patients taking narrow therapeutic index medications (e.g., warfarin, quinidine, and 
cyclosporine) should be monitored proactively.

Investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immunotherapy.
Therapeutic monitoring should be performed consistent with the local clinical standard of care 
following dose modification of the agent. In general, patients should be closely monitored for 
side effects of all concomitant medications regardless of path of elimination.
6.5.4
Documentation of prior and new concomitant therapies
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.6
Dose Modification
In case a dose reduction is necessary, the study treatment will be administered according to 
the following tables. Table 6–1 shows the dose modification levels for regorafenib. Table 6–2,
Table 6–3, Table 6–4, and Table 6–5 show the dose modification plans for specific known 
drug-related toxicities.
Table 6–1:  Dose modification levels for regorafenib
Dose Level
Daily Dose
Number of tablets
Dose level 0 (standard dose)
160 mg
4 tablets of regorafenib, 40 mg-tablet
Dose level -1
120 mg
3 tablets of regorafenib, 40 mg-tablet
Dose level -2
80 mg
2 tablets of regorafenib, 40 mg-tablet


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Table 6–2:  Dose Modification/Delay for Toxicities Related to Study Drug (Except 
Hand Foot Skin Reaction, Hypertension, and ALT and/or AST increases)a,c
Grade of Event
Dose 
Interruption
Dose 
modification
Dose for 
subsequent cycles
Grade 0-2
Treat on time
No change
No change
Grade 3
Delay until ≤Grade 2
b
Reduce 1 dose 
level
If toxicity remains ≤Grade 2, 
dose re-escalation can be 
considered at the discretion of 
the treating investigator. If 
dose is re-escalated and 
toxicity (≤Grade 3) recurs, 
institute permanent dose 
reduction.
Grade 4
Delay until ≤Grade 2
b
Reduce by 1 dose level.
Permanent discontinuation can be considered at 
treating investigator’s discretion.
Abbreviations: ALT – alanine transaminase; AST – aspartate transaminase 
a  Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity, non-clinically significant 
and asymptomatic laboratory abnormalities.
b  If no recovery after a 4-week delay, treatment should be permanently discontinued. In the event of severe 
bleeding necessitating urgent medical intervention, permanent discontinuation of regorafenib should be 
considered.
c  In subjects who develop cardiac ischemia and/or infarction, interruption of regorafenib is recommended until 
resolution. The decision to re-initiate regorafenib therapy should be based on careful consideration of the 
potential benefits and risks of the individual subject. Regorafenib should be permanently discontinued if there 
is no resolution.


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Table 6–3:  Dose modifications for HFSR related to regorafenib (dose expansion 
phase) (“Palmar-plantar erythrodysesthesia syndrome”)
Skin toxicity grade
Occurrence
Recommended dose modification and 
measures
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless swelling, 
erythema or discomfort of the 
hands or feet which does not 
disrupt the subject’s normal 
activities
Any
Maintain dose level and immediately institute 
supportive measures for symptomatic relief.
Grade 2: Painful erythema 
and swelling of the hands or 
feet and/or discomfort which 
affects the subject’s normal 
activities.
1st occurrence
Decrease dose by 40 mg (one tablet) and 
immediately institute supportive measures.
If no improvement occurs despite dose 
reduction, interrupt therapy for a minimum of 
7 days, until toxicity resolves to Grade 0-1.
A dose re-escalation is permitted at the 
discretion of the treating physician.
No improvement 
within 7 days or 
2nd occurrence
Interrupt therapy until toxicity resolves to 
Grade 0-1.  When resuming treatment, 
decrease dose by 40 mg (one tablet).  A 
dose re-escalation is permitted at the 
discretion of the treating physician.
3rd occurrence
Interrupt therapy until toxicity resolves to 
Grade 0-1.  When resuming treatment, 
decrease dose by 40 mg (one tablet).
A dose re-escalation is permitted at the 
discretion of the treating physician.
4th occurrence
Discontinue treatment.
Grade 3: Moist 
desquamation, ulceration, 
blistering or severe pain of 
the hands or feet, or severe 
discomfort that causes the 
subject to be unable to work 
or perform activities of daily 
living.
1st occurrence
Institute supportive measures immediately.  
Interrupt therapy for a minimum of 7 days 
until toxicity resolves to Grade 0-1.  When 
resuming treatment, decrease dose by 
40 mg (one tablet).  A dose re-escalation is 
permitted at the discretion of the treating 
physician.
2nd occurrence
Institute supportive measures immediately.  
Interrupt therapy for a minimum of 7 days 
until toxicity resolves to Grade 0-1. When 
resuming treatment, decrease dose by 
40 mg (one tablet).
3rd occurrence
Discontinue treatment.
Abbreviations:  HFSR – hand-foot-skin reaction


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Table 6–4:  Recommended dose modification and measures for hypertension
Hypertension 
grade
Occurrence
Recommended dose modification and measures a
Grade 1
Any
Maintain dose level.
Consider increased BP monitoring.
Grade 2
Any
Institute antihypertensive treatment with the aim to achieve 
diastolic BP ≤90 mmHg:

If BP previously within normal limits, start 
antihypertensive monotherapy.

If subject already on antihypertensive medication, 
titrate up the dose. 
Continue regorafenib, or if symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤90 mmHg.
b
When regorafenib is restarted, continue at the same dose level.
Grade 3
First occurrence
Institute antihypertensive treatment with the aim to achieve 
diastolic BP ≤90 mmHg:

Start antihypertensive medication 
AND/OR

Increase current antihypertensive medication
AND/OR 

Add additional antihypertensive medications. 
Hold regorafenib until diastolic BP ≤90 mm Hg, and if 
symptomatic, until symptoms resolve.
b
When regorafenib is restarted, continue at the same dose level.
If BP is not controlled with the addition of new or more intensive 
therapy, reduce by 1 dose level.
c
Re-occurrence
If Grade 3 hypertension recurs despite dose reduction and 
antihypertensive therapy, reduce another dose level.
d
Grade 4
Any
Discontinue therapy
Abbreviations: BP = blood pressure.
a  A more conservative management of hypertension is allowed if judged medically appropriate by the 
investigator.
b Subjects requiring a delay of >4 weeks should go off regorafenib. 
c  If BP remains controlled for at least one full cycle, dose re-escalation is permitted at the investigator’s 
discretion.
d Subjects requiring >2 dose level reductions (<80 mg reduction) should go off regorafenib.


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Table 6–5:  Dose modification/interruption for ALT/AST increases related to 
regorafenib
Observed elevations of 
ALT and / or AST
Occurrence
Recommended measures and dose 
modification
≤5 times ULN 
Any occurrence
Continue regorafenib treatment.  Monitor liver 
function weekly until transaminases return to 
<3 times ULN or baseline.
>5 times ULN to ≤20 
times ULN 
1st occurrence
Interrupt regorafenib treatment.  Monitor 
transaminases weekly until return to <3 times 
ULN or baseline.
Restart:  If the potential benefit outweighs the 
risk of hepatotoxicity, re-initiate regorafenib 
treatment, reduce dose by 40 mg (one tablet), 
and monitor liver function weekly for at least 
4 weeks.
Re-occurrence
Discontinue treatment with regorafenib 
permanently.
>20 times ULN 
Any occurrence
Discontinue treatment with regorafenib 
permanently.
>3 times ULN with 
concurrent bilirubin >2 
times ULN
Any occurrence
Discontinue treatment with regorafenib 
permanently. Monitor liver function weekly until 
resolution or return to baseline.  
Exception:  patients with Gilbert’s syndrome who 
develop elevated transaminases should be 
managed as per the above outlined 
recommendations for the respective observed 
elevation of ALT and / or AST.
Abbreviations: ALT – alanine transaminase; AST – aspartate transaminase; ULN = upper limit of normal.
If a dose reduction has been performed within this study protocol intra subject dose 
reescalation can be considered up to the staring dose in this rollover study protocol at the 
discretion of the treating physician.
6.7
Intervention after the End of the Study
There is no planned intervention following the end of the study.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
In rare instances, it may be necessary for a patient to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain 
in the study. See the SOA for data to be collected at the time of discontinuation of study 
intervention.
Patients must be withdrawn from the study intervention for the following reasons: 

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result.


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
If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being.

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Severe allergic reactions, such as exfoliate erythroderma, anaphylaxis, or vascular 
collapse.

Any other potential adverse reaction deemed sufficiently serious to warrant 
discontinuation of treatment by either the investigator or his designated associate(s).

Substantial non-compliance with the requirements of the study.

Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity.

Development of any intercurrent illness or situation which would, in the judgment of 
the investigator, may affect assessments of clinical status and study endpoints to a 
relevant degree.

Clinical progression (e.g. defined as worsening of the ECOG PS ≥3 or symptomatic 
deterioration including increase in liver function tests).

The development of a second malignancy.

Subject lost to follow-up.

Interruption in study drug administration for greater than 28 consecutive days 
(including the 1 week drug holiday in each cycle).

More than 2 dose reductions of the study drug are necessary.
Patients with a beta-human chorionic gonadotropin (hCG) test consistent with pregnancy. 
Pregnancy will be reported as an SAE using the Pregnancy Monitoring Form.
7.1.1
Temporary Discontinuation
For temporary interruption of study drug please refer to Section 6.6. The interval of drug 
interruption should not exceed 4 weeks including 1 week break. 
7.1.2
Rechallenge
Rechallenge should be done according to criteria specified in Section 6.6. The interval of drug 
interruption should not exceed 4 weeks including 1 week break. 
7.2
Participant Discontinuation/Withdrawal from the Study
In case a participant is withdrawn from study intervention he/she will be withdrawn from the 
study after the safety follow-up visit.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:


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
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening activities must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
8.1
Efficacy Assessments
There will be no formal assessments of efficacy during the rollover study.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the 
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs, considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study (see Section 7).


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8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the informed consent form (ICF until the 
safety follow-up visit (Section 1.3).
AEs, as described in the SoA, (ie, AEs leading to dose reduction, interruption/delay and 
discontinuation and any new CTCAE Ver 5.0 Grade 3 and 4 AEs, or Grade 2 AEs that affect 
vital organs (e.g. heart, liver) will be collected from the signing of the ICF until the safety 
follow up- visit
Any ongoing Grade 3 and 4 AEs, or Grade 2 AEs that affect vital organs (e.g. heart, liver) per 
feeder study protocol CTCAE version need to be reported as AEs in this rollover study. These
events need to be re-graded by the investigator according to CTCAE Ver 5.0.
Medical important events, e.g. Grade 3/4 (S)AEs, since the start of treatment in the feeder 
study should be reported as medical history in this rollover study.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the case report form (CRF).
Medical occurrences that started before but deteriorated after obtaining informed consent will 
be recorded as adverse events. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in Appendix 3 
(Section 10.3).
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.


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
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until
2 months after discontinuation of intervention.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4
Treatment of Overdose
For this study, any dose of study intervention greater than 160 mg within a 20-hour time 
period will be considered an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically.
2. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).
3. Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).
4. Adverse events associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
For detailed guidance on overdosing please refer to the most current version of the IB for 
regorafenib.
There is no specific treatment for regorafenib overdose.  The highest dose of regorafenib 
studied clinically is 220 mg QD.  The AEs observed at this dose were primarily 
dermatological events, hoarseness, diarrhea, mucositis, and nausea.  In the event of suspected 


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overdose regorafenib should be immediately withheld and supportive care instituted under the 
supervision of a qualified health care professional.  
There is no specific antidote for Stivarga® overdose.  Subjects who have overdosed should be 
treated with symptomatic support.  No additional data concerning management of overdose 
are available at this time. 
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
9.
Statistical Considerations
Data from participant who are transferred to a rollover study may be pooled and analyzed 
together with the data from the study in which the participant was initially included.
Data will be analyzed using summary or frequency statistics or data listings.
9.1
Statistical Hypotheses
No confirmatory statistical hypothesis testing is planned. All safety analysis will be done in a 
descriptive manner only.
9.2
Sample Size Determination
No formal sample size estimation will be done.
Participants of on-going or future feeder studies will be enrolled in the study; therefore the 
number of participants is not predictable. 
9.3
Populations for Analyses
For purposes of statistical analysis, the following analysis sets are defined:
Analysis set
Description
Enrolled 
All participants who signed the ICF
Safety
All participants who take at least 1 dose of regorafenib within 
this rollover study.


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9.4
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the analysis sets and procedures for any missing imputation method, if applicable.
Descriptive analysis/listings of data collected e.g. demography, medical history, drug 
accountability, concomitant medication, adverse events (including serious), dose 
modifications and reasons for termination of treatment may be provided, as appropriate.
9.4.1
Efficacy Analyses
Not applicable for this rollover study as no efficacy analyses are planned.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety analysis set.
Serious adverse events and protocol-specified AEs will be analyzed descriptively by 
providing frequency tables of SAEs and AEs observed during the study. 
Tolerability of the study drug will be evaluated by displaying the number of dose 
modifications in frequency tables. 
Details will be given in the statistical analysis plan.
9.4.3
Other Analyses 
Not applicable for this rollover study.
9.5
Interim Analyses 
No formal interim analysis is planned.
10.
Supporting Documentation and Operational Considerations
The focus of this rollover study is to provide regorafenib to patients and to collect safety 
information as specified in the SoA.  
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:


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o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.


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10.1.5
Dissemination of Clinical Study Data
Result Summaries of Bayer’s sponsored clinical trials in drug development phases 2, 3 and 4 
and phase 1 trials in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the “Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases”. In addition results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after January 01, 2014 as necessary for conducting legitimate research.
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.6
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.


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10.1.7
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
10.1.8
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
10.1.9
Publication Policy
Not applicable. It is not planned to publish data from this study, it might be that rollover study 
data will contribute to publications on feeder study data.
10.2
Appendix 2: Clinical Laboratory Tests
Not applicable as no blood samples will be taken in this rollover study. 
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 


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Events Meeting the AE Definition
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
1. Results in death
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 


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participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE (those AEs leading to dose 
reduction, interruption/delay and discontinuation and any new Any new CTCAE 
version 5.0 Grade 3 and 4 AEs, or Grade 2 AEs that affect vital organs [e.g. heart, 
liver]) and all SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the medical monitor or Bayer’s pharmacovigilance department in 


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lieu of completion of the completed/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by the medical monitor or Bayer’s pharmacovigilance department. In this 
case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to the medical 
monitor or Bayer’s pharmacovigilance department.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it as per CTCAE Ver 5.0.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Bayer’s pharmacovigilance 
department. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the 
SAE data to Bayer’s pharmacovigilance department.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Bayer’s 
pharmacovigilance department to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.

If a participant dies during participation in the study or during the safety follow-up 
period, the investigator will provide the medical monitor and/or Bayer’s 
pharmacovigilance department with a copy of any post-mortem findings including 
histopathology, if applicable. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the Bayer’s 
pharmacovigilance department within 24 hours of receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to Bayer’s pharmacovigilance department via an Electronic Data 
Collection Tool

The primary mechanism for reporting an SAE to Bayer’s pharmacovigilance 
department will be the electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section).

Contacts for SAE reporting can be found in in the SAE paper template.
SAE Reporting to Bayer’s pharmacovigilance department via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Bayer’s pharmacovigilance department.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE report sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.


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SAE Reporting to Bayer’s pharmacovigilance department via Paper CRF

Contacts for SAE reporting can be found in the SAE paper template.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive regorafenib.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 


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form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents of the neonate, unless local 
law or specific circumstances of the respective case allow otherwise, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and will be withdrawn from the study.


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10.5
Appendix 5: Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the activity curve
BCRP
Breast cancer resistance protein
BP
blood pressure
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CRC
Colorectal carcinoma
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
CYP
Cytochrome P450
CYP3A4
Cytochrome P450 3A4
DNA
Deoxy-ribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
e.g.
For example
EoT
End of treatment
FSH
Follicle stimulating hormone
GCP
Good clinical practice
G-CSF
Granulocyte colony-stimulating factor
GIST
Gastrointestinal stroma
GMP
Good Manufacturing Process
HCC
Hepatocellular carcinoma
hCG
Human chorionic gonadotropin
HFSR
hand-foot-skin reaction
HRT
Hormonal replacement therapy
IB
Investigators brochure
IEC
Independent ethics committee
ICF
Informed consent form
ICH
International conference on harmonization
i.e.
id est; that is
IRB
Institutional review board
PI
Principal Investigator
PK
Pharmacokinetics
RCC
Renal cell carcinoma
SAE
Serious adverse event
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse events
ULN
upper limit of normal
WOCBP
Women of childbearing potential


CONFIDENTIAL
Clinical Study Protocol 
BAY 73-4506 / 20328
Amendment 1
Page 43 of 43
10.6
Appendix 6 CYP3A4 inducers and inhibitors 
Table 10–1 presents an overview of CYP3A4 inducers and strong CYP3A4 inhibitors. 
CYP3A4 inducers and strong CYP3A4 inhibitors are NOT allowed due to drug-drug-
interaction with regorafenib. 
Table 10–1:  An overview of CYP3A4 inducers and strong CYP3A4 inhibitors 
STRONG CYP3A4 Inhibitors
CYP3A4 Inducers
Boceprevir 
Clarithromycin 
Cobicistat, only available in the combination with 
elvitegravir, emtricitabine, tenofovir or disoproxil fumarate
Conivaptan 
Delavirdine 
Idelalisib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Mibefradil 
Miconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir
Telaprevir 
Telithromycin 
Tipranavir
Troleandomycin 
Voriconazole
Avasimibe 
Bosentan
Carbamazepine 
Efavirenz
Enzalutamide 
Etravirine
Fosphenytoin 
Hypericum perforatum (St John’s 
Wort) 
Lersivirine
Lumacaftor 
Methylphenobarbital 
Mitotane 
Modafinil
Nafcillin
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin
Rifampicin 
Rifamycin 
Semagacestat 
Thioridazine
The CYP3A4 inducers and strong CYP3A4 inhibitors in Table 10–1 were identified using the 
Bayer-World Health Organization’s Drug Dictionary (WHO-DD) and Bayer drug groupings 
for CYP3A4 inducers and CYP3A4 inhibitors.
11.
References
Not applicable.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A single arm, open-label, multicenter Phase 2 study of regorafenib 
in participants who have been treated in a previous Bayer-
sponsored regorafenib study (monotherapy or combination 
treatment) that has reached the primary completion endpoint or the 
main data analysis, or has been stopped prematurely. 
NCT Number: 
NCT03890731 
Document Date: 
23 JUN 2023 
 


Statistical Analysis Plan 
BAY 73-4506 / 20328 
Page: 1 of 6
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Title page 
A single arm, open-label, multicenter Phase 2 study of regorafenib in 
participants who have been treated in a previous Bayer-sponsored 
regorafenib study (monotherapy or combination treatment) that has 
reached the primary completion endpoint or the main data analysis, or 
has been stopped prematurely. 
[Regorafenib rollover study] 
Bayer study drug 
BAY 73-4506 / Regorafenib  
Study purpose: 
Enable patients from the feeder studies to continue treatment 
Clinical study 
phase: 
II 
Date: 
23 JUN 2023 
Study No.: 
 
20328 
Version: 
2.0 
Author: 
, 
ClinStat GmbH 
 
 
 
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 73-4506 / 20328 
Page: 2 of 6
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table of Contents 
 
Title page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Abbreviations ........................................................................................................................ 2 
1. 
Introduction ................................................................................................................... 3 
2. 
Study Objectives ............................................................................................................ 3 
3. 
Study Design .................................................................................................................. 3 
4. 
General Statistical Considerations .............................................................................. 3 
4.1 
General Principles ........................................................................................................ 3 
4.2 
Handling of Dropouts .................................................................................................. 3 
4.3 
Handling of Missing Data ............................................................................................ 3 
4.4 
Interim Analyses and Data Monitoring ....................................................................... 4 
4.5 
Data Rules .................................................................................................................... 4 
4.6 
Blind Review ............................................................................................................... 4 
5. 
Analysis Sets .................................................................................................................. 4 
5.1 
Assignment of analysis sets ......................................................................................... 4 
6. 
Statistical Methodology ................................................................................................ 4 
6.1 
Population characteristics ............................................................................................ 4 
6.2 
Concomitant medication .............................................................................................. 4 
6.3 
Study drug exposure .................................................................................................... 5 
6.4 
Efficacy ........................................................................................................................ 5 
6.5 
Pharmacokinetics/pharmacodynamics ......................................................................... 5 
6.6 
Safety ........................................................................................................................... 5 
6.7 
Subgroup analysis ........................................................................................................ 5 
7. 
Document history and changes in the planned statistical analysis  .......................... 5 
8. 
References ...................................................................................................................... 6 
 
 
 
Abbreviations 
AE 
Adverse event 
ATC 
WHO Anatomical Therapeutic Chemical Classification system 
CRF 
Case Report Form 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
 


Statistical Analysis Plan 
BAY 73-4506 / 20328 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
1. 
Introduction 
The primary purpose of the study is to enable participants, currently receiving regorafenib in a 
Bayer sponsored clinical trial, to continue treatment after their respective study has been 
completed. A completed study is defined as one that has reached the primary completion 
endpoint for main data analysis, or has been stopped prematurely, and the respective data 
have been cleaned.  Participants will be able to continue treatment until the treating physician 
feels the participant is no longer benefiting from treatment. 
2. 
Study Objectives 
Primary 
• The primary purpose of the program is to enable participants, currently receiving 
regorafenib in a Bayer sponsored clinical trial and assessed by the principal 
investigator (PI) to be benefitting, to continue regorafenib treatment after their 
respective study has met its primary completion date, or main data analysis, or has 
been stopped prematurely. 
Secondary 
• Documentation of safety and tolerability 
 
3. 
Study Design 
This is an open label, single arm study. 
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). 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. 
Due to the low number of expected patients no subgroup analyses are planned. 
4.2 
Handling of Dropouts 
All data available will be analyzed. 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF).  
The number of subjects who prematurely discontinue the study and study treatment for any 
reason, as well as the reasons for premature discontinuation of study and study treatment, will 
be reported. 


Statistical Analysis Plan 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
4.4 
Interim Analyses and Data Monitoring 
Not applicable 
4.5 
Data Rules 
In general all analyses will be performed for the safety set. It is anticipated that the analysis 
sets will not differ. Otherwise valuable data wich is not available in the safety set will also be 
analysed. See section 5 for definition of the analysis sets. 
4.6 
Blind Review 
As this is an open label study, no unblinding is necessary. Patients will be assigned to the 
relevant analysis sets based on the rules described in section 5 for the analysis sets. This will 
be discussed and documented in the Blind Review Meeting.  
5. 
Analysis Sets 
For purposes of statistical analysis, the following analysis sets are defined: 
Analysis set 
Description 
Enrolled  
All participants who signed the ICF 
Safety 
All participants who take at least 1 dose of regorafenib 
within this rollover study.  
 
5.1 
Assignment of analysis sets 
Assignment of the subjects to the analysis sets will be made based on the available treatment 
information (i.e. if there is a record indicating that regorafenib was taken, a patient will be 
assigned to the safety set). 
6. 
Statistical Methodology 
The main objective of the study is to ensure continuation of treatment for eligible patients and 
only safety data are collected. Beyond summary statistics, no statistical analysis is planned. 
6.1 
Population characteristics 
If applicable, the number of subjects in each analysis set will be presented. 
Due to the low number of patients expected in this study, no further summary statistics will be 
produced. Demographic data will be provided by means of a summary table and individual 
subject data listingsdisplaying the collected demographic informations as per CRF for all 
patients enrolled. 
6.2 
Concomitant medication 
Concomitant medication will be analyzed in the safety set. 
The frequency of concomitant medications will be summarized by 1st and 3rd level ATC class. 
This table will be repeated for concomitant anti-cancer therapy, if applicable. 


Statistical Analysis Plan 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
6.3 
Study drug exposure 
Study drug exposure will be analyzed in the safety set. 
Treatment duration will be summarized as well as the number of applications and 
modifications of the study drug. 
6.4 
Efficacy 
Not applicable 
6.5 
Pharmacokinetics/pharmacodynamics 
Not applicable 
6.6 
Safety 
All analyses will be conducted in the safety set. 
AEs will be coded using the latest version of MedDRA during the study. A treatment-
emergent adverse event (TEAE) is defined as an AE that increase in severity or that is newly 
developed after the first study intervention.  
If the onset date of an AE is missing/incomplete, it is assumed to have occurred after the first 
study intervention (i.e., a TEAE) except if the partial onset date or stop date indicates 
differently. 
An overview over all patients experiencing AEs will be given. The total number of patients 
experiencing TEAEs will be presented and tabulated by SOC and PT and CTCAE grade.   
The following categories will be presented: 
• TEAEs 
• Drug-related TEAEs 
• TEAEs leading to discontinuation of study drug 
• Treatment-emergent serious adverse events (TESAEs 
• Drug-related TESAEs  
• TESAEs leading to discontinuation of study drug  
All deaths, TESAEs, TEAEs leading to discontinuation and pregnancies will be presented in 
subject listings, if applicable. 
6.7 
Subgroup analysis 
Due to the low sample size no subgroup analysis will be conducted.  
7. 
Document history and changes in the planned statistical analysis  
This is the second version of the SAP. In comparison to the the first version analysis were 
updated du to the small number of patients entering the study.  


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Reference Number: RD-SOP-1119 
Supplement Version: 10 
8. 
References 
Final study protocol of study 20328, version 2.0, dated 20 NOV 2018 
Final CRF of study 20328, dated 11 NOV 2020 
SAP version 1, dated 28 MAR 2019