Conditions: Colorectal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn if combination of the two drugs regorafenib and nivolumab is an effective treatment for pMMR - MSS colorectal cancer, a special type of cancer of the colon or rectum (pMMR stands for proficient Mismatch Repair; MSS stands for Microsatellite Stable) and whether it is safe for patients. Regorafenib works by blocking several different proteins involved in tumor growth. Nivolumab is an immunotherapy drug encouraging the body's own immune system to attack cancer cells.

Both drugs have been approved, but not for how they are being used as combination therapy in this study. Brand name of regorafenib is Stivarga; brand name of nivolumab is Opdivo.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Regorafenib (Stivarga, BAY73-4506) intervention 2: Nivolumab (Opdivo)
Intervention descriptions: intervention 1: Regorafenib administered as oral tablets given every day for 3 weeks of each 28 days treatment cycle (i.e., 3 weeks on, 1 week off) intervention 2: Administered on day 1 of every treatment cycle.

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
An Open-label, Single-arm, Phase II Study of Regorafenib and 
Nivolumab in Patients with Mismatch Repair-Proficient 
(pMMR)/Microsatellite Stable (MSS) Colorectal Cancer (CRC) 
NCT Number: 
NCT04126733 
Document Date: 
18 NOV 2020 
 


CONFIDENTIAL
Clinical Study Protocol Global Amendment 2
BAY 73-4506 / 20975
18 NOV 2020
Title Page
Protocol title:
An Open-label, Single-arm, Phase II Study of Regorafenib and 
Nivolumab 
in 
Patients 
with
Mismatch 
Repair-Proficient 
(pMMR)/Microsatellite Stable (MSS) Colorectal Cancer (CRC)
Protocol number:
20975
Compound 
number:
BAY 73-4506
Study phase
Phase II
Short title:
Regorafenib and Nivolumab in pMMR/MSS CRC
Sponsor Name and 
Legal Registered 
Address:
Sponsor (Non-US): Bayer AG, 51368 Leverkusen, Germany 
Sponsor (US territory): Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, Whippany NJ 07981-0915, 
USA
Regulatory Agency 
Identifier 
Number(s):
IND: 075642
Current Version
Amendment 2 
Previous Version
Amendment 1:
Original Protocol:
18 NOV 2020
08 JAN 2020
12 JUL 2019
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the Sponsor’s medically responsible person is filed in the TMF and available on 
request.
Confidential:
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.


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Protocol Global Amendment 2 Summary of Changes Table
Current Version
Amendment 2: 
Previous Versions
Amendment 1:
Original Protocol:
18 NOV 2020
08 JAN 2020
12 JUL 2019
Amendment 2 (18 NOV 2020)
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.
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Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis, 
Table 1-1: Objectives and 
Endpoints
3. Objectives and 
Endpoints,
Table 3-1: Objectives and 
Endpoints
4.1.2 Treatment Phase
Blinded independent central review (BICR) was 
removed from the assessment of primary (ORR per 
RECIST v1.1 ) endpoint and secondary endpoints 
(Duration of Response (DOR); Disease control rate 
(DCR) at 8 and 16 weeks; Progression free survival 
(PFS)). Respective table footnotes were deleted.
 
 
 
 
 
 
8.1 Efficacy 
Assessments
Text was reverted to wording in the original protocol.
 
 
 
 
 
 
 
 
1.1 Synopsis, 
Overall Design, Number 
of Participants
4.1 Overall Design
5. Study Population
Recruitment has been stopped at 70 treated 
participants. The number of participants has been 
changed throughout, accordingly.  
 
 
 
 
 
 
 
 
9.2 Sample Size 
Determination
Recruitment has been stopped at 70 treated 
participants. With this sample size of 70 participants, 
when the true underlying ORR is 17% or higher and a 
baseline response rate of 5% is assumed, a one-
sided exact binomial test at a type-I error of at 
approximately 2.5% would result in a power of 92.6%, 
with at least 8 responders needed to achieve 
significance.
The location of the primary tumor is a factor and it is 
expected that 40%-45% of participants will have the 
primary tumor on the right side. With 31 participants
with right-sided tumors, the probability of observing 4 
or more responders (ORR 13%) is approximately 80% 
when the true underlying response rate is 17%, and 
the probability of observing 2 or fewer responders 
(ORR 6.5%) is approximately 80% when the true 
ORR is 5%. 
With 39 participants with left-sided tumors, the 
probability of observing 6 or more responders (ORR 
15%) is approximately 67% when the true underlying 
response rate is 17%, and the probability of observing 
2 or fewer responders (ORR 5.1%) is approximately 
70% when the true ORR is 5%.
 
 
 
 
 
 
 
 
 
 
1.2 Schema
Figure 1-1: Study 
Schema
4.1.1 Screening Phase,
Figure 4-1: Study 
Schema
This study is composed of the following periods: 
Screening, treatment, active follow-up (FU), and long-
term follow up. Participants will be considered “on 
study” during these periods. 
Wording was clarified “Completion of active follow-
up”.
 
 
 
 
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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA),
Footnote m)
Footnote was clarified with a reference to 
Pharmacokinetic and Immunogenicity Sample 
Collection Plan.  
 
 
4.4 End of Study 
Definition
Language defining end of study (EOS) was clarified 
using appropriate terminology. 
 
5.1 Inclusion Criteria 
12. Women of childbearing potential (WOCBP) must 
agree to follow instructions for method(s) of 
contraception for the duration of study intervention 
and 210 120 d after last dose of regorafenib and 5 
months after the last dose of nivolumab.
7-month contraception period, after last dose of 
nivolumab, is no longer required for male study 
participants during sexual activity with a WOCBP 
partner.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. Study Intervention
Language defining continuation of study intervention 
after full treatment term (24 infusions/approximately 2 
years of treatment) was clarified using appropriate 
terminology.
 
 
6.7 Intervention after the 
End of the Study
Language was clarified on further therapeutic options 
after EOS, with the discretion of the Investigator.
 
 
 
 
 
 
7. Discontinuation of 
Study Intervention,
7.1 Withdrawal from 
active FU
Language on withdrawal from active follow-up (FU) 
was updated by adding a requirement of performed 
safety visits.
 
 
 
 
 
 
 
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Section # and Name
Description of Change
Brief Rationale
10.1.3 Informed Consent 
Process
Wording for reconsent for participants continuing 
study treatment following disease progression was 
clarified: In order to continue treatment after initial 
documentation of disease progression as per RECIST 
1.1, participant must be re-consented once.
 
Sponsor Signatory page
The signature of the Sponsor’s medically responsible 
person was removed from the clinical study protocol.
 
.
In addition to the substantive changes summarized in above table, several changes were made 
to update administrative details, correct typographical errors, and add clarity; such changes 
are not itemized in the table.
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Table of Contents
Title Page................................................................................................................................... 1
Protocol Global Amendment 2 Summary of Changes Table ............................................... 2
Table of Contents...................................................................................................................... 6
Table of Tables.......................................................................................................................... 8
Table of Figures........................................................................................................................ 9
1.
Protocol Summary........................................................................................................... 10
1.1
Synopsis ......................................................................................................................... 10
1.2
Schema........................................................................................................................... 12
1.3
Schedule of Activities (SoA) ......................................................................................... 13
3.
Objectives and Endpoints............................................................................................... 28
4.
Study Design .................................................................................................................... 28
4.1
Overall Design ............................................................................................................... 28
4.1.1
Screening Phase.......................................................................................................... 29
4.1.2
Treatment Phase.......................................................................................................... 29
4.1.3
Active Follow-Up....................................................................................................... 30
4.1.4
Long-Term Follow-Up ............................................................................................... 30
4.4
End of Study Definition................................................................................................. 33
5.
Study Population ............................................................................................................. 33
5.1
Inclusion Criteria ........................................................................................................... 33
5.2
Exclusion Criteria .......................................................................................................... 35
5.3
Lifestyle Considerations ................................................................................................ 37
5.3.1
Meals and Dietary Restrictions................................................................................... 37
5.3.2
Caffeine, Alcohol, and Tobacco................................................................................. 37
5.4
Screen Failures............................................................................................................... 37
6.
Study Intervention........................................................................................................... 37
6.1
Study Intervention(s) Administered............................................................................... 39
6.2
Preparation/Handling/Storage/Accountability............................................................... 39
6.3
Measures to Minimize Bias: Randomization and Blinding ........................................... 40
6.4
Study Intervention Compliance ..................................................................................... 40
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6.6
Dose Modification ......................................................................................................... 44
6.6.1
Toxicity Management and Dose Modification Recommendations for Regorafenib.. 45
6.6.2
Toxicity Management and Dose Modification Recommendations for Nivolumab.... 48
6.7
Intervention after the End of the Study.......................................................................... 52
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 53
7.1
Discontinuation of Study Intervention........................................................................... 53
7.2
Lost to Follow-up........................................................................................................... 55
8.
Study Assessments and Procedures............................................................................... 56
8.1
Efficacy Assessments..................................................................................................... 56
8.2
Safety Assessments........................................................................................................ 59
8.2.1
Physical Examinations................................................................................................ 59
8.2.2
Vital Signs .................................................................................................................. 59
8.2.3
Electrocardiograms..................................................................................................... 60
8.2.4
Clinical Safety Laboratory Assessments .................................................................... 60
8.2.5
ECOG Performance Status ......................................................................................... 60
8.2.6
Pregnancy Tests.......................................................................................................... 61
8.2.7
Baseline Characteristics.............................................................................................. 61
8.3
Adverse Events and Serious Adverse Events ................................................................ 62
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 62
8.3.2
Method of Detecting AEs and SAEs .......................................................................... 63
8.3.3
Follow-Up of AEs and SAEs...................................................................................... 63
8.3.4
Regulatory Reporting Requirements for SAEs........................................................... 63
8.3.5
Pregnancy ................................................................................................................... 64
8.4
Treatment of Overdose................................................................................................... 64
9.
Statistical Considerations ............................................................................................... 68
9.1
Statistical Hypotheses .................................................................................................... 68
9.2
Sample Size Determination............................................................................................ 68
9.3
Populations for Analyses ............................................................................................... 69
9.4
Statistical Analyses ........................................................................................................ 69
9.4.1
General Considerations............................................................................................... 69
9.4.2
Primary Endpoint(s).................................................................................................... 69
9.4.3
Secondary Endpoint(s)................................................................................................ 70
9.4.5
Other Safety Analyse(s).............................................................................................. 70
9.4.6
Other Analyses............................................................................................................ 70
9.5
Interim Analyses ............................................................................................................ 71
9.6
Data Monitoring Committee (DMC) or other Review Board........................................ 71
10. Supporting Documentation and Operational Considerations .................................... 71
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10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 71
10.1.1
Regulatory and Ethical Considerations ...................................................................... 71
10.1.2
Financial Disclosure ................................................................................................... 71
10.1.3
Informed Consent Process.......................................................................................... 72
10.1.4
Data Protection ........................................................................................................... 73
10.1.5
Committees Structure ................................................................................................. 74
10.1.6
Dissemination of Clinical Study Data ........................................................................ 74
10.1.7
Data Quality Assurance.............................................................................................. 74
10.1.8
Source Documents...................................................................................................... 76
10.1.9
Study and Site Start and Closure ................................................................................ 76
10.1.10 Publication Policy....................................................................................................... 77
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 77
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................................. 79
10.3.1
Definition of AE ......................................................................................................... 79
10.3.2
Definition of SAE....................................................................................................... 80
10.3.3
Recording and Follow-up of AE and/or SAE............................................................. 81
10.3.4
Reporting of SAEs...................................................................................................... 82
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 84
10.5
Appendix 5: Genetics..................................................................................................... 86
10.6
Appendix 6: FU Assessments ........................................................................................ 86
10.7
Appendix 7: Response Assessment for CRC - RECIST v1.1 Criteria .......................... 87
10.8
Appendix 8: Response Assessment for CRC - iRECIST............................................... 91
10.9
Appendix 9: New York Heart Association (NYHA) Classification.............................. 95
10.10 Appendix 10: CYP3A4 Inhibitors and Inducers............................................................ 96
10.11 Appendix 11: Guidance for Management of Immune-Related Adverse Events ........... 96
10.12 Appendix 12: Abbreviations........................................................................................ 100
12. Protocol Amendments................................................................................................... 108
12.1
Amendment History..................................................................................................... 108
12.2
Global Amendment 1................................................................................................... 108
Table of Tables
Table 1–1: Objectives and Endpoints....................................................................................... 11
Table 1–2: Schedule of Activities ............................................................................................ 13
Table 3–1: Objectives and Endpoints....................................................................................... 28
Table 6–1: Administration of Study Intervention .................................................................... 39
Table 6–2: Dose Modification for Regorafenib ....................................................................... 45
Table 6–3: Regorafenib Dose Modification/Dose Interruption Guide: (except HFSR, 
Hypertension, and Liver Function Test Abnormalities)........................................ 46
Table 6–4: Regorafenib Dose Modification Guidance: HFSR/ Palmar-Plantar 
Erythrodysesthesia Syndrome ............................................................................... 46
Table 6–5: Regorafenib Dose Modification Guidance, Non-Immune Toxicities: Hypertension
............................................................................................................................... 47
Table 6–6: Regorafenib Dose Modifications for Liver Function Test Abnormalitiesa............ 47
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Table 8–1: Definitions for ECOG PS Grading......................................................................... 61
Table 9–1: Populations for Analyses........................................................................................ 69
Table 10–1: Protocol-Required Safety Laboratory Assessments............................................. 78
Table 10–2: Target and Non-Target Lesion Response............................................................. 90
Table 10–3: Assessment of Best Response According to RECIST v1.1 Criteria for 
Participants with Non-Target Lesions Only.......................................................... 90
Table 10–4: Imaging and Treatment after First Radiologic Evidence of PD........................... 94
Table 10–5: New York Heart Association (NYHA) Classification......................................... 95
Table 10–6: An Overview of CYP3A4 Inducers and Strong CYP3A4 Inhibitors................... 96
Table 10–7: Abbreviations ..................................................................................................... 100
Table 12–1: Summary of Changes to the Protocol................................................................. 109
Table of Figures
Figure 1–1: Study Schema ....................................................................................................... 12
Figure 4–1: Study Schema ....................................................................................................... 29
Figure 10–1: iRECIST: Process for Assessment of Disease Progression................................ 95
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1.
Protocol Summary
1.1
Synopsis
Protocol Title: An Open-label, Single-arm, Phase II Study of Regorafenib and Nivolumab in 
Patients with mismatch repair-proficient (pMMR)/Microsatellite Stable (MSS) Colorectal 
Cancer (CRC)
Short Title: Regorafenib and Nivolumab in pMMR/MSS CRC
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Objectives and Endpoints:
Table 1–1: Objectives and Endpoints
Objectives
Endpoints
Primary
!
To evaluate efficacy of the regorafenib and 
nivolumab combinationa
!
ORR per RECIST v1.1a
Secondary
!
Further evaluation of the efficacy of the 
regorafenib and nivolumab combination by 
measuring progression and survival 
intervals
!
To evaluate safety of the combination
!
Duration of Response (DOR)a
!
Disease control rate (DCR) at 8 and 16 
weeksa
!
Progression free survival (PFS)a
!
Overall survival (OS)
!
Incidence and severity of AEs per CTCAE 
v5 
 AE = adverse event; CTCAE = common terminology criteria for 
adverse events; iRECIST = response evaluation criteria in solid tumors for trials testing 
immunotherapeutics; DCR = disease control rate; DOR = duration of response; ORR = objective response 
rate; OS = overall survival; PFS = progression free survival; 
 RECIST = response 
evaluation criteria in solid tumors
a)
The efficacy endpoints will be based on the local Investigator’s assessment according to RECIST 1.1.
Overall Design:
Disclosure Statement:
This is an open-label, single-arm, Phase II Study of Regorafenib in combination with   
Nivolumab in participants with pMMR/MSS CRC.
Number of Participants: Recruitment has been stopped at 70 treated patients. 
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In Amendment 1, it was planned that: approximately 143 participants will be screened to 
achieve 100 treated participants of which approximately 50-60 participants would have a left 
sided primary tumor. In order to allow appropriate balance of participants with right and left 
sided primary tumors, enrollment may be restricted to either left or right sided tumors during 
the study. (Information about right and left sided primary tumors of the participant will be 
recorded by the investigator or delegate in the Interactive voice/web response system (IxRS)
when the participant is registered in IxRS after signing off the PI/ICF.).
Data Monitoring Committee:
Not applicable.
1.2
Schema
This study is composed of the following periods: Screening, treatment, active follow-up (FU), 
and long-term follow up. Participants will be considered “on study” during screening, 
treatment ,active FU periods, and long-term FU periods. An overview of the study schema is 
presented in Figure 1–1.
Figure 1–1: Study Schema 
Screening
Treatmenta
Active FUb
Long-term 
FU
1st dosing 
Informed
consent
Start of treatment 
(nivolumab Q4W + 
regorafenib 
q.d. 
21 days
on /7 
days off)
Last dosing of 
study 
drugs 
(EoT)
Completion 
of 
active 
follow-up
Abbreviations: C = cycle; D = day; EoT = End of treatment; FU = follow-up; i.v. = intra venous; LD = last dose; min = minute; 
q.d. = quaque die (once daily); Q4W = every 4 weeks
a)
Nivolumab 480 mg using a 30-min i.v. infusion every 4 weeks (Q4W). Regorafenib starting dose 80 mg 
orally every day (q.d.) for 21 days of each 28-day every 4 weeks (i.e. 21 days on, 7 days off). If starting 
dose is well tolerated (absence of any rash/HFSR any other or other Grade 2 or higher clinically 
significant toxicity) dose should be escalated to 120 mg orally daily starting with C2D1.
b)
Mandatory safety FU visit (at least 30 d after LD of regorafenib/nivolumab and 100 d after LD of 
nivolumab) and other active FU visits to collect safety and efficacy information for participants who 
discontinue study treatment without disease progression, if applicable.


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1.3
Schedule of Activities (SoA)
Table 1–2: Schedule of Activities
Procedure
Screening 
Treatment perioda
EoT visit
Active
FU
Long-
term
FU
Notes
Cycle1
Cycle 2
Cycle ≥3
within 28 d 
prior to first 
dose
within 7 d 
prior to first 
dosec
D 1
D 8
D15
D22
D1
D8
D15
D1
within 14 d after 
permanent 
discontinuation 
of regorafenib 
and nivolumab
30 d after 
LD of 
regorafenib
and 
nivolumabb
100 d after 
LD for
nivolumabb
every 3 
months
acceptable deviation
± 2 d
± 2 d
± 3 d
+ 7 d
+ 7 d
± 14 d
Informed consent
X
Contact IxRSd
X
X
X
X
X
General
Inclusion and exclusion criteria 
X
X
X
Sections 5.1
and 5.2
Cancer classification (Stage per 
AJCC for CRC) 
X
Section 8.2.7
Primary diagnosis using 
complete pathological report
X
Demography
X
Full physical examination 
X
X
X
X
X
Section 8.2.1
Directed physical examination 
X
X
X
X
X
X
X
Section 8.2.1
Relevant medical history
X
Section 8.2.7
Previous anti-cancer
treatment
X
Section 6.5
Tumor molecular alteration data 
collection (MSI status, BRAF, 
extended RAS)e
X
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Procedure
Screening 
Treatment perioda
EoT visit
Active
FU
Long-
term
FU
Notes
Cycle1
Cycle 2
Cycle ≥3
within 28 d 
prior to first 
dose
within 7 d 
prior to first 
dosec
D 1
D 8
D15
D22
D1
D8
D15
D1
within 14 d after 
permanent 
discontinuation 
of regorafenib 
and nivolumab
30 d after 
LD of 
regorafenib
and 
nivolumabb
100 d after 
LD for
nivolumabb
every 3 
months
acceptable deviation
± 2 d
± 2 d
± 3 d
+ 7 d
+ 7 d
± 14 d
AE reviewf
X
X
=======================================================
Sections 8.3
and 10.3
ECOG performance status
X
X
X
X
X
X
X
X
Section 8.2.5
Serum pregnancy test if 
applicable (WOCBP only)g
X
X
X
X
X
X
Table 10–1
Serology testing for Hepatitis 
B/C incl. HIV-1 (if applicable) 
X
If clinically indicated
Clinical chemistryh
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Table 10–1
PT/INR and aPTT
X
X
X
If clinically indicated
Urine analysis by dipsticki
X
X
X
X
X
Thyroid function testing
X
X
X
X
12-lead ECG
X
X
Section 8.2.3
Vital signs (including weight)
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
Efficacy
Tumor assessment (CT/MRI)j
X
X
X
X
X
Section 8.1
Survival status
X
X
X
Review of subsequent anti-
cancer therapy 
X
X
X
 
 
X
X
X
X
X
X
X
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Procedure
Screening 
Treatment perioda
EoT visit
Active
FU
Long-
term
FU
Notes
Cycle1
Cycle 2
Cycle ≥3
within 28 d 
prior to first 
dose
within 7 d 
prior to first 
dosec
D 1
D 8
D15
D22
D1
D8
D15
D1
within 14 d after 
permanent 
discontinuation 
of regorafenib 
and nivolumab
30 d after 
LD of 
regorafenib
and 
nivolumabb
100 d after 
LD for
nivolumabb
every 3 
months
acceptable deviation
± 2 d
± 2 d
± 3 d
+ 7 d
+ 7 d
± 14 d
Study intervention 
administration
Study treatment: Nivolumabk
X
X
X
Section 6.1
Study treatment: Regorafenibk
===============================
21 days on/ 7 days off
Section 6.1
Drug accountability 
===============================
X
Concomitant medication review 
(including vaccination)
X
=======================================================
Section 6.5
Research sample collection
X
X
X
Section 8.8
Baseline tumor tissueo
X
On-treatment biopsyo
X
Progression biopsyo
X
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Procedure
Screening 
Treatment perioda
EoT visit
Active
FU
Long-
term
FU
Notes
Cycle1
Cycle 2
Cycle ≥3
within 28 d 
prior to first 
dose
within 7 d 
prior to first 
dosec
D 1
D 8
D15
D22
D1
D8
D15
D1
within 14 d after 
permanent 
discontinuation 
of regorafenib 
and nivolumab
30 d after 
LD of 
regorafenib
and 
nivolumabb
100 d after 
LD for
nivolumabb
every 3 
months
acceptable deviation
± 2 d
± 2 d
± 3 d
+ 7 d
+ 7 d
± 14 d
Abbreviations: AE = adverse event; AJCC = American Joint Committee on Cancer; aPTT = activated partial thromboplastin time; BRAF = proto-oncogen BRAF; C = cycle; CEA 
= carcinoembryonic antigen; CRC = colorectal cancer; CT = computed tomography; CTCAE = common terminology criteria for adverse events; D (d) = day; ECG = electro 
cardiogram; EoT = end of treatment; ECOG = Eastern Cooperative Oncology Group; FU = follow-up; GGT = gamma-glutamyl transferase; HIV = human immunodeficiency 
virus; hr = hour(s); INR = international normalized ratio; IxRS = interactive voice/web response system; LD = last dose; MRI = magnetic resonance imaging; MSI = 
microsatellite instability; PI/ICF = Participant information (informed consent form); PK = pharmacokinetics; PT = prothrombin time; RAS = proto-oncogen RAS; RECIST = 
response evaluation criteria in solid tumors; SAE = serious adverse event; WOCBP = women of childbearing potential.
a)
Note: The ± 2 d and ± 3 d assessment windows do not apply to collection of PK blood samples.
b)
A mandatory clinical visit to monitor safety will take place 30 d (window of +7 d) after the last administration of regorafenib/nivolumab and 100 d (window of +7 d) after 
the last dose of nivolumab, with the exception of death or withdrawal of consent.
c)
If tested within 7 days prior to first dose no additional testing on D1 required except for pregnancy testing and abnormal liver function tests.
d)
Contact IxRS to record the following: 1. to register the participant who has signed the PI/ICF f (a unique participant identifier will be assigned), 2. the patient is a 
screening failure (failed to meet the criteria during the screening period), 3. on D1 of every treatment cycle so that the specific participant drug bottle/vial can be 
provided for dispensing purposes and also in case the participant has discontinued the study treatment (EOT) for any reason.
e)
Tumor genetic alteration(s), as determined by local testing results for MSI status, BRAF, extended RAS
f)
Participant will be followed for treatment related toxicities until these toxicities resolve, return to baseline or are deemed irreversible. All AEs will be documented for a 
minimum of 100 d after LD of nivolumab or 30 d after LD of regorafenib, whatever occurs later. CTCAE v5.0 will be used.
g)
Serum pregnancy test (for females of childbearing potential only). A negative pregnancy test must be available within 24 hr before study drug administration. Monthly 
pregnancy testing independent of study drug dosing should be conducted as per local regulations where applicable.
h)
Amylase and GGT will be assessed if clinically indicated.
i)
If protein dipstick result is 3+ or abnormal (based on type of urine test strip used), a laboratory urine analysis should be done for the quantification of proteinuria by 
urinary protein/creatinine ratio on a random urine sample preferably taken at mid-morning.
j)
Tumor assessments should be performed according to RECIST v1.1 criteria. Obtain a contrast-enhanced CT scan and/or MRI with contrast of the chest, abdomen, and 
pelvis and any other known sites of disease (as clinically indicated) within 28 d prior to C1D1 (Scans can be used as baseline scans if not older than 4 weeks at C1D1), 
then in the first year every 8 weeks ± 7 d and thereafter every 12 weeks ±14 d. Radiological tumor evaluation within 14 days after last study treatment is not necessary 
if the previous tumor evaluation was performed within 4 weeks (for the first year) or within 8 weeks (thereafter). For participants who discontinue study treatment without 
disease progression, FU tumor evaluations will be performed until progression of malignancy and/or start of subsequent systemic anti-cancer treatment, whichever 
comes first, or any other criterion for withdrawal is met. 
k)
Regorafenib and Nivolumab will start on the same day C1D1. When the two study drugs are administered on the same day, regorafenib is to be taken first orally 
followed by nivolumab infusion. Participants who complete 24 infusions of nivolumab (after approximately 2 years of treatment) will discontinue treatment.
l)
For PK collection details, see Section 8.5, Table 8–2. Pre- and end of infusion of nivolumab sampling C1D1 as well pre-infusion on C2, C5 and C19.
m)
For Immunogenicity collection details, see Section 8.5, Table 8-2. Pre-infusion (C1, C2, C5 and C19)
n)
Collection of stool can be performed at any time during visit or within ±7 d of the planned visit.
o)
Tumor tissue requirement: Formalin-fixed paraffin-embedded block or minimum of 20 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical 
specimen. Baseline: mandatory recent tumor tissue samples, defined as tumor tissue obtained within 180 d of enrollment and after the last dose of most recent anti-
cancer therapy or tissue from a new biopsy. New tumor collection should be performed after confirmation of preliminary safety eligibility. Exceptions for patients with no 
recent baseline tumor tissues may be considered after documented discussion and approval by the sponsor. Archival tumor tissue must be provided if available. On 
treatment: C2D8 (+7d), mandatory if medically feasible. At progression: EoT (+7d), mandatory if medically feasible. The lesion accessible for biopsy may not be the only 


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Table 1–3: Schedule of Biomarker Blood Sampling 
Procedure
Screening
Treatment
Cycle 1
Cycle 2
Cycle 4
Cycle 6
Cycle 8 and 
every even 
cycles
EoT
within 7 d
prior to 1st dose
D1
D8
D1
D8
D1
D1
D1
pre-dose
pre-dose
pre-dose
pre-dose
pre-dose
pre-dose
pre-dose
acceptable 
deviation
- 30 min
- 30 min
- 30 min
- 30 min
- 30 min
- 30 min
- 30 min
Abbreviations: ctDNA =circulating tumor deoxyribonucleic acid; D (d) = Day; EoT = end of treatment; RNA = ribonucleic acid 
a)
For details please refer to the biomarker Section 8.8.
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antibodies targeting VEGF pathway (bevacizumab, aflibercept, ramucirumab) and epidermal 
Even with the recent approvals of these two agents, a high unmet need remains in this patient 
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angiogenic, inflammatory and immunosuppressive signature, with a high density of 
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randomization (i.e., 2 years after treatment initiation), suggesting that there may be minimal 
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3.
Objectives and Endpoints
Table 3–1: Objectives and Endpoints
Objectives
Endpoints
Primary
!
To evaluate efficacy of the regorafenib and 
nivolumab combinationa
!
ORR per RECIST v1.1a
Secondary
!
Further evaluation of the efficacy of the 
regorafenib and nivolumab combination by
measuring progression and survival 
intervals
!
To evaluate safety of the combination
!
Duration of Response (DOR)a
!
Disease control rate (DCR) at 8 and 16 
weeksa
!
Progression free survival (PFS)a
!
Overall survival (OS)
!
Incidence and severity of AEs per CTCAE 
v5 
 AE = adverse event; CTCAE = common terminology criteria for 
adverse events; iRECIST = response evaluation criteria in solid tumors for trials testing 
immunotherapeutics; DCR = disease control rate; DOR = duration of response; ORR = objective response 
rate; OS = overall survival; PFS = progression free survival; PK = pharmacokinetics; RECIST = response 
evaluation criteria in solid tumors
a)
The efficacy endpoints will be based on the local Investigator’s assessment according to RECIST 1.1.
4.
Study Design
4.1
Overall Design
This is an open label, multicenter, single arm, Phase II study of regorafenib and nivolumab 
combination in participants with advanced or metastatic pMMR/MSS CRC who have been
previously treated with no more than two (for extended RAS mutant) or three (for extended 
RAS wild type) lines of systemic chemotherapy. The study will be conducted at 
approximately 17 sites in North America. In Amendment 1, it was planned that at least 100 
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participants who qualify for the study will be treated with regorafenib plus nivolumab. 
Recruitment has been stopped at 70 treated patients. 
4.1.1
Screening Phase
The start of the study period is defined by signing of the informed consent form (ICF). 
Participants with advanced pMMR/MSS colorectal cancer will be screened for eligibility up 
to 28 days (d) immediately prior to starting study intervention on cycle (C)1 day (D)1. During 
this time, the inclusion and exclusion criteria will be assessed, and all screening procedures 
will be performed. Results of all screening/baseline evaluations must be reviewed by the 
investigator or his/her designee prior to enrollment of each participant into the study to ensure 
that all inclusion and exclusion criteria have been satisfied.
Figure 4–1: Study Schema
Screening
Treatmenta
Active FUb
Long-term 
FU
1st dosing 
Informed
consent
Start of treatment 
(nivolumab Q4W + 
regorafenib 
q.d. 
21 days on/7 days 
off)
Last dosing of 
study 
drugs 
(EoT)
Completion 
of 
active 
follow-up
Abbreviations: C = cycle; D = day; FU = follow-up; i.v. = intra venous; LD = last dose; min = minute; q.d. = quaque die (once 
daily); Q4W = every 4 weeks
a)
Nivolumab 480 mg using a 30-min i.v. infusion every 4 weeks (Q4W). Regorafenib starting dose 80 mg orally every 
day (q.d.) for 21 days of every 28 -day cycle (i.e. 21 days on, 7 days off). If starting dose is well tolerated (absence 
of any grade rash/HFSR or other Grade 2 or higher clinically significant toxicity) dose should be escalated to 120 
mg orally daily starting with C2D1.
b)
Mandatory safety FU visit (at least 30 d after LD of regorafenib/ nivolumab and100 d after LD of nivolumab) and 
other active FU visits to collect safety and efficacy information for participants who discontinue study treatment 
without disease progression, if applicable.
4.1.2
Treatment Phase
Participants will be treated with nivolumab i.v. given on D1 and regorafenib orally every day 
for 21 days in a 28-d cycle. Nivolumab will be administered as a flat dose of 480 mg using a 
30 min i.v. infusion Q4W. Regorafenib will be given at a starting dose of 80 mg for 21 days
of every 28-day cycle (i.e., 21 days on, 7 days off). If the starting dose of 80 mg daily is well 
tolerated (absence of any grade rash/HFSR or other Grade 2 or higher clinically significant 
toxicity) the dose should be escalated to 120 mg orally daily starting with C2D1. Dose 
modification guidelines for dose reduction in case of toxicity are detailed in Section 6.6. The 
Sponsor should be consulted, if the Investigator decides to not escalate the dose to 120 mg 
despite meeting the criteria.  
Participants will continue treatment until disease progression as defined by RECIST v1.1, 
unacceptable toxicity or consent withdrawal, withdrawal from the study at the discretion of 
the investigator or his/her designated associate(s) or any other withdrawal criteria are met. 
Treatment beyond radiological progression as per Response evaluation criteria in solid tumors 
for trials testing immunotherapeutics (iRECIST) is possible if the participant is still benefiting 
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Patients who complete 24 infusions of nivolumab (after approximately 2 years of treatment) 
need to discontinue treatment. Regorafenib monotherapy treatment can be continued beyond 2 
years until discontinuation criteria are met.
During the study, participants will undergo evaluations for safety, efficacy, and tissue and 
blood for biomarker will be collected. Tumor assessments will be at baseline, every 8 weeks 
± 7 d for the first year and thereafter every 12 weeks ±14 d until progressive disease. 
Treatment with individual drugs (regorafenib or nivolumab) may continue on schedule even if 
the other drug is interrupted or permanently discontinued due to toxicity.
Primary endpoint of the study is ORR measured by RECIST v1.1 as determined by 
investigator. Scans will be prospectively collected and stored by a vendor in case independent 
central review is needed.
4.1.3
Active Follow-Up
A mandatory clinical visit to monitor safety will take place 30 d (window of +7 d) after the 
last administration of regorafenib/nivolumab and 100 d (window of +7 d) after the last dose of 
nivolumab. Longer safety FU for nivolumab is required due to the long half-life of the 
antibody.
Participants who discontinue study intervention due to radiologically progressive disease will 
terminate the active FU period after the clinical safety visits.
Participants, who have not progressed clinically or radiologically or have discontinued study 
intervention for reasons other than death, withdrawal of consent or lost to FU, will continue 
with radiological tumor assessments. During the active follow-up period, CT (computed 
tomography) /MRI (magnetic resonance imaging) evaluations will be performed at the same 
intervals as during study treatment (every 8 weeks for the first year, and thereafter, every 12
weeks). In addition, study intervention-related toxicity/AE and information about survival 
status and subsequent anti-cancer therapy will be followed up until completion of the active 
FU. 
4.1.4
Long-Term Follow-Up
All surviving participants will enter the long-term FU period after discontinuing from the 
active FU period except for participants who explicitly withdraw consent or are lost to FU.  
Participants will be followed for overall survival and subsequent anti-cancer therapy at 3-
month intervals (± 14 d) until end of study, 2 years after the last participant started study 
intervention (telephone contact is sufficient) or consent withdrawal or death or lost to FU.
Participants may be contacted at additional times throughout the course of the study in order 
to collect survival data to ensure that long-term FU data is current.
 
 
 
 
 
 
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patients with mCRC. Primary endpoint for the study is ORR by RECIST, which is an 
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4.4
End of Study Definition
The end of the study (EOS) is defined as the date when the last visit of the last participant has 
been achieved in all participating centers.
Last patient last visit (LPLV) of a participant is reached if he/she has completed the last 
scheduled procedure shown in the Schedule of Activities (this also includes phone contacts 
during long-term FU) unless the patient died or withdrew consent or is lost to FU. 
The LPLV date may also be reached based on the last participant switching to a roll-over 
study or being switched to commercial drug supply with no cost to the participant.
Furthermore, to reach EOS, the following criteria need to be satisfied in this study: 

All participants have discontinued nivolumab treatment.

The last included participant has been followed for at least 24 months since first study 
treatment administration.
If the study is stopped by the Sponsor but benefits are observed for ongoing participant s, 
further treatment options may be discussed and agreed between the investigator, sponsor and 
the participant (for further information refer to Section 10.1.9). 
Primary completion
The primary completion is defined by the event when all participants have been assessed for 
response rate (as defined by RECIST v1.1) by at least 5 post-baseline scans unless they have 
discontinued before due to progression or any other reason i.e., have been followed for 
approximately 10 months from 1st dose.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Recruitment has been stopped at 70 treated patients.
In Amendment 1, it was planned that approximately 143 participants would be screened to 
achieve 100 treated participantsof which approximately 50-60 participants would have a left 
sided primary tumor. In order to allow appropriate balance of participants with right and left 
sided primary tumors, enrollment may be restricted to either left or right sided tumors during 
the study. (Information about right and left sided primary tumors of the participant will be 
recorded by the investigator or delegate in IxRS when the participant is registered in IxRS 
after signing off the PI/ICF.).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the ICF and in this 


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protocol. A signed informed consent must be obtained prior to conducting any study-
specific procedures. 
2. Male and female adult participants 18 years of age or older on day of signing informed 
consent.
3. Histological or cytological confirmed advanced, metastatic, or progressive
pMMR/MSS adenocarcinoma of colon or rectum.
a) Microsatellite status should be performed per local standard of practice. (e.g., IHC 
and/or PCR, next-generation sequencing). Only participants with pMMR/MSS 
mCRC are eligible.
4. Known extended RAS and BRAF status as per local standard of practice.
5. Participant must have progressed (radiologically or clinically) or been intolerant to no 
more than two (for extended RAS mutant) or three (for extended RAS wild type) lines 
of systemic chemotherapy regimens for advanced or metastatic CRC. Maintenance 
regimens, such as 5-fluorouracil or capecitabine, with or without bevacizumab, should 
not be counted as separate lines of treatment.
Reintroduction of previously 
administered 
chemotherapy 
containing 
oxaliplatin, 
irinotecan
or 
5-
fluorouracil/capecitabine, without newly added biologics like EGFR inhibitor for RAS 
wild type patients and locoregional treatments such as hepatic arterial infusion therapy
or Yttrium-90 radioembolization should not be counted as separate lines of treatment.
O Prior line of therapy must include ALL of the following agents 
a) Fluoropyrimidines
b) Irinotecan
c) Oxaliplatin
d) anti-VEGF therapy, and, if extended RAS wild type, an anti-
EGFR therapy (if appropriate and patient is eligible) 
o Patient must have evidence of progression on or after the last treatment 
regimen received and within 6 months prior to study enrollment
o Patients who were intolerant to prior systemic chemotherapy regimens are 
eligible if there is documented evidence of clinically significant intolerance 
despite adequate supportive measures.
O Adjuvant/neoadjuvant chemotherapy can be considered as one line of
chemotherapy for advanced/metastatic disease if the participant had disease 
recurrence within 6 months of completion
6. ECOG (Eastern Cooperative Oncology Group) PS of 0 to 1.
7. Adequate hematologic and organ function as assessed by the following laboratory tests 
performed within 7 d before treatment initiation:

Total bilirubin ≤1.5 x the upper limit of normal (ULN). Total bilirubin (≤3 x ULN) 
is allowed if Gilbert’s syndrome is documented.

Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN
(≤5 x ULN for patients with liver involvement of their cancer)

Platelet count ≥100,000 /mm3, Hemoglobin (Hb) ≥9 g/dL, WBC ≥2000/μL 
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
Serum creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min (measured or 
calculated using the Cockroft-Gault formula)

Prothrombin time-international normalized ratio (PT/INR) <2.3 and activated 
partial thromboplastin time (aPTT) <1.5 x ULN. 
8. Measurable disease as determined by RECIST v1.1
9. Provision of recent tumor tissue (as defined below) is mandatory for all participants at 
screening (Formalin-fixed paraffin-embedded block or minimum of 20 slides). 

Tumor tissue obtained within 180 d of enrollment and after the last dose of most 
recent anti-cancer therapy 

Or a new biopsy  
Exceptions for patients with less than required tumor tissues may be considered after 
documented discussion and approval by the sponsor.
10. Anticipated life expectancy greater than 3 months
11. Be able to swallow and absorb oral tablets.
12. Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study intervention and 210 d after last 
dose of regorafenib and 5 months after the last dose of nivolumab.
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study intervention and 120 d after last 
dose of regorafenib. In addition, male participants must be willing to refrain from 
sperm donation during this time.
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Please refer to Section 10.4 for more information. 
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Participants with dMMR/MSI-H colorectal cancer.
2. Prior therapy with regorafenib, anti-PD-1, PD-L1, or CTLA-4 inhibitors, or any form 
of immunotherapy to treat cancer 
3. Systemic anti-cancer treatment within 14 d or less than 5 half-lives (whichever is 
shorter) of the first dose of study treatment
4. Has unresolved clinically significant toxicity of greater than or equal to National 
Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE, v5.0) Grade 2 
attributed to any prior therapies (excluding anemia, lymphopenia, alopecia, skin 
pigmentation, and platinum-induced neurotoxicity)
5. Arterial thrombotic or embolic events such as cerebrovascular accident (including 
transient ischemic attacks) within 6 months before the start of study medication. 
Active pulmonary emboli or deep vein thrombosis that are significant or not 
adequately controlled on anticoagulation regimen
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7. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last
3 months), myocardial infarction less than 6 months before start of study drug
8. Uncontrolled cardiac arrhythmias
9. Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 
mmHg despite optimal medical management
10. Persistent proteinuria of NCI-CTCAE Grade 3. Urine dipstick result of 3+ or 
abnormal, based on type of urine test strip used, is allowed if protein excretion 
(estimated by urine protein/creatinine ratio on a random urine sample) is <3.5 g/24 hr
11. Major surgical procedure or significant traumatic injury within 28 d before start of 
study medication. Note: If participants received major surgery, they must have 
recovered adequately from the toxicity and/or complications from the intervention 
prior to starting therapy
12. Non-healing wound, non-healing ulcer, or non-healing bone fracture
13. Participants with evidence or history of any bleeding diathesis, irrespective of severity
14. Any hemorrhage or bleeding event ≥ NCI-CTCAE Grade 3 within 28 d prior to the 
start of study medication 
15. Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., 
Crohn’s disease, malabsorption, or ≥ NCI-CTCAE Grade 2 diarrhea of any etiology.
16. Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus
(T1DM), hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll.
17. Participants with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 d of start of study treatment. Inhaled or topical steroids, and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.
18. History of (non-infectious) pneumonitis that required steroids or current pneumonitis
19. History of interstitial lung disease
20. Subjects with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 3 years prior to 
study entry and no additional therapy is required or anticipated to be required during 
the study period. 
21. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy. 
22. Presence of symptomatic central nervous system (CNS) metastases, or CNS 
metastases that require local CNS-directed treatment (such as radiotherapy or surgery). 
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entry. In addition, subjects must be either off corticosteroids, or on a stable or 
decreasing dose of 10 mg daily prednisone (or equivalent).
23. Ongoing infection > Grade 2 NCI-CTCAE requiring systemic therapy.
24. Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 
antibodies).
25. Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) 
indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia 
antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA 
negative).
26. Pregnancy or breast feeding. 
27. Psychological, familial, or sociological condition potentially hampering compliance 
with the study protocol and FU schedule. 
28. Previous treatment with live vaccine within 30 d of planned start of study drugs 
(seasonal flu vaccines that do not contain a live virus are permitted).
29. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
the formulation.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
For details please refer to Sections 6.1 and 6.5.
5.3.2
Caffeine, Alcohol, and Tobacco
Not applicable for this protocol. 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention. 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 and any serious AE (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Whether the participant can repeat the screening will be discussed with the 
Sponsor. Sponsor’s approval of re-screening for a participant must be documented. 
Also, for re-screening, the participant has to re-sign the informed consent form, even if it was 
not changed after the patient’s previous screening. The screening failure will be registered in 
Interactive Voice/Web Response System (IxRS) to close the participant identification number 
(PID), and re-screening will start again by signing a new informed consent form and being 
assigned a new PID via IxRS. 
6.
Study Intervention
Study intervention is defined as any investigational intervention intended to be administered 
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Participants will receive nivolumab intravenously on day 1 of every cycle. Nivolumab will be 
administered as a dose of 480 mg using a 30-min i.v. infusion Q4W. 
Regorafenib will be given orally every day for 21 days of each 28-day cycle. Each treatment 
cycle will be 28 days in duration. Regorafenib will be given as 40 mg tablets q.d. for 21 days 
of every 28-day cycle (i.e., 21 days on, 7 days off) as a starting dose of 80 mg. If starting dose 
of 80 mg daily is well tolerated (absence of any grade rash/HFSR or other Grade 2 or higher 
clinically significant toxicity) dose should be escalated to 120 mg orally daily starting with 
C2D1. Sponsor should be consulted, if the Investigator decides to not escalate the dose to 120 
mg despite meeting the criteria. 
When the two study drugs are administered on the same day, regorafenib is to be taken first 
orally followed by nivolumab infusion.
Regorafenib should be taken within 2 hr 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 hr interval between doses). Tablets should not be 
chewed. If a dose of regorafenib is missed, the missed dose should not be made up for 
(vomited tablets cannot be made up), and the next dose should be taken at the regular time. 
The subsequent dose of regorafenib should not be doubled. The investigator should be 
informed if the dose of regorafenib taken exceeded the scheduled dose.
On days when pre-dose PK blood samples will be collected (Table 8–2), participants will take 
the morning dose of regorafenib at the clinic after all required samples are collected. On days 
PK samples are not required, regorafenib can be taken at home or in clinic.
Participants will continue treatment until disease progression as defined by RECIST v1.1, 
unacceptable toxicity or consent withdrawal, withdrawal from the study at the discretion of 
the investigator or his/her designated associate(s) or any other withdrawal criteria are met. 
Treatment beyond radiological progression is possible if the participant is still benefiting from 
treatment. In order to continue treatment after initial documentation of disease progression, 
participant must be re-consented. In case of treatment interruption or discontinuation due to 
Nivolumab or Regorafenib related toxicities participants may continue treatment with either 
Nivolumab or Regorafenib single agent respectively. 
Participants who complete 24 infusions of nivolumab (after approximately 2 years of 
treatment) need to discontinue treatment. Regorafenib treatment can be continued until 
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6.1
Study Intervention(s) Administered
Table 6–1: Administration of Study Intervention
Study Intervention 
Regorafenib 
Nivolumab
Type 
small molecule drug (MKI)
monoclonal antibody, biologic
Dose Formulation
tablet
concentrate for solution for infusion
Unit Dose 
Strengths
40 mg / tablet
240 mg / 24 mL vial (10 mg/mL)
Dosage Levels
2x 40 mg tablets every day (q.d.) for 21 
days of every 28-day cycle (i.e. 21 days on, 
7 days off) as a starting dose of 80 mg.
If the starting dose is well tolerated dose 
should be escalated to 120 mg (3x40 mg 
tablets) starting with C2D1.
480 mg (2x240 mg / 24 mL vials) on D1 
of each cycle
Route of 
Administration
oral
i.v. infusion
IMP and NIMP
IMP
IMP
Sourcing
Regorafenib will be provided centrally by 
the Sponsor.
Nivolumab will be provided centrally by 
the Sponsor. 
Packaging and 
Labeling
Regorafenib is available in high density 
polyethylene bottles with a white child 
resistant closure and induction seal. The 
packaging configuration is 30 tablets 
Regorafenib 40 mg and a 3 g desiccant per 
bottle of Regorafenib 40 mg. The bottles
will be labeled as required per country 
requirement.
Nivolumab will be provided in glass
injection vial. Each glass injection vial will 
be labeled as required per country
requirement.
Abbreviations: IMP = investigational medicinal product; i.v. = intravenous; MKI = multikinase inhibitor; NIMP = non-
investigational medicinal product
6.2
Preparation/Handling/Storage/Accountability
The Investigator (or designee) must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Study intervention should be stored in a secure locked location and at the recommended label 
temperature for the regorafenib 40 mg tablets in bottles and the nivolumab 240 mg / 24 mL 
vials.
Note: The regorafenib bottle contains a desiccant. 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, tablets should be used within 7 weeks. Any unused tablets 
must be returned to study site by the patient. Beyond that, no special precautions are required, 
when handling the study drug.
The personnel will use the study intervention only within the framework of this clinical study 
and in accordance with this protocol. Only participants enrolled in the study may receive 
study intervention and only authorized site staff may supply or administer study intervention. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. The Investigator, institution, or the head of 
the medical institution (where applicable) is responsible for study intervention accountability, 


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reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records).
Further guidance and information for the final disposition of unused study interventions are 
provided in a separate document.
6.3
Measures to Minimize Bias: Randomization and Blinding
Randomization and blinding are not applicable for this study.
This is an open-label study and all open label intervention at all visits must be assigned by the 
IxRS for tracking and accountability purpose. 
Participant identification
After a participant has signed the PI/ICF, the participant identification number will be 
provided to the investigators through an IxRS. Participants will be identified by a 9-digit 
participant identification number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9
= Current patient number within the center
In order to allow appropriate balance of participants with right and left sided primary tumors, 
enrollment may be restricted to either left or right sided tumors during the study. Information
about right and left sided primary tumors of the participant will be recorded by the 
investigator or delegate in IxRS when the participant is registered in IxRS after signing off the 
PI/ICF.
The IxRS procedure is described in detail in a separate IxRS instruction manual that will be 
maintained in the electronic trial master file (eTMF) and in each center’s investigator site file.
6.4
Study Intervention Compliance
The administration of intravenous nivolumab will be performed in the clinic on D1 of every 
treatment cycle. The date and time of each infusion administered in the clinic will be recorded 
in the source documents and recorded in the electronic case report form (eCRF). Reasons for 
dose delay or infusion interruption will also be recorded in the source data and in the eCRF. 
The number of vials used will be recorded on the appropriate treatment dispensing form. 
When participants are dosed at the site, they will receive regorafenib directly from the 
Investigator or designee.
Additionally, for treatment compliance oral administration of regorafenib will be done under 
supervision of site staff on PK visit days, and the dosing and time must be documented in the 
source data and eCRF on the following days: D1, D8 and D15 of C1, and on D1 and D15 of 
C2.
When participants self-administer regorafenib at home, compliance with regorafenib will be 
assessed at each study visit. Compliance will be assessed by counting returned tablets. A 
record of the number of regorafenib tablets dispensed to and returned by each participant must 
be maintained and reconciled with regorafenib start and stop dates, including dates for dose 
delays and/or dose reductions which will also be recorded in the eCRF. Any discrepancies 
between actual and expected amount of returned study medication must be discussed with the 
participant at the time of the visit, and any explanation must be documented in the source 


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records. An adequate record of receipt, distribution, and return/destruction of all study 
intervention must be kept.
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6.6
Dose Modification 
Based on the known toxicity profiles of regorafenib and nivolumab, certain AEs are likely to 
be associated with one drug versus the other. For example, treatment emergent hypertension 
and HFSR are likely to be associated with regorafenib rather than nivolumab; similarly, 
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immune-related AEs are likely to be associated with nivolumab rather than regorafenib. 
However, some drug-related AEs such as diarrhea, abnormal thyroid function, and fatigue are 
overlapping. Therefore, it is important to evaluate each AE to confirm etiology or exclude 
other causes in order to determine proper management of the adverse reaction and action 
regarding study treatment. A careful decision should be made by Investigators based on all 
clinical information, e.g., relatedness to study medications. 
Dose modifications must be based on the maximum toxicity experienced during a cycle. If 
appropriate, the Investigator may attribute each toxicity event to regorafenib or nivolumab 
alone or to the combination. In situations where clear attribution cannot be made to individual 
drugs, more conservative dose modification approach should be used for both drugs. In case 
of dose modifications, any efforts should be made to restart study intervention as per original 
schedules for regorafenib and nivolumab.
6.6.1
Toxicity Management and Dose Modification Recommendations for 
Regorafenib
Table 6–2 outlines different regorafenib dose levels for the purpose of dose modification. In 
case a dose reduction for regorafenib is necessary, the study intervention will be administered 
as outlined in Table 6–2 to Table 6–6.
Table 6–2: Dose Modification for Regorafenib
Dose Level
Daily Regorafenib (21 days on, 
7 days off)
Daily Regorafenib (21 days 
on, 7 days off)
Current Dose
80 mg
120 mg
Dose Level -1
80 mg every other daya
80 mg
Dose Level -2
NA
80 mg every other daya
Abbreviations: mg = milligram; NA = not applicable  
a)
If reductions are required resulting in regorafenib daily dose of less than 80 mg every other day, the regorafenib will 
be permanently discontinued.


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Table 
6–3: 
Regorafenib 
Dose Modification/Dose Interruption
Guide:
(except HFSR, 
Hypertension, and Liver Function Test Abnormalities)
CTCAE 
Grade
Occurrences
Dose Interruption
Dose modification (when resuming 
treatment)
Grade 0-2
Any
No change 
No change
Grade 3
1st and 2nd
occurrence
Hold until recovery to 
<G2 or baselinea
Restart at same dose level or reduce 1 
dose level (at the investigator’s discretion)
3rd occurrence 
Hold until recovery to 
<G2 or baselinea
Reduce 1 dose level or consider permanent 
discontinuationb
Grade 4
1st occurrence 
Hold until recovery to 
<G2 or baselinea
Reduce 1 dose level or consider permanent 
discontinuationb
2nd occurrence 
Hold until recovery to 
<G2 or baselinea
Discontinue
Abbreviations: CTCAE = common terminology criteria for adverse events; G = Grade; HFSR = hand-foot 
skin reaction
a)
Excludes alopecia, non-refractory nausea/vomiting, lymphopenia and asymptomatic laboratory abnormalities. 
Treatment can be resumed with Grade 2 fatigue or hypothyroidism.
b)
If reductions are required resulting in regorafenib daily dose of less than 80 mg eve ry other day, the 
regorafenib will be permanently discontinued. If toxicity returns to Grade 0-1 after dose reduction, dose 
reescalation is permitted in the subsequent cycle at the investigator’s discretion. Subjects requiring a delay of 
>4 weeks should discontinue regorafenib treatment. However, continuation of regorafenib may be considered 
if, in the investigator's opinion, the patient may continue to benefit from the regorafenib treatment, and after 
consultation with Sponsor
Table 6–4: Regorafenib Dose Modification Guidance: HFSR/ Palmar-Plantar Erythrodysesthesia 
Syndrome
Skin toxicity 
grade (CTCAE)
Occurrence
Dose Interruption
Dose modification (when 
resuming treatment)
G1
Any
Maintain dose level and institute 
supportive measures immediately 
for symptomatic relief
No Change
G2
1st occurrence
Interrupt therapy for a minimum
of 7 days, until toxicity resolves to 
Grade 0–1
Institute supportive measures 
and continue same dose or 
consider decrease by 1 dose 
level 
No improvement 
within 7 d or 2nd
occurrence
Interrupt until toxicity resolves or 
improves to G1. 
When resuming treatment, treat 
at reduced dose level or 
consider discontinuationa
3rd occurrence
Discontinue
G3
1st occurrence
Institute supportive measures 
immediately. Interrupt therapy for 
≥ 7 d until toxicity resolves or 
improves to G1. 
When resuming treatment, 
decrease by 1 dose level
2nd occurrence
Institute supportive measures 
immediately. Interrupt therapy for 
≥ 7 d until toxicity resolves or 
improves to G1. 
When resuming treatment, 
decrease by 1 additional dose 
level or consider 
discontinuationa
3rd occurrence
Discontinue 
Abbreviations: CTCAE = common terminology criteria for adverse events; G = Grade; HFSR = hand-foot skin 
reaction
a)
If reductions are required resulting in regorafenib daily dose of less than 80 mg every other day, the regorafenib will 
be permanently discontinued. If toxicity returns to Grade 0-1 after dose reduction, dose reescalation is permitted in 
the subsequent cycle at the Investigator’s discretion. Subjects requiring a delay of >4 weeks should discontinue 
regorafenib treatment. However, continuation of regorafenib may be considered if, in the investigator's opinion, the 
patient may continue to benefit from the regorafenib treatment, and after consultation with Sponsor.


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Table 6–5: Regorafenib Dose Modification Guidance, Non-Immune Toxicities: Hypertension
CTCAE Grade
Suggested regorafenib dose interruption 
Suggested regorafenib 
dose modification
Specific guidance for HYPERTESION
G1
No change. 
Consider increased BP 
monitoring
G2
If symptomatic, hold until symptoms resolve and
diastolic BP ≤ 90 mmHg. Treat with anti-
hypertensive medications
At restart, continue at the same 
dose level
G3
Hold until diastolic BP ≤ 90 mm Hg, and if 
symptomatic, until symptoms resolve. Treat with 
additional anti-hypertensive medications
At restart, 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
If G3 hypertension recurs despite dose reduction 
and optimal antihypertensive therapy
Reduce another dose level or 
consider discontinuationa
G4
Discontinue
Abbreviations: BP = blood pressure; CTCAE = common terminology criteria for adverse events; G = Grade; Hg 
= mercury 
a)
If reductions are required resulting in regorafenib daily dose of less than 80 mg every other day, the regorafenib will 
be permanently discontinued. If toxicity returns to Grade 0-1 after dose reduction, dose reescalation is permitted in 
the subsequent cycle at the investigator’s discretion. Subjects requiring a delay of >4 weeks should discontinue 
regorafenib treatment. However, continuation of regorafenib may be considered if, in the investigator's opinion, the 
patient may continue to benefit from the regorafenib treatment, and after consultation with Sponsor.
Table 6–6: Regorafenib Dose Modifications for Liver Function Test Abnormalitiesa
Increases in AST/ALT/Bilirubin
Occurrence
Dose Interruption
Dose Modification (when 
resuming treatment)
(from baseline within normal limits)
AST and/or ALT < 3 times ULN or total 
bilirubin < 1.5 times ULN
Any
Continue dosing
No Change
(from baseline AST/ALT more than 1 
and up to 3 times ULN)
AST or ALT more than 3 and up to 5 times 
the ULN
Any
Continue dosing
No Change
(from baseline within normal limits)
AST or ALT more than 3 and up to 5 times 
the ULN or total bilirubin more than 1.5 and 
up to 3 times the ULN
1st occurrence
Delay dosing until 
return to Grade ≤ 1 
or baseline
Reduce 1 dose levelb
Re-occurrence
Discontinue
(from baseline any grade)
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN
1st occurrence
Delay dosing until
return to Grade ≤ 1 
or baseline
If the potential to reinitiate 
regorafenib is considered to 
outweigh the risk of 
hepatotoxicity: reduce 1 dose
level
Re-occurrence
Discontinue
(from baseline any grade)
Any
Discontinue 


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Increases in AST/ALT/Bilirubin
Occurrence
Dose Interruption
Dose Modification (when 
resuming treatment)
AST and/or ALT > 20 x ULN
AST and/or ALT > 3 x ULN with concurrent 
bilirubin > 2 x ULN
Any
Discontinuec
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN = upper limit of normal
a)
For any of the events listed above (dose interruption or modification): monitor liver function tests weekly or more 
frequently until recovery to baseline or stabilization
b)
If all values remain stable for 2 full cycles, dose re-escalation may be considered at the discretion of the Investigator. 
After re-escalation AST, ALT, bilirubin should be checked 2×/week for 2 weeks, followed by weekly assessments for at 
least 4 weeks. 
c)
Exception: participants 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.
The dose modification can occur independently for the 2 drugs used if toxicity can be clearly 
attributed to one of the drugs. Resumption of regorafenib dosing is not required to receive 
further nivolumab dosing and vice versa. Treatment with individual drugs (regorafenib or 
nivolumab) may continue on schedule even if other drug is interrupted or permanently 
discontinued due to toxicity.
6.6.2
Toxicity Management and Dose Modification Recommendations for 
Nivolumab
AEs (both non-serious and serious) associated with nivolumab exposure may represent an 
immunologic etiology. These AEs may occur shortly after the first dose or several months 
after the last dose of treatment. Therefore, early recognition and initiation of treatment is 
critical to reduce complications. 
There will be no dose reductions for nivolumab. Treatment can be delayed for nivolumab 
related AEs. If the criteria to resume treatment are met, the subject should restart treatment at 
the next scheduled time point per protocol.
Nivolumab administration should be delayed for the following:

Grade 2 non-skin, drug-related AE, with the exception of fatigue

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities

Grade 3 skin, drug-related AE

Grade 3 drug-related laboratory abnormality, with the following exceptions: 
-
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require 
dose delay
-
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see 
Section 6.6.2.1)

Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication.
There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 
Interrupt or slow the rate of infusion in participants with mild or moderate (Grade 1 -2) 


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infusion reactions. Discontinue nivolumab in participants with severe or life-threatening 
infusion reactions (Grade 3-4) (see Section 6.6.2.4).
Participants who require delay of nivolumab should be re-evaluated weekly or more
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria are 
met (see Section 6.6.2.2). The dose modification can occur independently for the 2 drugs used 
if toxicity can be clearly attributed to one of the drugs. Resumption of regorafenib dosing is 
not required to receive further nivolumab dosing and vice versa. Treatment with individual 
drugs (regorafenib or nivolumab) may continue on schedule even if other drug is interrupted 
or permanently discontinued due to toxicity.
6.6.2.1
Nivolumab Treatment – Permanent Discontinuation

Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 

Any Grade 3 non-skin, drug-related AE lasting >7 d or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
o
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
o
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:

Grade 3 drug-related thrombocytopenia >7 d or associated with bleeding requires 
discontinuation

Grade 3 drug-related AST, ALT or total Bilirubin requires discontinuation

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN

In most cases of Grade 3 AST or ALT elevation, nivolumab treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of nivolumab treatment, a discussion between the investigator and 
the Sponsor must occur.

Any Grade 4 drug-related adverse event or laboratory abnormality (including but not 
limited to creatinine, AST, ALT, or Total Bilirubin), except for the following events 
which do not require discontinuation:
o
Grade 4 neutropenia 7 d
o
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
o
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
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o
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or 
hypothyroidism, or glucose intolerance, which resolve or are adequately controlled 
with physiologic hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after discussion with 
and approval from the Sponsor.

Any event that leads to delay in dosing lasting >10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
o
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 
o
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-
related reasons may be allowed if approved by the Sponsor. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the 
Sponsor must be consulted. Tumor assessments should continue as per protocol even if dosing 
is delayed. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the participant with 
continued nivolumab dosing.
6.6.2.2
Criteria to Resume Nivolumab Treatment
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve to 
Grade 1 or baseline value, with the following exceptions:
Participants may resume treatment in the presence of Grade 2 fatigue
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by Sponsor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the Sponsor. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
6.6.2.3
Management of Immune-Mediated AEs
Because of the potential for clinically meaningful nivolumab related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected pulmonary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, 
neurological toxicity, and renal toxicity. These adverse event management algorithms are 
included in Section 10.11.
These general guidelines constitute guidance to the Investigator and may be supplemented by
discussions with the Sponsor. A general principle is that differential diagnoses should be 


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diligently evaluated according to standard medical practice. Non-inflammatory etiologies 
should be considered and appropriately treated. Corticosteroids are a primary therapy for 
immune related adverse events. The oral equivalent of the recommended IV doses may be 
considered for ambulatory patients with low-grade toxicity. The lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. Consultation with a medical or surgical specialist, especially prior to an 
invasive diagnostic or therapeutic procedure, is recommended.
6.6.2.4
Treatment of Nivolumab related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the Sponsor and reported as an SAE 
if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE, v5.0
guidelines. Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate:
For Grade 1 symptoms:

Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes 
before additional nivolumab administrations.
For Grade 2 symptoms:

Stop the study drug infusion, begin an IV infusion of normal saline, and treat the 
participant with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
participant closely. If symptoms recur, then no further study medication will be 
administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
Diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 
mg should be administered at least 30 minutes before nivolumab and/or ipilimumab 
infusions. If necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may 
be used.
For Grade 3 or 4 symptoms:

Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be 
monitored until the Investigator is comfortable that the symptoms will not recur. Study 


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drug will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant 
until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine or corticosteroids).
Additional details on the immune mediated AEs of nivolumab, including results from other 
clinical studies, are also available in the nivolumab IB.
6.7
Intervention after the End of the Study
At the EOS intervention for each individual participant, further therapeutic options are at the 
discretion of the Investigator.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
General procedures
In all cases, the reason for withdrawal must be recorded in the patient's medical records and in 
the eCRF. For patients who withdraw consent, no further study related procedures will be 
allowed. The patient will not suffer any disadvantage as a result. 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for disease progression and/or OS. See the 
SoA for data to be collected at the time of discontinuation of study intervention, in FU, and 
for any further evaluations that need to be completed.
If the existing local governance (for example, Health Authorities or Ethics Committees) 
prohibits patients who withdraw consent from study drug treatment to continue into 
FU, additional consent processes should be implemented to invite patients to participate in the 
FU or to request that survival data will be available. 
All patients who discontinue due to AEs should be followed up until they recover or stabilize, 
and the subsequent outcome recorded. If any participant dies during treatment, or within 30 d
after the last dose of regorafenib or within 100 d after the last dose of /nivolumab  
administration, the investigator or his/her designated associate(s) will inform the sponsor and 
the cause of death should be recorded in detail within 24 hr of awareness on a Serious AE
(SAE) Form and transmitted to the sponsor.
7.1
Discontinuation of Study Intervention
Withdrawal from study treatment period
Patients MUST be withdrawn from the study treatment combination if any of the following 
occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study treatment would be harmful 
to the patient's well-being.

Clinical progression as per iRECIST (every effort should be made to obtain 
radiological confirmation of disease progression [PD] during active FU). Note: In 
cases where radiographic evaluation is not possible, clinical progression may be used. 
Clinical progression is based on the judgment of the investigator (e.g., defined as 
worsening of the ECOG PS ≥3 or symptomatic deterioration including increase in 
liver function tests).

The development of a second primary malignancy that requires a different treatment.

Development of any intercurrent illness or situation which may, in the judgment of the 
investigator, affect assessments of clinical status and study endpoints to a relevant 
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
Severe allergic reactions, such as exfoliate erythroderma, anaphylaxis, or vascular 
collapse.

Start of subsequent systemic anti-cancer treatment

Use of illicit drugs or other substances that may, in the opinion of the investigator or 
their designated associate(s), have a reasonable chance of contributing to toxicity or 
otherwise confound the results.

Pregnancy

Participant lost to follow-up

Death

Withdrawal of regorafenib only: 
o
Patients who halt therapy for more than 28 consecutive days - including the 1 
week drug holiday. However, continuation of regorafenib may be considered 
if, in the investigator's opinion, the patient may continue to benefit from the 
regorafenib treatment, and after consultation with sponsor.
o
Unacceptable toxicity, i.e., event requiring permanent discontinuation of 
regorafenib according to dose modification guidance in Section 6.6.

Withdrawal of nivolumab only: 
o
Patients who experience a delay of more than 10 weeks to receive the 
subsequent nivolumab infusion due to treatment related toxicity (see 
exceptions in Section 6.6.2.1)
o
Patients who complete 24 infusions of nivolumab (after approximately 2 years 
of treatment)
o
Unacceptable toxicity, i.e. event requiring permanent discontinuation of 
nivolumab according to dose modification guidance in Section 6.6.2.1.
Withdrawal from active FU
Participants must be withdrawn from active FU if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a participant may decline to 
participate further. The participant will not suffer any disadvantage as a result. 

Radiologically confirmed PD is observed and/or clinical progression occurs (provided 
safety visits have been performed)

Start of subsequent systemic anti-cancer treatment (provided safety visits have been 
performed)

Development of a second primary malignancy that requires a different treatment

Substantial non-compliance with the requirements of the study

Withdrawal of consent to active FU visits


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
If, in the investigator's opinion, continuation of the active FU visits would be harmful 
to the participant’s well-being

Participants lost to FU

Death
Withdrawal from long-term FU
Participants must be withdrawn from long-term FU if any of the following occurs:

Withdrawal of consent to long-term FU

Participants lost to FU

Death
Participants MAY be withdrawn from the study treatment combination for the following 
reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g.,
obvious non-compliance, safety concerns).

Withdrawal of nivolumab only: discontinuation of nivolumab may be considered 
for participants who have attained a confirmed complete response (CR), that have 
been received at least 8 infusions (32 weeks) of nivolumab and had at least 2 
infusions with nivolumab beyond the date when the initial CR was declared.
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Table 6–6 or if the 
Investigator believes that it is in best interest of the participant.
If a clinically significant electrocardiogram (ECG) finding is identified (including, but not 
limited to changes from baseline in QT interval corrected using Fridericia’s formula [QTcF] 
after enrollment, the Investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. This revie w of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE.
See the SoA for data to be collected at the time of intervention discontinuation and FU and for 
any further evaluations that need to be completed.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. If a 
participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.
7.2
Lost to Follow-up
A participant will be considered lost to FU 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 
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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 FU.
Discontinuation of specific sites or of the study as a whole are handled as part of 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 (pre-specified exceptions requiring discussion with the 
Sponsor are not considered protocol waivers).
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 evaluations 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.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed
within the time frame defined in the SoA.
8.1
Efficacy Assessments
Primary endpoint for efficacy assessment is ORR measured by RECIST v1.1 as determined 
by Radiologist/Investigator. DOR, DCR and PFS will be based on local 
radiologist/investigator assessment per RECIST v.1.1.
Scans will be prospectively collected and stored at vendor in case independent central review 
is needed.
All participants who received at least one dose of study drug (regorafenib and nivolumab) will 
be valid for efficacy evaluations. Contrast-enhanced multi-detector CT is the preferred 
method to measure lesions selected for response assessment. MRI (typically with gadolinium-
based intravenous contrast) may be performed instead of CT (e.g., when local regulations or 
allergy to CT contrast media do not permit the use of CT as requested per protocol schedule, 
or when there is concern about radiation exposure from CT, or when MRI is deemed a more 
appropriate imaging method). Recommended slice thickness for CT/MRI is ≤5mm. PET-CT 


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scans may be used provided that measurements are obtained from the CT scan and the CT 
scan is of the same diagnostic quality as a diagnostic CT (with IV and oral contrast). If a CT 
scan for tumor assessment is performed in a positron-emission-tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standard for a diagnostic CT scan (i.e., 
adequate radiation dose and i.v. contrast) if intended to be used for target lesion 
measurements. The non-contrast low-dose CT performed as part of the PET scan for 
attenuation correction is not adequate as a diagnostic CT. 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Previously irradiated lesions should not be counted as target lesions unless 
there has been demonstrated progression in the lesion since radiotherapy prior to study 
enrollment.
For consistency, the same imaging modality and equivalent technique (e.g., slice thickness, 
field of view) should be used for all scans performed on an individual participant, including 
baseline scans. At a minimum, anatomical regions that should be included in scans performed 
at baseline and during study treatment include the chest, abdomen and pelvis, as well as any 
other areas of known disease and areas prone to metastatic disease for pMMR/MSS CRC.
Tumor assessments will be performed locally by participating radiologists/Investigators and 
whenever possible all scans taken at each clinical site will be interpreted by the same 
radiologist/Investigator at that site. Scans must meet the standard of care for imaging of 
lesions in the respective organ system(s). Unless progression is noted, all lesions will be 
assessed and reported at each scheduled scan.
All imaging scans (coded with study participant number and in digital imaging and 
communications in medicine [DICOM] format) as well as imaging-related adjunctive data 
(e.g., fluorodeoxglucose [FDG] dose and tracer uptake time) must be prospectively collected 
and transferred to Bayer, or Bayer-designated imaging core lab, in case independent central 
review is needed.
The tumor markers CEA and CA 19-9 will be evaluated on an exploratory basis in 
participants with CRC and will not be used to assess objective tumor response.
Assessment of disease
RECIST v1.1 will be applied by the Investigator as the primary measure for categorization of 
disease on the baseline imaging and assessment of tumor response until progressive disease 
(see Section 10.7). CR and PR must be confirmed with repeated imaging performed at least 4 
weeks after initial documentation of response.
iRECIST is based on RECIST v1.1, but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs. iRECIST will be used by the Investigator to assess tumor 
response and progression, and make treatment decisions (see Section 10.8).
Tumor scans are required at screening, during study treatment and at the End of Treatment:
see section 1.3 SoA Table 1–2. Tumor scans are also required during active follow-up, if 
applicable.
Baseline assessments will be conducted during the screening period and target lesions 
should to be selected, measured, and recorded before start of study intervention. Scans 
that were obtained prior to the participant signing the ICF document for this study can be 
used as baseline assessments provided that they were performed within 28 d of starting 
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Assessments during study treatment will be performed every 8 weeks (±7d) for the first 
year and every 12 weeks ±14 d thereafter. Tumor assessment during the study 
intervention period includes the same anatomic areas as baseline and will be done until 
radiological disease progression or the end of the study.
Radiological tumor evaluation (within 14 days after last study treatment is not necessary if 
the previous tumor evaluation was performed within 4 weeks (for the first year) or within 
8 weeks (thereafter).
For participants who discontinue study treatment without disease progression, FU tumor 
evaluations will be performed until progression of malignancy and/or start of subsequent 
systemic anti-cancer treatment, whichever comes first, or any other criterion for 
withdrawal is met. During the active FU period, CT/MRI evaluations will be performed at 
the same intervals as during study treatment.
At the Investigator’s discretion, tumor scans may be repeated at any time if p rogressive 
disease is suspected. For further details, see Sections 10.7 and 10.8.
For participants who show evidence of radiological PD by RECIST v1.1 and are clinically 
stable, the Investigator will decide whether to continue a participant on study treatment until 
repeat imaging is obtained using iRECIST for participant management. Participant must be re-
consented for continuation of treatment beyond initial documentation of disease progression
(If repeat imaging does not confirm PD per iRECIST (iCPD), as assessed by the Investigator, 
and the participant continues to be clinically stable, study treatment may continue and follow 
the regular imaging schedule. If PD is confirmed (iCPD), participants will be discontinued 
from study treatment).
Treatment beyond confirmed progression as per iRECIST is possible if the participant is still 
benefiting from treatment after documented discussion and approval by the Sponsor.
When clinically stable, participants should not be discontinued until progression is confirmed 
by the Investigator, working with local radiology, according to the rules outlined in 
Section 10.8. This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first few 
months after the start of immunotherapy, and then experience subsequent disease response. 
This data will be captured in the clinical database.
For treatment beyond progression as per iRECIST the following needs to be fulfilled: 
Evidence of clinical benefit as assessed by the investigator
Absence of symptoms and signs indicating unequivocal progression of disease. 
Absence of clinical signs or symptoms of progression despite a rising CEA level.
No decline in ECOG PS that can be attributed to disease progression
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol−allowed medical interventions
Participant must be re-consented once for continuation of treatment beyond initial 
documentation of disease progression. Tumor imaging beyond progression will follow the 
originally planned intervals and will be conducted using iRECIST.


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8.2
Safety Assessments
Investigators should refer to the Safety Information section of the current IB of regorafenib 
and nivolumab for the expected side effects including unexpected AEs and hypersensitivity 
reactions. The IB will be updated if any new relevant safety data are obtained. 
Safety will be assessed by monitoring and recording all AEs and SAEs, cardiac, hematologic 
and blood chemistry parameters, vital signs, ECG, performance status, and any abnormal 
findings observed during the performance of physical examinations.
Planned time points for all safety assessments are provided in the SoA (Table 1–2). 
Therapeutic monitoring should be performed following dose modification of study drugs in a 
manner consistent with the local clinical standard of care. In general, participants should be 
closely monitored for adverse drug reactions of all concomitant medications regardless of the 
path of drug elimination.
In the event of implausible results, the laboratory may measure additional parameters to assess 
the quality of the sample (e.g., clotted or hemolyzed) and to verify the results. The results 
from such additional analyses may neither be included in the clinical database of this stu dy 
nor evaluated further. If the results are relevant, the Investigator will be informed to determine 
FU activities outside of this protocol.
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 8.3). Additional assessments may be indicated at any time during the course of the 
study at the discretion of the Investigator. In addition, lab tests may be repeated at the 
discretion of the Investigator, if clinically indicated.  
8.2.1
Physical Examinations
A full physical examination will be performed by the investigator or qualified designee at 
screening, start of each cycle and EOT visit. Full physical examination includes, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal and neurological 
systems and of skin status. Height will be measured at screening only.  
On all other visits, the investigator or qualified designee will perform a symptom directed 
physical exam as clinically indicated. New clinically significant abnormal findings should be 
recorded as AEs. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2
Vital Signs
Body temperature, heart rate, oxygen saturation and blood pressure will be assessed.
BP and heart rate measurements should be preceded by at least 5 min of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).
When vital signs measurements and ECG measurements are scheduled at the same time point, 
ECG must be obtained before vital signs.
When blood pressure (BP) measurement and PK sample collection are scheduled at the same 
time point, participant’s blood pressure must be measured before collection of PK sample.


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8.2.3
Electrocardiograms
12-lead ECG will be locally obtained as outlined in the SoA (Table 1–2) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
8.2.4
Clinical Safety Laboratory Assessments
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 d (active FU period for regorafenib) or within 100 
d (active FU period for nivolumab) after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator.
○
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor
notified.
○
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the SoA.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (e.g., SAE or AE or dose modification), then the 
results must be recorded in the eCRF.
8.2.5
ECOG Performance Status
Participant’s ability to manage activities of daily living will be appraised utilizing the 
performance status scale by ECOG. The participant’s ECOG PS will be estimated according 
to the schedule summarized in Section 1.3. An ECOG PS score of 0 or 1 is required for study 
inclusion (see Section 5.1). Change of ECOG PS will be measured for safety reasons.
Grading definitions for ECOG PS are given in Table 8–1 below.


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Table 8–1: Definitions for ECOG PS Grading
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without restriction. 
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5
Dead.
Abbreviation.: ECOG PS = Eastern cooperative oncology group performance status.
8.2.6
Pregnancy Tests
Serum pregnancy tests are performed at Screening and during treatment. Specific time points 
can be found in the SoA in Section 1.3. The frequency of pregnancy tests may be higher, if 
required by local regulations. More details can be found in Section 10.4.
8.2.7
Baseline Characteristics
Demographic
Baseline participant data pertaining to demographic information should be documented 
accordingly in the appropriate eCRFs include the following:

Date of birth (year, age) if allowed according to local law

Gender

Race, if legally allowed

Ethnicity, if legally allowed

Weight

Height

Childbearing status (if applicable)
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the Investigator:

Start before signing of the informed consent.

Considered relevant for the participant’s study eligibility.
Other baseline characteristics
Other baseline characteristics will be collected, including but not limit to:

Baseline cancer characteristics, including cancer type, location of the primary tumor, 
histology, tumor stage at study entry, date of diagnosis of first metastasis, presence of 
liver and/or lung metastasis, tumor mutational burden (TMB) and PD-L1 expression 


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(if available), presence of extended RAS and BRAF mutation (when known), MSI 
status, date of most recent progression, prior cancer therapies and procedures

All medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the participant within 30 d 
prior to the study intervention.
All the population characteristic data should be recorded in the eCRF. Detailed instructions on
baseline characteristics can be found in the eCRF completion guidelines.
8.3
Adverse Events and Serious Adverse Events
Progression per se should not be regarded as AE. Instead, the associated signs and s ymptoms 
should be recorded as AEs.
The intensity of AEs should be documented using the NCI-CTCAE, v5.0.  
The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF.

Drug withdrawn

Drug interrupted

Drug delayed

Dose reduced

Dose not changed

Dose increased

Not applicable

Unknown
The definitions of an AE or SAE can be found in Section 10.3.
AEs 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). 
Investigators should refer to the Safety Information section of the current IB of regorafenib 
and the current IB of nivolumab for the expected side effects. As with any agent, there is 
always the potential for unexpected AEs, including hypersensitivity reactions. The IB will be 
updated if any new relevant safety data are obtained.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the end of active FU
visit (30 d after last dose of regorafenib and 100 d after last dose of nivolumab at the time 
points specified in the SoA (Section 1.3).


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Medical occurrences that begin before obtaining informed consent will be recorded on the 
medical history section of the eCRF. Medical occurrences that begin before the start of study 
intervention but after obtaining informed consent will be recorded on the AE section of the 
eCRF. Medical occurrences that started before but deteriorated after obtaining informed 
consent will be recorded as AEs.
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hr, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hr 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 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, and AEs of special interest will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to FU (as defined in Section 7.2). Further information on FU procedures is provided in 
Section 10.3.
8.3.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to the Sponsor of a 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.
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 a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.


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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 outcome.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hr of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
For a pregnancy in the partner of a male study participant, all efforts will be made to obtain 
similar information on course and outcome, participant to the partner’s consent.
For all reports, the forms provided are to be used. The Investigator should submit them within 
the same timelines as an SAE.
8.4
Treatment of Overdose
Overdose of regorafenib
For this study, any dose of study intervention greater than 160 mg within one day 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 d from the date of detection of 
overdose if requested by the Sponsor (determined on a case-by-case basis).
3. Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF.
4. AE associated with an overdose or incorrect administration of study drug should be 
recorded on the AE eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor 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 q.d.  The AEs observed at this dose were primarily dermatological 
events, hoarseness, diarrhea, mucositis, and nausea. In the event of suspected 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 regorafenib overdose. Subjects who have overdosed should 
be treated with symptomatic support. No additional data concerning management of overdose 
are available at this time. 
Overdose of nivolumab
An overdose is defined as the accidental or intentional administration of any dose of 
nivolumab that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. In the event of an overdose, the investigator should:


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1. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically, at least 28 days. 
2. Obtain a plasma sample for PK analysis within 3 days from the date of detection of 
overdose if requested by the Sponsor (determined on a case-by-case basis).
3. Any overdose or incorrect administration of nivolumab should be noted on the Study 
Drug Administration eCRF.
4. AE associated with an overdose or incorrect administration of study drug should be 
recorded on the AE 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 nivolumab 
IB. 
CCI


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CCI


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Timing: See SoA (Table 1–2) and Schedule of Biomarker Blood Sampling (Table 1–3) for 
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9.
Statistical Considerations
This is a single arm, Phase II study with ORR as primary endpoint. Background response rate 
for the combination is estimated to be at most 5%. Target response rate for the combination 
treatment will be 17%. 
A one-sided exact binomial test will be conducted to test the hypothesis.
9.1
Statistical Hypotheses
The underlying hypotheses to be tested in this study is
H0: ORRCombination ≤ 5% versus H1: ORRCombination > 5%
9.2
Sample Size Determination
As of amendment 2, it is decided to stop recruitment at 70 treated patients. With this sample 
size of 70 patients, when the true underlying ORR is 17% or higher, and a baseline response 
rate of 5% is assumed, a one-sided exact binomial test at a type-I error of at approximately 
2.5% would result in a power of 92.6%, with at least 8 responders needed to achieve 
significance.
The location of the primary tumor is a factor and it is expected that 40%-45% of patients will 
have the primary tumor on the right side. With 31 patients with right-sided tumors, the 
probability of observing 4 or more responders (ORR 13%) is approximately 80% when the 
true underlying response rate is 17%, and the probability of observing 2 or fewer responders 
(ORR 6.5%) is approximately 80% when the true ORR is 5%.
With 39 patients with left-sided tumors, the probability of observing 6 or more responders 
(ORR 15%) is approximately 67% when the true underlying response rate is 17%, and the 
probability of observing 2 or fewer responders (ORR 5.1%) is approximately 70% when the 
true ORR is 5%. 
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For this calculation SAS PROC POWER was used.
9.3
Populations for Analyses
The following populations are defined:
Table 9–1: Populations for Analyses
Population
Description
Enrolled 
All participants who sign the ICF
FAS
All participants who have received at least 1 dose of study intervention will be 
included in the efficacy and safety evaluation.
r-PKS
All patients who have received at least 1 dose of regorafenib and with at least 1 
valid regorafenib concentration after dosing and no protocol deviations affecting 
the validity of the regorafenib PK will be included in the regorafenib PK analysis 
set.
n-PKS
All patients who have received at least 1 dose of nivolumab and with at least 1 
valid nivolumab concentration after dosing and no protocol deviations affecting 
the validity of the nivolumab PK will be included in the nivolumab PK analysis 
set.
IMS
All patients who have received at least one dose of nivolumab and have at least 
one ADA sample taken (during the treatment or follow-up observation period) 
that is appropriate for ADA testing (with reportable result) will be included in the 
analysis set for the immunogenicity analysis of nivolumab, which is defined as 
the immunogenicity analysis set.
Abbreviations: ADA = anti-drug antibodies; FAS = full analyses set; ICF = informed consent form; PK = pharmacokinetics; r-
PKS = regorafenib PK analysis set; n-PKS = nivolumab PK analysis set; IMS = immunogenicity analysis set
9.4
Statistical Analyses
Analysis will be performed using SAS (SAS Institute, Cary, North Carolina, USA), Version 
9.2 or higher. The specific version used will be mentioned in the statistical analysis plan 
(SAP).
The SAP will be developed and finalized before FPFV and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary,
secondary and tertiary/exploratory endpoints (see also Section 2.3).
9.4.1
General Considerations
All analyses will be conducted at one-sided type-I error level of 2.5% or two-sided type-I 
error level of 5% respectively. The primary endpoint will be tested by an exact binomial test.
No further confirmatory analysis is intended, and no further tests are conducted. Confidence 
intervals will be presented for selected variables.
9.4.2
Primary Endpoint(s)
ORR based on RECIST v1.1 is the primary endpoint of the study and the population used for 
the primary analysis will be the Full Analysis Set (FAS). Response is defined as a best overall 
response of CR or PR.
The primary efficacy variable will be analyzed after all participants met the criteria for 
primary completion and the data base is closed. Methods used will include frequency tables 
(with the ORR table also including all “Best overall response” categories) as well as 95% two-
sided Clopper-Pearson confidence intervals. The result of the exact binomial test will be 
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Descriptive statistics for the primary endpoint will be displayed by side of primary tumor 
(right vs. left).
9.4.3
Secondary Endpoint(s)
Secondary efficacy endpoints include duration of response (DOR), disease control rate at 8 
and 16 weeks, progression free survival (PFS), and overall survival (OS). DOR is defined for 
responders only as the time from first documentation of response (i.e. CR or PR) until disease 
progression or death (if death without documented disease progression). Disease control is 
defined as tumor response of stable disease (SD) or better. PFS is the time from first dose of 
study medication to disease progression or death, whichever is earlier. For patients who did 
not progress or die, PFS will be censored at the last evaluable tumor assessment. For patients 
that started subsequent therapy, PFS will be censored at the start of subsequent therapy. OS is 
defined as time from first dose to death. For patients who did not die, OS will be censored at 
the last time point at which the survival status is known to be alive.
For analyses of the secondary endpoints, proportion-based efficacy variables will be using 
frequency tables as well as 95% two-sided Clopper-Pearson confidence intervals. With regard 
to time to event data, these will be summarized descriptively using Kaplan Meier
methodology and plots, as well as median estimates based on Greenwood’s formula, including 
95% two-sided confidence interval. Continuous endpoints will be analyzed using summary 
statistics tables including 95% two-sided confidence intervals.
For the analysis of PFS and OS, PFS and OS rates at specific time points such as 6, 12, and 18 
months will also be provided based on the Kaplan-Meier method.
 
 
9.4.5
Other Safety Analyse(s)
For all safety analyses, the FAS will be used as the FAS definition matches the one of the 
safety set. The incidence of TEAE (new or worsening from baseline) will be summarized by 
system organ class and preferred term, severity (based on CTCAE grades), type of AE and 
relation to study treatment. Deaths reportable as SAEs and non-fatal serious AEs will be listed 
by participant and tabulated by type of AE. AEs leading to study treatment discontinuation 
and/or modifications will be summarized. Laboratory abnormalities will be summarized by 
severity. Frequency and incidence rates will be provided. Frequency tables will also be 
provided for changes in severity from baseline to worst value post-baseline. Laboratory data 
considered as AE will be graded according to CTCAE v. 5.0, if applicable. The following 
summaries will be generated separately for hematology and biochemistry, overall and by 
cohort with the same dose:
!
Frequency table for newly occurring on-treatment all CTCAE grades and CTCAE 
Grades 3 or 4
!
Shift tables using CTCAE grades to compare baseline to the worst on-treatment value
 
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9.5
Interim Analyses
No formal interim analysis is planned in this study.
However, it is planned to look at the data after approximately 30-40participants have had at 
least the first response evaluation, in order to get better information for the planning of the 
intended Phase III study. 
No formal conclusions for this study will be drawn from this look at the data and  no formal 
adjustment of the type-I error will be performed.
9.6
Data Monitoring Committee (DMC) or other Review Board
No DMC is planned for this study.
10.
Supporting Documentation and Operational Considerations
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 International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.,
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:

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

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

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
Each Investigator (including principal and/or any sub Investigators) who is directly involved 
in the treatment or evaluation of research participants has to provide a financial disclosure 


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according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
10.1.3
Informed Consent Process
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the Sponsor or the study center. 
Sample patient information and informed consent forms are provided as documents separate 
to this protocol.
Based on this patient information sheet, the Investigator or designee will explain all relevant 
aspects of the study to each participant prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The Investigator will also mention that written approval of the IRB/IEC has been obtained.
Each participant will be informed about the following aspects of premature withdrawal:
Each participant has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The participant’s consent covers end-of-study examinations as specified in the visit 
description described in the SoA (Table 1–3) to be conducted after withdrawal of consent. 
The participant’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Participant-specific data on the basis of material obtained before withdrawal may be generated 
after withdrawal (e.g., image reading, analysis of biological specimen such as blood, urine or 
tissues); these data would also be retained and statistically analyzed in accordance with the 
statistical analysis plan. The participant has the right to object to the generation and 
processing of this post-withdrawal data. The participant’s oral objection may be documented 
in the patient’s source data.
Each participant will have ample time and opportunity to ask questions:
The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative (if acceptable by local law) and answer all 
questions regarding the study
Participants will 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.
Only if the participant voluntarily agrees to sign the general informed consent form and has 
done so, may he/she enter the study. Additionally, the Investigator or his/her representative 
will personally sign and date the form. The participant will receive a copy of the signed and 
dated form.
The signed informed consent statements are to remain in the Investigator site file or, if locally 
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In the event that informed consent is obtained on the date that baseline study procedures are
performed, the study record or participant’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
If the participant is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the Sponsor and the 
Investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
The informed consent forms and any other written information provided to participants will be 
revised whenever important new information becomes available that may be relevant to the 
participant’s consent, or there is an amendment to the protocol that necessitates a change to 
the content of the patient information and / or the written informed consent form. The 
Investigator will inform the participant of changes in a timely manner and will ask the 
participant to confirm his/her participation in the study by signing the revised informed 
consent form. A PI/ICF on study updates may be used for update information (e.g. if new 
safety information is available) for patients who are already participating in the study.
Any revised written informed consent form and written information must receive the 
IEC/IRB`s approval / favorable opinion in advance of use.
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.
Participants who are rescreened are required to sign a new ICF. For details with regard to 
rescreening please refer to Section 5.4.
PI/ICF for continuing study treatment following disease progression
Treatment beyond radiological progression is possible if the participant is still benefiting from 
treatment. In order to continue treatment after initial documentation of disease progression as 
per RECIST 1.1, participant must be re-consented once. 
PI/ICF for collection of data on pregnancy and birth
A PI/ICF for collection of data on pregnancy and birth will be used for female participants 
who become pregnant or for those fertile male patients whose female partner becomes 
pregnant. The PI/ICF will be signed by the female patient or the male patient and their 
pregnant female partner.
10.1.4
Data Protection
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.

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 
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
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 who will be required to give consent for their data to 
be used as described in the informed consent.

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.
10.1.5
Committees Structure
Not applicable.
10.1.6
Dissemination of Clinical Study Data
The Sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. All data and results and all intellectual property rights in 
the data and results derived from the study will be the property of the Sponsor who may 
utilize them in various ways, such as for submission to government regulatory authorities or 
disclosure to other Investigators. Regarding public disclosure of study results, the Sponsor
will fulfill its obligations according to all applicable laws and regulations. The Sponsor is 
interested in the publication of the results of every study it performs. 
The Sponsor recognizes the right of the Investigator to publish the results upon completion of
the study. However, the Investigator, whilst free to utilize study data derived from his/her
center for scientific purposes, must obtain written consent of the Sponsor on the intended
publication manuscript before its submission. To this end, the Investigator must send a draft
of the publication manuscript to the Sponsor within a time period specified in the contract.
The Sponsor will review the manuscript promptly and will discuss its content with the
Investigator to reach a mutually agreeable final manuscript.
Result Summaries of Bayer’s sponsored clinical trials in drug development phases II, III and 
IV and phase I trials in participants 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”. 
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 participants for medicines and indications approved in the US and 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.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator
is responsible for verifying that data entries are accurate and correct by physically or 
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The data collection tool for this study will be a validated electronic data capture system called
RAVE. Patient data necessary for analysis and reporting will be transmitted into a validated
database or data system (LSH; SAS).
Data required according to this protocol will be recorded by investigational site personnel via
data entry into the internet-based electronic data capture (EDC) software system RAVE,
which Bayer has licensed from Medidata Solutions Worldwide. RAVE has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively applies 
the logic to ensure data are complete and reflect the clinical data requirements of the study. 
Data queries resulting from the application of the software logic are resolved by the site 
personnel. The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via a 
secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is part of
the RAVE software. All internal Bayer and external Investigator site personnel seeking access
must go through a thorough RAVE training process before they are granted access to RAVE
for use in Bayer's clinical studies. Training records are maintained.
The RAVE System contains a system-generated audit trail that captures any changes made to
a data field, including who made the change, why the change was made and the date and time
it was made. This information is available both at the Investigator’s site and at Bayer. 

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

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 (e.g., 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 (e.g.,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF 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 after study completion for the retention period as 
set forth in the Investigator Agreement unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 


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period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.
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 (e.g., Contract 
Research Organizations).
10.1.8
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.

Definition of what constitutes source data can be found in the Monitoring Plan.

The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at 
the site to identify the source data for key data points collected and the monitor will 
work with the site to complete this.

It is the expectation of the Sponsor that all data entered into the eCRF have source 
documentation available at the site. 

Data reported on the eCRF 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.
10.1.9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The principal Investigator of each center must sign the protocol signature page and must
receive all required external approvals (e.g., health authority, ethics committee, Sponsor)
before patient recruitment may start at the respective center. Likewise, all amendments to the
protocol must be signed by the principal Investigator and must have received all required
external approvals before coming into effect at the respective center.
Study 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

Inadequate recruitment of participants by the Investigator


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
Discontinuation of further study intervention development

The study is terminated due to safety concerns or lack of proven efficacy;

The participant can obtain medication used in this study as treatment from a 
government sponsored or private health program;

The clinical development of the study treatment is stopped, no marketing authorization 
is pursued, and therapeutic alternatives are available in the local market.
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or FU.
10.1.10
Publication Policy
All data and results and all intellectual property rights in the data and results derived from the
study will be the property of the Sponsor who may utilize them in various ways, such as for
submission to government regulatory authorities or disclosure to other Investigators.
Regarding public disclosure of study results, the Sponsor will fulfill its obligations according
to all applicable laws and regulations. The Sponsor is interested in the publication of the
results of every study it performs.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

The Sponsor recognizes the right of the Investigator to publish the results upon 
completion of the study. Investigators may publish or present individual study data 
(including case reports) obtained in the course of this study but only after the primary 
report and/or publication of the study results in their entirety. If publishing individual 
site data is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.
10.2
Appendix 2: Clinical Laboratory Tests
The laboratory analyses detailed in Table 1–2 and Table 1–3 will be performed by the local 
laboratory. These tests will not be performed centrally. Testing will generally be performed at 
a laboratory associated with each participating clinical site. In some cases, participants may 
have testing performed at a location other than the participating clinical site (e.g., at their local 
hospital), and in these cases the results are to be sent to the relevant participating clinical site.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations.


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Table 10–1: Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC count
Hemoglobin
Hematocrit
WBC count with differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Chemistry panel
BUN
Creatinine/CGb
Lipase
LDH
Albumin
Potassium
Sodium
Chloride
Amylasec
Phosphate
AST/SGOT
ALT/SGPT
Total protein
Calcium (total 
calcium), calcium 
ionized or adjusted 
calcium
Uric acid
Magnesium
Total and direct bilirubin
ALP
Glucose (fasting or non-
fasting)
Triglycerides
GGTc
Routine 
Urinalysisa
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick
Microscopic examination (if blood or protein is abnormal)
Coagulation
aPTT
PT/INR
Thyroid
FT3
FT4
TSH
Other Screening 
Tests
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)
At screening if status is unknown or if a previous test is >3 months old

HIV antibody, Hepatitis B surface antigen, and Hepatitis C virus antibody
Abbreviations: ALT = alanine aminotransferase; ALP = alkaline phosphatase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; CG = Cockcroft-Gault (equation); FT3 = free 
triiodothyronine; FT4 = free thyroxine; hCG = human chorionic gonadotropin; LDH = lactic dehydrogenase; PT/INR =
prothrombin time-international normalized ratio; PTT = partial thromboplastin time; RBC = red blood cell count; SGOT = 
serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; TSH = thyroid stimulating 
hormone; WBC = white blood cell count.
a)
If protein dipstick result is 3+ or abnormal (based on type of urine test strip used), a laboratory urine analysis should be 
done for the quantification of proteinuria by urinary protein/creatinine ratio on a random urine sample preferably taken at 
mid-morning. 
b)
Cockcroft Gault formula for GFR: 
c)
Will be assessed if clinically indicated. 
d)
Fasting or non-fasting glucose per local practice.
Investigators must document their review of each laboratory safety report.


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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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., 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.

“Lack of efficacy” or “failure of expected pharmacological action” (i.e. disease 
progression) per se will not be reported as an AE or SAE. Such instances will be 
captured in the efficacy assessments. However, 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.
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.


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Events NOT Meeting the AE Definition
Medical or surgical procedure (e.g., 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 (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
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.
c) 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.
d) 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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e) Is a congenital anomaly/birth defect
f)
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.


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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 (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The Investigator will then record all relevant AE/SAE information in the eCRF.
It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to Bayer in lieu of completion of the AE/SAE eCRF page.
There may be instances when copies of medical records for certain cases are 
requested by Bayer. 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 Sponsor.
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 based on NCI-CTCAE version 5.0. and assign it to 1 of the following categories: 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The Investigator is obligated to assess the relationship between study intervention 
(regorafenib and nivolumab) 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 
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Assessment of Causality
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 IBs and/or Product Informations, 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 for both, 
regorafenib and nivolumab.
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to Bayer. 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.
The Investigator may change his/her opinion of causality in light of FU information 
and send a SAE FU report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-
mediated mechanism or immune-mediated component for which non-inflammatory 
etiologies (e.g., infection or tumor progression) have been ruled out. IMAEs can 
include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the 
participant’s eCRF.
Every AE must be assessed by the investigator with regard to whether it is 
considered immune-mediated.
FU 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 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 a recognized FU
period, the Investigator should provide access to any post-mortem findings including 
histopathology

New or updated information will be recorded in the originally completed eCRF.

The Investigator will submit any updated SAE data to Bayer within 24 hr of receipt 
of the information.
10.3.4
Reporting of SAEs
SAE Reporting to Bayer via an Electronic Data Collection Tool
The primary mechanism for reporting a SAE to Bayer will be the electronic data 


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SAE Reporting to Bayer via an Electronic Data Collection Tool
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 hr.
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) or to the Medical Monitor by telephone.
Contacts for SAE reporting can be found in the Monitoring Plan.
SAE Reporting to Bayer via Paper eCRF
Facsimile transmission of the SAE paper eCRF is the preferred method to transmit 
this information to the Medical Monitor.
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool 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 eCRF pages within the designated reporting time frames.
Contacts for SAE reporting can be found in the Monitoring Plan.


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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 (e.g., 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, (e.g., 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 in a woman over age 45 years

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. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause

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.
Contraception Guidance: Please refer to the inclusion criteria for details (Section 5.1).
The Investigator or a designated associate is requested to advise the participants how to 
achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) 
contraception methods include:


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
Combined (estrogen and progesterone containing: oral, intravaginal, transdermal) or
progesterone-only (oral, injectable, implantable) hormonal contraception.
○
Hormonal contraception may be susceptible to interaction with the study treatment, 
which may reduce the efficacy of the contraceptive method. Hormonal 
contraception is permissible only when there is sufficient evidence that the 
investigational medicinal product (IMP) and other study medications will not alter 
hormonal exposures such that contraception would be ineffective or result in 
increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 

Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole 
sexual partner and has received medical assessment of the surgical success).

Intrauterine devices and intrauterine hormone releasing systems are acceptable 
methods of contraception in the absence of definitive drug interaction studies when 
hormone exposures from intrauterine devices do not alter contraception effectiveness

Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the participant
○
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
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 study intervention.

After obtaining the necessary signed informed consent from both the study participant 
and the pregnant female partner, the Investigator will record pregnancy information on 
the appropriate form and submit it to Bayer within 24 hr 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 FU 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. The initial information will be 
recorded on the appropriate form and submitted to Bayer within 24 hr of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect FU 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, FU will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 


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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 for medical reasons will be 
reported as an AE or SAE. 
!
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) 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.
 
10.6
Appendix 6: FU Assessments 
Active FU visits
All participants who withdraw from study treatment period for any reason (except death or 
lost to FU) will be followed for safety at mandatory active FU visits, which will be performed 
30 d (+7 d) after the last administration of study treatment regorafenib/nivolumab and 100 d 
(+7 d) after the last dose of nivolumab. 
If the treatment was
permanently discontinued after
the maximal allowed dose 
interruption/delay period, 28 d for regorafenib and 6 weeks for nivolumab, the 1st active FU
visit should occur within 14 d of the permanent discontinuation. AE assessment and 
concomitant medication review must be updated at these active follow-up visits and all AEs 
starting within 30 d after the last dose of study treatment regorafenib (100 d after the last dose 
nivolumab) should be collected and recorded in the eCRF.
Additionally, for participants who discontinue study treatment without radiological disease
progression, drug-related AEs will continue to be collected FU tumor evaluations (by CT or 
MRI with contrast unless contraindicated) will be performed until radiological progression, 
occurrence of secondary malignancy and/or start of first subsequent systemic anticancer
treatment, whichever comes first, or any other criterion for withdrawal is met. 
During the efficacy FU visits, CT/MRI evaluations will be performed at the same intervals as 
during study treatment (see Table 1–2). Note: all images still need to be prospectively 
collected and submitted in DICOM format in case independent central review is needed. 
Long-term FU
All participants who withdraw from study treatment period with radiological PD, or from 
active FU for any reason will be followed for survival and first subsequent anti-cancer
treatment, every 3 months (±14 d) during the long-term FU period, until either data
CCI


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maturation for the final analysis is reached, or death of the patient, or any other criterion for
withdrawal from long-term FU is met. The long-term FU contacts may occur at more frequent 
intervals at the discretion of the Sponsor. If a patient is lost to FU, the site will try to contact 
the patient, the patient’s relatives, or another doctor treating the patient, unless prohibited by 
local requirements.
All participants in the long-term FU period will be contacted (telephone contact is sufficient) 
every month (±7 d) to determine survival status and obtain information on subsequent 
systemic anti-cancer treatment.
10.7
Appendix 7: Response Assessment for CRC - RECIST v1.1 Criteria
Efficacy response and progression for participants with CRC will be evaluated using RECIST 
v1.1 criteria (59). Contrast-enhanced multi-detector CT is the preferred method to measure 
lesions selected for response assessment. MRI (typically with gadolinium-based intravenous 
contrast) may be performed instead of CT (e.g., when local regulations or allergy to CT 
contrast media do not permit the use of CT as requested per protocol schedule, or when there 
is concern about radiation exposure from CT, or when MRI is deemed a more appropriate 
imaging method). At a minimum, anatomical regions that should be included in scans 
performed at baseline and during study intervention treatment include the chest, abdomen and 
pelvis, as well as any other areas of known disease and areas prone to metastatic disease for 
the particular tumor type under evaluation. CT scans of the chest, abdomen and pelvis should 
be contiguous throughout all the anatomic region of interest. Ultrasound is not useful in 
assessment of lesion size and should not be used as a method of measurement. X-ray is not an 
accepted method for lesion assessment in this study. Recommended slice thickness for 
CT/MRI is ≤ 5mm. PET-CT scans may be used provided that measurements are obtained 
from the CT scan and the CT scan is of the same diagnostic quality as a diagnostic CT (with 
IV and oral contrast and diagnostic quality radiation dose). The same method of assessment 
and the same technique should be used to characterize each identified and reported lesion at 
baseline and during study conduct. When lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective. Previously 
irradiated lesions should not be counted as target lesions unless there has been demonstrated 
progression in the lesion post radiotherapy before study enrollment and no other lesions are 
available for selection as target lesions. Lesions identified later during the study in a part of 
the body not scanned at baseline would be considered as a new lesion representing disease 
progression.
The tumor marker carcinoembryonic antigen (CEA) will be evaluated on an exploratory basis 
in participants with CRC and will not be used to assess objective tumor response. 
RECIST
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST v1.1 criteria (long axis diameter for non-nodal lesions; short axis 
diameter for lymph nodes). Rules described below for CT are also valid for MRI.
Measurable disease
Selection of target lesions should be based on lesion size (the largest lesions, with at least 
10mm at longest diameter if non-nodal lesions, and 15mm at short axis if nodal lesions), 
organ representation of involved organs (up to a maximum of two per organ and five total) 
and suitability for repeated evaluations. 


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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability. 
Cystic lesions thought to be cystic metastases can be considered as measurable lesions if they 
meet the definition of measurability. However, if non-cystic lesions are present in the same 
participant, those lesions should be preferably selected for assessment.
Non-measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 to <15 mm short axis) are considered non-measurable 
disease. In addition, leptomeningeal disease, ascites, pleural or pericardial effusion, 
lymphangitic involvement of skin or lung, inflammatory breast disease, lesions that meet 
radiographic criteria for simple cysts and blastic bone lesions are all non-measurable.
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable (previously treated lesions can only 
be selected as target lesions when they have progressed post radiotherapy until baseline).
Target lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) will be identified as target lesions 
and will be recorded and measured at baseline. Thus, in instances where participants have 
only one or two organ sites involved, a maximum of two and four lesions, respectively, will 
be recorded. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and should be representative of all involved organs and amenable to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which case the next largest lesion which 
can be measured reproducibly should be selected. A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. If there are >5 measurable lesions, those not selected as target lesions will be 
considered together with non-measurable disease as non-target lesions.
Optimally, lesions selected as target lesions should not be biopsied. In this study, tumor 
biopsies for biomarker analysis are optional and biopsies for biomarker analysis should not be 
performed on target lesions.
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes (with short axis 
≥10 mm and < 15 mm) any measurable lesions over and above the 5 listed as target lesions 
are to be identified as non-target lesions and should also be recorded at baseline.
Measurements are not required, and these lesions should be followed as ‘present’, ‘absent’, or 
in rare cases ‘unequivocal progression’. In addition, it is possible to record multiple non-target
lesions involving the same organ as a single item on the eCRF (e.g., ‘multiple enlarged pelvic 
lymph nodes’ or ‘multiple liver metastases’).
Evaluation of response in target lesions


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Best Response
The best overall response is the best response recorded from the start of the study intervention 
until the end of treatment. The participant’s best overall response assignment will depend on 
the findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. While some non- target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. All participants will have their Best Response on-study classified 
according to the RECIST v1.1 criteria as outlined below and summarized in Table 10–3.
Complete Response (CR)
Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether 
target or non-target) must have decreased in size to have a short axis of < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions taking as reference the 
baseline sum diameters. 
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
Non-CR/Non-PD 
To be used for participants with non-target lesions only at baseline. Persistence of one or more 
non-target lesion(s).
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). I n 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. Unequivocal progression of existing non-target lesions (see comments 
below), or the appearance of one or more new lesions, also constitutes progressive disease.
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response 
criteria are met, since a normal lymph node is defined as having a short axis of < 10 mm.
To achieve unequivocal progression in participants with measurable disease on the basis of 
the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal.
In the absence of measurable disease, the same general concepts apply here as noted above.


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Table 10–2: Target and Non-Target Lesion Response
Target Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Response requires
CR
CR
No
CR
Tumor response is to be 
documented approximately 
every 2 cycles (6 weeks) from 
C1D1.
SD requires documentation at 
least once approximately 2 
cycles (6 weeks) from C1D1.
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: C= cycle; CR = complete response; D = day; PD = progressive disease; PR = partial response; SD = stable 
disease.
Participants with a global deterioration of health current to the objective progression even after discontinuation of treatment 
without current evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every 
effort should be made to document the objective progression even after discontinuation of treatment
Table 10–3: Assessment of Best Response According to RECIST v1.1 Criteria for Participants 
with Non-Target Lesions Only
Non-target lesions
New lesions
Overall response
Complete response
No
Complete response
Non-complete response / 
Non-progressive disease
No
Non-complete response / 
non-progressive disease a
Not evaluated
No
Not evaluable
Unequivocal progressive disease
Yes or No
Progressive disease
Any
Yes
Progressive disease
a)
Non-complete response / non-progressive disease" is preferred over “stable disease” for non-target lesions.
Response duration
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
sum of diameters (nadir) recorded on study).
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
Stable disease duration
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD).


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10.8
Appendix 8: Response Assessment for CRC - iRECIST
iRECIST is RECIST v1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs (Table 10–4). iRECIST will be used by site 
Investigator/local radiology review to make treatment decisions. This data will be collected in 
the clinical database
Description of the iRECIST Process for Assessment of Disease Progression
Assessment at Screening and Prior to RECIST v1.1 Progression
Until radiographic disease progression based on RECIST v1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST v1.1 Progression
For participants who show evidence of radiological PD by RECIST v1.1, the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
using iRECIST for participant management (see Table 10–4 and Figure 10–1). This decision 
by the Investigator should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 
Absence of symptoms and signs indicating clinically significant progression of disease
No decline in ECOG PS
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST v1.1, 
including:
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 
mm from nadir
Note: the iRECIST publication uses the terminology “sum of measurements”, but “sum of 
diameters” will be used in this protocol, consistent with the original RECIST v1.1 
terminology.
Unequivocal progression of non-target lesion(s) identified at baseline
Development of new lesion(s)
iRECIST defines new response categories, including unconfirmed progressive disease by 
iRECIST (iUPD) and iCPD. For purposes of iRECIST assessment, the first visit showing 
progression according to RECIST v1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST v1.1 will be 
assessed as usual.


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New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST v1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively as 
New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
Any of the factors that were the basis for the initial iUPD show worsening
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
For non-target lesions, worsening is any significant growth in lesions overall, compared to 
a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST v1.1
For new lesions, worsening is any of these:
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point 
Visible growth of new non-target lesions 
The appearance of additional new lesions
Any new factor appears that would have triggered PD by RECIST v1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
None of the progression-confirming factors identified above occurs AND
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST v1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
None of the progression-confirming factors identified above occurs, AND
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
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The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has iCPD as defined above, but the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in this protocol (See SoA 
Table 1–2) 
Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
Target lesions
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) either 
for the first time, or after resolution of previous pseudo-progression. The nadir is 
always the smallest sum of diameters seen during the entire trial, either before or after 
an instance of pseudo-progression.
Non-target lesions
If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD.
If non-target lesions have shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target 
lesions, taken as a whole.
New lesions
New lesions appear for the first time
Additional new lesions appear
Previously identified new target lesions show an increase of ≥5 mm in the new lesion sum 
of diameters, from the nadir value of that sum
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.


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The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication (60).
Table 10–4: Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic evidence 
of PD by RECIST v1.1 
Repeat imaging 
at 4 to 8 weeks 
at site to 
confirm PD
May continue 
study treatment at 
the local site 
Investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST at the local 
site
No additional 
imaging 
required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor)
No additional 
imaging required
N/A
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
Investigator
assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor imaging 
shows iSD, iPR, or iCR 
by iRECIST per 
Investigator
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
local site 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next tumor 
image should occur 
according to the 
every 6 weeks (±7 d) 
imaging schedule for 
the 32 weeks (until 
Week 31 D1 ± 7 d) 
and 12 weeks (±14 d) 
thereafter 
Abbreviations: D/d = day(s); iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST 
= modified Response Evaluation Criteria in Solid Tumors v1.1 for immune-based therapeutics; iPR = iRECIST partial 
response; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; N/A = not applicable; PD = 
progressive disease; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors v1.1


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Figure 10–1: iRECIST: Process for Assessment of Disease Progression
Abbreviation: iRECIST = immune RECIST; PD = progressive disease
10.9
Appendix 9: New York Heart Association (NYHA) Classification
The stages of heart failure will be assessed according to the NHYA functional classification 
system.  This system relates symptoms to everyday activities and the participant’s quality of 
life.
Table 10–5: New York Heart Association (NYHA) Classification
Class
Participant symptoms
Class I (mild)
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea.
Class III (moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (severe)
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased.


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10.10
Appendix 10: CYP3A4 Inhibitors and Inducers
CYP3A4 inducers and inhibitors 
Table 10–6 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 10–6: 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
A STRONG inhibitor is NOT allowed during this clinical trial.
CYP3A4 inducers are NOT allowed during this clinical trial.
The CYP3A4 inducers and strong CYP3A4 inhibitors in Table 10–6 were identified using the 
Bayer-World Health Organization’s Drug Dictionary (WHO-DD) and Bayer drug groupings 
for CYP3A4 inducers and CYP3A4 inhibitors.
10.11
Appendix 11: Guidance for Management of Immune-Related Adverse 
Events
The following AE management algorithms apply criteria from NCI-CTCAE v4


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10.12
Appendix 12: Abbreviations
Table 10–7: Abbreviations
5-FU
5-fluorouracil
ADA
Anti-drug-antibodies
AE
Adverse event
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
ALP
Alkanine phosphatase
Ang1
Angiopoietin 1
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
BCRP
Breast cancer resistance protein
BICR
Blinded independent central review
BP
Blood pressure
BRAF
Proto-oncogen BRAF
BUN
Blood urea nitrogen
BTLA
B- and T-lymphocyte attenuator
C
Cycle
CCL
cc-chemokine ligand
CD
Cluster of differentiation


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CEA
Carcinoembryonic antigen
CI
Confidence interval
Cmax
maximum observed drug concentration
CMS
Consensus molecular subtypes
CMV
Cytomegalovirus 
CNS
Central nervous system
CR
Complete response
c-RAF
Proto-oncogen c-RAF
CRC
Colorectal cancer
CSF1R
Colony stimulating factor 1 receptor
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CYP
Cytochrome P450 (derivates)
D / (d)
Day(s)
DCR
Disease control rate
DICOM
Digital imaging and communication in medicine
DLT
Dose limiting toxicity
DMC
Data monitoring committee
dMMR
Mismatch repair deficient
DOR
Duration of response
EC50
Half maximal effective concentration
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EU
European Union
FAS
Full analyses set
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FU
Follow-up
GC
Gastric cancer
GCP
Good clinical practice
GIST
Gastrointestinal stroma tumor
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HFSR
Hand foot skin reaction
HIV
Human immunodeficiency virus
HNSCC
Head and neck squamous-cell carcinoma
HR
Hazard ratio
HRT
Hormonal replacement therapy
IB
Investigators brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
ICOS
Inducible T-cell co-stimulator
iCPD
Confirmed radiographic progression by iRECIST
IEC
Independent Ethics Committees
IFN-γ
Interferon-gamma


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IgG
Immunoglobulin
IL
Interleukin 
IMAE
Immune-mediated adverse event
INR
International normalized ratio
IRB
Institutional Review Board
iRECIST
Response evaluation criteria in solid tumors for trials testing 
immunotherapeutics
iUPD
Unconfirmed progressive disease by iRECIST
i.v.
Intravenous
IxRS
Interactive voice/web response system
LPLV
Last patient last visit
M-2
N-oxide
M-5
N-oxide plus N-desmethyl
mCRC
Metastatic colorectal cancer
pMMR
Mismatch repair-proficient
MRI
Magnetic resonance imaging
MSI
Microsatellite instable 
MSS
Microsatellite stable
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed cell death protein 1 ligand 1
PET
Positron-emission tomography
PFS
Progression free survival
PID
Participant identification number
PK
Pharmacokinetics
PPK
Population pharmacokinetics
PR
Partial response
PS
Performance status
q.d.
Quaque die (once daily)
RANKL
receptor activator of nuclear factor kappa-B ligand
RAS
rat sarcoma viral oncogene homolog
RCC
Renal cell cancer
RECIST
Response evaluation criteria in solid tumors
RET
Rearranged during transfection
r-PKS
Regorafenib PK analysis set
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
TIL
Tumor infiltrating lymphocytes
TMB
Tumor mutational burden
UGT
UDP-glucuronosyltransferase (derivates)
ULN
Upper limit of normal
UPD
Unconfirmed progressive disease
US
United States


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VEGFR
Vascular endothelial growth factor receptor
WOCBP
Woman of childbearing potential


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CCI


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CCI


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CCI


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CCI


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12.
Protocol Amendments
12.1
Amendment History
12.2
Global Amendment 1
Amendment 1 is a global amendment forming integrated protocol Amendment 1, dated 08
JAN 2020.
Overall rationale for the amendment
The primary purpose of this amendment is to:
1) To further evaluate safety and efficacy of the regorafenib and nivolumab combination, 
sample size of the study will be increased from 53 to approximately 100 treated
patients. The primary completion is defined by the event when the last enrolled 
participant was assessed for response rate as defined by RECIST v1.1 during at least 5 
post-baseline scans i.e., has been followed for approximately 10 months from the first 
dose. With increased sample size of 100 patients, when the true underlying ORR is 
17% or higher, there is >95% likelihood that the lower bound of the 95% CI will be 
above 5%.  For this ORR analysis, the primary analysis will be based on blinded 
independent central review. In addition to ORR, duration of response will also be 
analyzed and reported descriptively.
2) To clarify inclusion criteria 5 regarding prior lines of treatment. 
3) To modify exclusion criteria 5 to allow inclusion of patients with deep vein 
thrombosis and pulmonary emboli who have been adequately treated with 
anticoagulation.
4) To remove exclusion of participants with BRAF V600E mutation
5) To provide guidance regarding interrupting regorafenib treatment during on treatment 
biopsy. 
6) To modify criteria for nivolumab discontinuation due to delay in dosing. Delay in 
nivolumab dosing that requires discontinuation has been changed to 10 weeks instead 
of 6 weeks to be consistent with other nivolumab studies using 480 mg dose Q4W.
7) To align wording for tolerance and escalation of regorafenib starting dose. Tolerance 
defined as: Absence of any grade rash/HFSR or other Grade 2 or higher clinically 
significant toxicity.
Changes to the protocol text
Changes to the protocol text are provided in a separate track-changes version.
High-level description of the changes and the affected sections are listed in the table below.
Current Version
Amendment 2: 
Previous Versions
Amendment 1:
Original Protocol:
18 NOV 2020
08 JAN 2020
12 JUL 2019


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Table 12–1: Summary of Changes to the Protocol
Protocol Section
Amendment 1 Revisions
Throughout
Use RECIST v1.1 and iRECIST 
1.1 Synopsis
3. Objectives and Endpoints
Modified footnote of Tables 1.1 and 3-1 Objectives and Endpoints: 
ORR and DOR will be based on blinded independent central review 
(BICR) and local investigator assessment per RECIST 1. The 
primary efficacy endpoint (ORR) will be based on the local investigator’s 
assessment on blinded local investigator’s assessment. Central 
independent central review (BICR) may be implemented as needed for 
ORR assessment by RECIST 1.1.DCR and PFS will be based on 
local investigator assessment.
1.1 Synopsis
4.1 Overall Design
5. Study Population
9.2 Sample Size
Determination 
Adjusted/modified wording to account for increased participant numbers 
(...approximately 143 instead of 80; treated 100 instead of 53, 
approximately 50-60 instead of 30-35 for left sided tumor) and to reflect 
statistical implications for right- and left sided tumors, ORR and true 
underlying response rate:
Approximately 143 participants will be screened to achieve 100 treated 
participants. Approximately 50-60 participants with left sided primary
At least 100 participants who qualify for the study will be treated
As of amendment 1, additional 47 patients will be treated to achieve 
approximately 100 treated patients. With increased sample size of 100 
patients
The location of the primary tumor is a factor and it is expected that 50-
60 patients will have the primary tumor on the left side
1.2 Schema, Figure 1-1
4.1.1 Screening Phase, 
Figure 4-1, footnote a
4.1.2 Treatment Phase
4.3 Justification of Dose
6 Study Intervention
Alignment of wording for tolerance and escalation of regorafenib starting 
dose: Absence of any grade rash/HFSR or other Grade 2 or higher 
clinically significant toxicity
1.3 Schedule of Activities
Updated sampling timepoint for several screening assessments from 7 
days prior to 28 days prior to first dose to allow more time for planning 
biopsy 
Added footnote ‘c’: If tested within 7 days prior to first dose no 
additional testing on D1 required except for pregnancy testing and 
abnormal liver function tests
Added to footnote ‘b: If disease progression and start of a new anti-
cancer treatment happens before the 30/100 d safety visit, the 
safety visits should still be performed.
3 Objectives and Endpoints, 
Table 3-1
Removed reference to iRECIST v.1.1 as iRECIST is used.
4.1 Study Design
5.1 Inclusion Criteria #5
Modified details on prior lines of treatment: …treated with no more than 
two (for extended RAS mutant) and or three (for extended RAS wild 
type) lines of systemic chemotherapy
4.1.2 Treatment Phase
Deleted “as determined by investigator” and central review is 
needed: Primary endpoint of the study is ORR measured by RECIST 
v1.1 as determined by investigator.   … by a vendor for BICR. central 
review is needed.
4.1.4 Long-Term Follow-Up
Added detail on consent withdrawal: Participants will be followed for 
overall survival …. or consent withdrawal or death or lost to FU
4.4 End of Study Definition
Modified definition of primary completion/clarification of appropriate 
terminology: The primary completion is defined by the event when
the last all enrolled participants have been was assessed for 
response rate (as defined by RECIST v1.1) during at least 3 5 post-
baseline scans unless they have discontinued before due to 
progression or any other reason i.e. have been followed for 
approximately 6 10 months from 1st dose
5.1 Inclusion Criteria #5
Added details on progression: Participant must have progressed 


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Protocol Section
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(radiologically or clinically) or been was intolerant to no more than
two (for extended RAS mutant) and or three (for extended RAS wild 
type) lines of systemic chemotherapy …
Added details on prior lines of treatment: Reintroduction of 
previously administered chemotherapy containing oxaliplatin, 
irinotecan or 5-fluorouracil/capecitabine, without newly added 
biologics like EGFR inhibitor for RAS wild type patients and 
locoregional treatments such as hepatic arterial infusion therapy, 
or Yttrium-90 radioembolization should not be counted as 
separate lines of treatment.
Added: Adjuvant/neoadjuvant …considered as one line of 
chemotherapy ...
5.1 Inclusion Criteria #9
Modified wording on tumor tissue requirements: Exceptions for patients 
with less than required no recent baseline tumor tissue may be 
considered …
5.2 Exclusion Criteria #1
Added dMMR to reflect the IHC testing methodology and deleted BRAF 
V600E mutation to be consistent with Phase III protocol:
Participants with dMMR/MSI-H colorectal cancer or BRAF V600E 
mutation
5.2 Exclusion Criteria #5
Modified language to allow inclusion of patients with deep vein 
thrombosis and pulmonary emboli who have been adequately treated 
with anticoagulation: Arterial thrombotic or embolic events such as 
cerebrovascular accident (including transient ischemic attacks) 
within 6 months before the start of study medication. Active 
pulmonary emboli or deep vein thrombosis that are significant or 
not adequately controlled on anticoagulation regimen 
 
 
 
 
 
 
 
6.6.1.1 Nivolumab Treatment 
– Permanent 
Discontinuation
7.1 Discontinuation of Study 
Intervention
To modify criteria for Nivolumab discontinuation due to delay in dosing. 
Delay in nivolumab dosing that requires discontinuation has been 
changed from 6 weeks to 10 weeks.
7.1 Discontinuation of Study 
Intervention
Harmonized wording throughout section 7.1: Start of subsequent 
systemic anti-cancer treatment a new anti-cancer therapy.
8.1 Efficacy Assessment
Deleted: “as determined by Radiologist/Investigator”
Specified wording on tumor assessment: Primary endpoint for 
efficacy assessment is ORR based on BICR measured by per 
RECIST 1.1. as determined by Radiologist/Investigator. Radiological 
tumor assessments will be done locally by the investigator, and in 
addition centrally by a blinded independent central imaging 
review. Scans will be prospectively collected and stored at vendor
in case for independent central review is needed BICR. Treatment 
response for primary efficacy endpoint (ORR) will be based on 
BICR.ORR and DOR will be assessed by BICR and local 
CCI
CCI


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Protocol Section
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investigator per RECIST 1.1. DCR and PFS will be based on local 
investigator assessment.
… scans … must be collected ... for in case blinded independent 
central review is needed. For patients with objective response (CR 
and PR), scans will be collected till start of subsequent systemic 
anti-cancer treatment.
Moved up subsection “Assessment of disease” for better 
understanding and added “CR and PR must be confirmed with 
repeated imaging performed at least 4 weeks after initial 
documentation of response.” to description of RECIST v1.1
9.2. Sample Size 
Determination
Rewrote and adjusted section to account for changed patient numbers: 
As of amendment 1, additional 47 patients will be treated to 
achieve approximately 100 treated response evaluable patients. 
With increased sample size of 100 patients, when the true 
underlying ORR is 17% or higher, there is >95% likelihood that the 
lower bound of the 95% CI will be above 5%.  
The sample size of 100 patients for a one-sided exact binomial test 
at a type-I error of at most 2.5% would result in a power of 96.4%, 
with at least 11 responders needed to achieve significance.
The sample size in this study was determined by the need to have a 
sufficient number of patients with the primary tumor located on each 
side (right and left). The location of the primary tumor is a factor and 
it is expected that 50-60 patients will have the primary tumor on 
the left side. This sample size of 53 patients for a one-sided exact 
binomial test at a type-I error of at most 5% would result in a power of 
90.6%. Approximately 30-35 participants with left sided primary tumor 
will be treated. In order to allow appropriate balance of participants with 
right and left sided primary tumors, enrollment may be restricted to 
either left or right sided tumors during the study.
With 45 18 patients with right-sided tumors, the probability of observing 
5 2 or more responders (ORR 11%) is approximately 90% 83% when 
the true underlying response rate is 17%, and the probability of 
observing 3 1 or fewer responders (ORR 6.6%) is approximately 81%
77% when the true ORR is 5%. 
With 55 35 patients with left-sided tumors, the probability of observing 6
4 or more responders (ORR 11%) is approximately 92% 87% when the 
true underlying response rate is 17%, and the probability of observing 3
2 or fewer responders (ORR 6%) is approximately 70% 75% when the 
true ORR is 5%. 
The critical number of responders to be achieved or surpassed to reject 
the null hypothesis of a 5% response rate for overall population is 6 
patients. 
For this calculation SAS PROC POWER was used.
9.4 Statistical Analysis
Correction; SAP will be finalized before database lock FPFV rather than 
at database lock as stated in the original version
9.4.1 General 
Considerations
Corrected error levels: All analyses will be conducted at one-sided type-
I error level of 2.5% 5% or two-sided type-I error level of 5% 10%
respectively
9.4.2 Primary Endpoints
9.4.3 Secondary Endpoints
Corrected confidence intervals to 95% from 50%.
Added to 9.5.3: For patients that started subsequent therapy, PFS 
will be censored at the start of subsequent therapy.
9.5 Interim Analysis
Modified …after approximately 50% of the 30-40 participants
Correction; main data analysis may be conducted by study statistician 
and does not require an external statistician. Analyses do not require to 
be pre-specified in SAP. 
Deleted: ….due to the exploratory nature of this study…
In order to avoid bias during the main analysis, the data look will be 
conducted by a statistician not involved in the study and the analyses to 


CONFIDENTIAL
Clinical Study Protocol Global Amendment 2
BAY 73-4506 / 20975
18 NOV 2020
Page 112 of 112
Protocol Section
Amendment 1 Revisions
be conducted will be pre-specified in an interim SAP.
10.1.3 Informed Consent 
Process
Deleted non-required details: Only if the participant voluntarily agrees to 
sign the pharmacogenetics (PGx) research project informed consent 
form and has done so, optional study procedures can be performed 
(e.g., sample collection for optional biomarker testing).
10.2 Appendix 2: Clinical 
Laboratory Tests
Total Calcium assessment of chemistry panel changed to Calcium 
(total calcium), calcium ionized or adjusted calcium. Total bilirubin 
and indirect bilirubin changed to: total and direct bilirubin. Deleted 
assessments not required; RBC Indices, MCV, MCH, %Reticulocytes
In addition to the substantive changes summarized in above table, several changes were made 
to update administrative details, correct typographical errors, and add clarity; such changes 
are not itemized in the table.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
An Open-label, Single-arm, Phase II Study of Regorafenib and 
Nivolumab in Patients with Mismatch Repair-Proficient 
(pMMR)/Microsatellite Stable (MSS) Colorectal Cancer (CRC) 
NCT Number: 
NCT04126733 
Document Date: 
11 NOV 2020 
 


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Reference Number: RD-SOP-1119
Supplement Version: 10
Title page
An Open-label, Single-arm, Phase II Study of Regorafenib and 
Nivolumab in Patients with Mismatch Repair-Proficient 
(pMMR)/Microsatellite Stable (MSS) Colorectal Cancer (CRC)
Regorafenib and Nivolumab in pMMR/MSS CRC
Bayer study drug
BAY 73-4506
Study purpose:
Determine the safety and efficacy of the combination of regorafenib 
and nivolumab
Clinical study 
phase:
II
Date:
11 NOV 2020
Study No.:
20975
Version:
2.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD
CCI


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Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
4.1
General Principles............................................................................................................ 4
4.2
Handling of Dropouts ...................................................................................................... 4
4.3
Handling of Missing Data................................................................................................ 5
4.4
Interim Analyses and Data Monitoring ........................................................................... 5
4.5
Analysis of long-term follow-up...................................................................................... 5
4.6
Data Rules........................................................................................................................ 6
4.7
Validity Review ............................................................................................................... 6
4.8
Subgroup analyses ........................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 7
5.1
Assignment of analysis sets ............................................................................................. 7
6.
Statistical Methodology .................................................................................................... 7
6.1
Population characteristics ................................................................................................ 8
6.2
Efficacy............................................................................................................................ 8
6.2.1
Sample size................................................................................................................... 8
6.2.2
Primary Endpoint: Overall response rate (ORR) based on RECIST v1.1.................... 9
6.2.3
Secondary endpoints................................................................................................... 10
6.5
Safety ............................................................................................................................. 11
6.5.1
Extent of exposure...................................................................................................... 12
6.5.2
Adverse events............................................................................................................ 12
6.5.3
Deaths and Serious Adverse events............................................................................ 14
6.5.4
Pregnancies................................................................................................................. 14
6.5.5
Clinical laboratory data .............................................................................................. 14
6.5.6
12-Lead ECG, QTc..................................................................................................... 16
6.5.7
ECOG status ............................................................................................................... 17
6.5.8
Other safety measures................................................................................................. 17
7.
Document history and changes in the planned statistical analysis............................. 17
CCI
C
CI


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Abbreviations
AE
Adverse event
Anti-PD-1
Anti-programmed cell death protein-1
BICR
Blinded independent central review
BMI
Body mass index
CI
Confidence interval
CRF
Case report form
CRC
Colorectal cancer
CSR
Clinical study report
CTCAE
Common terminology criteria adverse event
ECG
Electrocardiogram
FAS
Full analysis set
IMAE
Immune modulating adverse event
MedDRA
Medical dictionary for regulatory activities
MSS
Microsatellite stable CRC
N/A
Not applicable
NCI
National cancer institute
PD
Pharmacodynamics
pMMR
mismatch repair-proficient CRC
PK
Pharmacokinetics
QT
Q wave to T wave interval
QTc
Corrected QT
RECIST
Response evaluation criteria in solid tumors
SAE
Serious adverse event
SAP
Statistical analysis plan
TEAE
Treatment emergent AE
VEGF
Vascular endothelial growth factor
WHO
World health organization


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2.
Study Objectives
The purpose of this study is to determine the safety and efficacy of the combination of 
regorafenib and nivolumab in patients with advanced or metastatic pMMR/MSS colorectal 
cancer.
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.
All data from the data base will also be given in subject data listings. Those will not be 
described in further detail as they will just represent the database.
4.2
Handling of Dropouts
All patients who discontinue the study after enrollment for any reason except death before the 
protocol defined end are considered drop-outs. Data of drop-outs will be used up to the point 
of study discontinuation, however no imputation for missing values will be done, except for 
dates (see below).
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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.
Missing or unevaluable tumor assessments, including scheduled assessments that were not 
done and incomplete assessments that did not result in an unambiguous tumor response 
evaluation according to RECIST 1.1, will not be used in the calculation of derived efficacy 
variables related to tumor assessments unless a new lesion occurred or the lesions that were 
evaluated already showed progressive disease. No imputation will be performed for missing 
lesion assessments and tumor response evaluation.
If a date is incomplete, (e.g. only year and month of date of tumor assessment or date of death 
is available), then day 15 of the month will be used for the calculation of, for example, overall 
survival and progression free survival. For imputation of AE dates, if the range of possible 
dates (e.g. a month, if day is missing) and during this time period “treatment emergent” and 
“non treatment emergent” is possible, the date will be imputed such that the AE will be 
“treatment emergent” (e.g. the day of treatment start if day is missing).
If the actual scan date of the radiological progression is missing and radiological or clinical 
progression has been documented based on criteria specified in the protocol, the scheduled 
scan date will be used to calculate the time to progression.
Safety variables, medical history and concomitant medications:
Treatment emergent AEs, treatment phases, period and relative days will be derived according 
to data management programming, the operations manual and standard guidelines.
4.4
Interim Analyses and Data Monitoring
No formal interim analysis is planned in this study. 
However it is planned to look at the data after 30-40 participants have had at least the first 
response evaluation, in order to get better information for the planning of the intended Phase 
III study. This data look will be focused on the response data only and the analyses will be 
described in a separate data look SAP.
No formal conclusions for this study will be drawn from this look at the data and due to the 
exploratory nature of this study, no formal adjustment of the type-I error will be performed.
4.5
Analysis of long-term follow-up
During the long term follow-up data on survival and subsequent anti-cancer therapies are 
collected by either telephone contact or onsite visit. After the last patient finished the long-
term follow-up, a final analysis of the long-term follow-up will be conducted. This will be 
conducted on the follow-up set of patients and will include population characteristics, overall 
survival analysis and anti-cancer medication. Details of the FU analysis will be specified in a 
separate document, either as addendum to this SAP or in a separate SAP.


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4.6
Data Rules
Dates:
Generally, for each date stored in the database a set of organizational variables will be derived 
in order to describe the temporal context of that date in the specific study in terms of: the 
phase of treatment (pre, during or post study treatment), the day relative to the start of study 
treatment, the day relative to the end of study treatment.
Year will be calculated as (days/365.25) rounded up to 1 decimal place.
Month will be calculated as (days/30.44) rounded up to 1 decimal place.
Time to event or duration of event endpoints will be based on the actual date rather than Visit 
Day.
Baseline:
Unless specified otherwise, baseline is the last pre-dose measurement performed prior to the 
first administration of the first study drug.
Post-Baseline:
Every value taken after the Baseline measurement is considered a post-Baseline value.
Change from Baseline:
Change from baseline is defined as (post-baseline value - baseline value).
Indirect Bilirubin:
Indirect Bilirubin is calculated as: 
total Bilirubin – direct Bilirubin
Indirect Bilirubin was entered in the CRF at the beginning of the study. These values will not 
be analyzed and only presented in the subject data listings for completeness. Summary 
statistics will only be created from the derived indirect Bilirubin as per formula given above.
Unscheduled Visits:
Unscheduled Visits will not be used in the analysis (i.e. section 14) and will only be presented 
as part of the subject data listing (i.e. section 16).
4.7
Validity Review
The results of the  final validity review meeting will be documented in the final list of 
important deviations, validity findings and assignment to analysis set(s). Any changes to the 
statistical analysis prompted by the results of the  review  of study data will be documented in 
an amendment and, if applicable, in a supplement to this SAP.
4.8
Subgroup analyses
All efficacy and adverse events analyses are also done by subgroups for the following 
subgroups:

Sex

Race

Age (<65, 65-74, 75-84, >=85)


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
Presence of liver metastases at baseline (yes / no)
The presence of liver metastases is defined as having a liver lesion (target or non-
target) at baseline. The respective question of the baseline cancer characteristics page 
is not used for this subgroup definition.

Primary cancer (colon / rectal)
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
validity review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis set(s) (see section 4.7).
Population
Description
Enrolled 
All participants who sign the ICF
FAS
All participants who have received at least 1 dose of study intervention will be 
used for efficacy analysis.
SAF
All participants who have received at least 1 dose of study intervention will be 
used for safety analysis.
IMS
All patients who have received at least one dose of nivolumab and have at least 
one ADA sample taken (during the treatment or follow-up observation period) 
that is appropriate for ADA testing (with reportable result) will be included in the 
analysis of the immunogenicity of nivolumab, which is defined as the 
immunogenicity analysis set.
Follow-Up (FUP)
All patients who entered the long-term follow-up and have had at least one data 
collection during the long-term follow-up will be analyzed in the final analysis 
after study end.
Abbreviations: ADA = anti-drug antibodies; FAS = full analyses set; ICF = informed consent form; PK = pharmacokinetics; r-
PKS = regorafenib PK analysis set; n-PKS = nivolumab PK analysis set; IMS = immunogenicity analysis set
No additional treatment assignments to compensate for potential unevaluable patients (e.g. 
lack of post baseline tumor scans) beyond the needed number of 70 treated patients is 
planned. Therefore SAF and FAS will be equal and only FAS will be referenced in the 
analyses.
6.
Statistical Methodology
All variables will be analyzed at least descriptively, which includes summary statistics (N, 
mean, std. dev. minimum, median, maximum) for continuous variables and frequency tables 
(N, % per category) for categorical variables.
A confirmatory analyses will be conducted only for the primary endpoint at one-sided type-I 
error level of 2.5% or two-sided type-I error level of 5% respectively. No further confirmatory 
analysis is intended, and no further tests are conducted. Confidence intervals will be presented 
for selected variables.
Covid-19:
All COVID-19 related findings will be presented as a separate listing and in applicable tables 
(e.g. protocol deviations) as separate finding as well.


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6.1
Population characteristics
Baseline values and demographic characteristics are defined in section 8.2.7 of the protocol. 
All baseline and demographic values will be summarized by descriptive tables as described 
above. 
Baseline cancer characteristics:
Baseline cancer characteristics will be summarized by a table using appropriate summaries. 
The lines of previous therapies will be analyzed as continuous variable, as well as categorical 
variable. The variable “liver metastases at baseline according to scans” which is used for the 
subgrouping of tables, will be added to this table as well as information about patients who 
had a liver resection.
Medical history
Data for medical history will be coded using the most recent version of MedDRA. Summary 
statistics (frequency and percentage) will be provided by system organ class (SOC), high level 
term (HLT) and preferred term (PT). 
Medications
The dictionary used for coding medications is the WHO Drug dictionary. Systemic anti-
cancer therapies will be displayed by frequency of subjects for each drug, (prior and during
follow-up). Diagnostic and therapeutic procedures will be tabulated by frequency of subjects 
by procedure (prior, concurrent and during follow-up), other concomitant medications will be 
presented by frequency of subjects for each drug category. 
In addition the prior anti-cancer therapies will be displayed, grouped by:
1. Neoadjuvant/adjuvant setting
2. Advanced/metastatic setting
Disposition of Subjects
Since the study is only conducted in the US, the number of subjects enrolled and included in 
each of the analysis populations will be tabulated overall and by center only. A summary table 
will also be presented for the number of subjects enrolled and the number and percentage of 
subjects in each of the defined populations. The reasons for subjects excluded from each of 
the subject populations will also be tabulated. The reasons for discontinuation of study 
treatment will be tabulated.
6.2
Efficacy
Analyses will be based on the FAS population.
6.2.1
Sample size
As of amendment 2, it was decided to stop recruitment at 70 treated patients. With this sample 
size of 70 patients, when the true underlying ORR is 17% or higher and a baseline response 
rate of 5% is assumed, a one-sided exact binomial test at a type-I error of at approximately 
2.5% would result in a power of 92.6%, with at least 8 responders needed to achieve 
significance.
The location of the primary tumor is a factor and it is expected that 40%-45% of patients will 
have the primary tumor on the right side. With 31 patients with right-sided tumors, the 
probability of observing 4 or more responders (ORR 13%) is approximately 80% when the 


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true underlying response rate is 17%, and the probability of observing 2 or fewer responders 
(ORR 6.5%) is approximately 80% when the true ORR is 5%. 
With 39 patients with left-sided tumors, the probability of observing 6 or more responders 
(ORR 15%) is approximately 67% when the true underlying response rate is 17%, and the 
probability of observing 2 or fewer responders (ORR 5.1%) is approximately 70% when the 
true ORR is 5%. 
For this calculation SAS PROC POWER was used.
6.2.2
Primary Endpoint: Overall response rate (ORR) based on RECIST
v1.1
Primary endpoint for efficacy assessment is ORR per RECIST v1.1. Radiological tumor 
assessments will be done locally by the investigator.. ORR is defined as the percentage of 
subjects with complete response (CR) or partial response (PR) and will be analyzed after all 
participants met the criteria for primary completion, which is to have 5 post-baseline scans 
i.e., to have been followed for 10 months, or to have dropped out of the trial. The data base 
will then be locked for analysis.
The primary analysis of the primary endpoint will investigate the hypothesis
H0: ORRCombination ≤ 5%   versus 
H1: ORRCombination > 5%
The hypothesis will be tested by a one-sided exact binomial test, assuming a background 
response rate for the combination to be at most 5%. The target response rate for the 
combination treatment will be 17%. Using a one-sided exact binomial test at a type-I error of 
at most 2.5% at least 8 responders out of the 70 patients are needed to achieve significance.
The result of the exact binomial test will be presented in a table, giving the response rate, the 
number of responders needed, the number of responders observed, the test-statistic and the p-
value. Inferential testing will not be repeated by subgroup, only confidence intervals will be 
presented for the subgroup analysis.
Further analysis of the primary endpoint includes frequency tables (with the ORR table also 
including all “Best overall response” categories) as well as corresponding 95% two-sided 
Clopper-Pearson confidence intervals. RECIST results will be displayed by visit as well. All
descriptive analyses (incl. confidence intervals) of the primary endpoint will be repeated by 
two subgroups:

primary tumor side (right and left). The information about tumor side does not come 
from the CRF, but is stored in the IxRS system and has to be transferred to the 
database. .

ECOG performance status at baseline (0 vs 1)
Formal testing of ORR will not be done for these subgroups.


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6.2.3
Secondary endpoints
Overall survival (OS):
Overall survival is defined as the time (days) from the date of first treatment to the date of 
death. 
OS for subjects who are still alive and in the study or who are lost to follow-up at the point of 
analysis will be censored at the last available date.
OS for subjects who have no post baseline information will be censored at day 1.
Progression free survival (PFS):
PFS is defined as the time (days) from the date of first treatment to the date of radiological or 
clinical disease progression or death due to any cause, if death occurs before progression is 
documented.
PFS for subjects without radiological or clinical  tumor progression or death at the time of 
analysis will be censored at their last date of tumor evaluation. 
PFS for subjects who have no tumor assessment post baseline and are still alive will be 
censored at day 1. Patients that report a PD after missed tumor assessment(s) will be censored 
at the last scan date the patient was known to be progression free.
Disease control rate (DCR):
Disease control rate is defined as the proportion of patients whose best response was complete 
response (CR), partial response (PR) or stable disease (SD). DCR will be evaluated at 8, 16,
24, 32 and 40 weeks
Scans collected after first progression disease (PD) will not be considered.
Duration of response (DOR):
Duration of response (for PR and CR) is defined as the time (days) from the first documented 
objective response of PR or CR, whichever is noted earlier, to disease progression or death (if 
death occurs before progression is documented). Duration of response will be defined for 
responders only, i.e. subjects with CR or PR.
Time to response (TTR):
Time to response is defined as the time (days) from first treatment until CR or PR and will be 
derived for responders only.
Duration of stable disease (DoSD):
Duration of stable disease is defined as the time (days) from first treatment to date that disease 
progression or death (if death occurs before progression) is first documented. This variable 
will only be calculated for subjects who failed to achieve a best response of CR or PR (i.e. 
calculated for subjects with SD as best overall response). Also subjects, who have no 
evaluable tumor assessments post-baseline available, will be excluded. The actual dates that 
the tumor scans were performed will be used for this calculation. Duration of stable disease 
for subjects without disease progression or death before progression at the time of analysis 
will be censored at the date of their last tumor assessment.
For analyses of the secondary endpoints, proportion-based efficacy variables will be using 
frequency tables as well as 95% two-sided Clopper-Pearson confidence intervals. With regard 
to time to event data, these will be summarized descriptively using Kaplan-Meier 


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methodology and plots, as well as median estimates based on Greenwood’s formula, 
including 95% two-sided confidence interval. Kaplan-Meier analysis will be displayed in a 
table as well, giving the number of patients under risk, the number of events and the number 
of censoring for time intervals of 3 months duration. Kaplan-Meier Plots will present the 
number of patients under risk for each time point of the x-axis. Kaplan-Meier Plots and 
matching tables will be created for the subgroups

Presence of liver metastases at baseline

Primary tumor

Primary side of tumor only.
Continuous endpoints will analyzed using summary statistics tables including 95% two-sided 
confidence intervals.
6.5
Safety
No formal statistical tests will be done for the safety endpoints. All analyses for safety will be 
performed in the FAS population.
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6.5.1
Extent of exposure
Extent of exposure will be summarized for the FAS, using descriptive statistics.
Duration of study treatment will be calculated in days and presented in months as the date of 
the last dose of any study treatment – date of the first dose of any study treatment + 1.
Dose modification, if applicable, will be summarized for both treatments separately.
6.5.2
Adverse events
All adverse events (AE) whether considered drug-related or not, will be reported on the CRF 
with diagnosis, start/stop dates, dates of any grade change, action taken, whether treatment 
was discontinued, any corrective measures taken, and outcome. For all events, the relationship 
to treatment and the severity of the event will be determined by the Investigator. AEs will be 
classified and coded using the National Cancer Institute (NCI) Common Terminology Criteria 
Adverse Event (CTCAE), version 5.0 .
According to the protocol (See section 8.3.1 of the final study protocol) AE will be collected 
from the signing of the informed consent form (ICF) until the end of active FU visit, which 
should be 30 days after last dose of regorafenib and 100 days after last dose of nivolumab. An 
AE is considered as treatment-emergent (TEAE) if it starts during treatment or within the 
post-treatment time window.
For further definitions of the terms AE, SAE, seriousness, intensity, causal relationship with
treatment, causal relationship to protocol-required procedures, action taken, and outcome 
please refer to the respective section of the protocol.
In the CRF only the worst action taken with regard to the study medication was captured, if 
nothing else changed while the AE was ongoing. Therefore all tables using this field, will 
have a footnote, mentioning this fact.
In addition to standard medDRA grouping, treatment-emergent AE of importance will be 
defined as follows:

Rash grade 3 or higher. Rash consists of the following MedDRA LLT*:
10037893, 10037894, 10005876, 10005877, 10012483, 10012884, 10013784, 
10013785, 10058692, 10015138, 10015139, 10015143, 10015241, 10015242, 
10015243, 10015244, 10015283, 10015285, 10015286, 10015585, 10015587, 
10058694, 10058693, 10058721, 10015724, 10015725, 10016064, 10018081, 
10018087, 10077181, 10018093, 10018094, 10018095, 10062432, 10062439, 
10077163, 10062442, 10062443, 10049201, 10019117, 10024426, 10024437, 
10079448, 10062704, 10079449, 10062705, 10025418, 10025422, 10049195, 
10025423, 10025424, 10027022, 10027967, 10027968, 10027969, 10027970, 
10028837, 10075807, 10074762, 10068748, 10033726, 10033727, 10033728, 
10033729, 10033730, 10033737, 10033740, 10034120, 10054770, 10078918, 
10074684, 10037844, 10037845, 10037872, 10048332, 10037848, 10037851, 
10037855, 10048310, 10037856, 10037858, 10037863, 10037867, 10037868, 
10037869, 10037870, 10037873, 10079349, 10037874, 10037875, 10037876, 
10037878, 10037880, 10063646, 10066739, 10057984, 10037890, 10059872, 
10038183, 10038186, 10038187, 10038188, 10081713, 10082785, 10080343, 
10062880, 10040806, 10081571, 10040841, 10040913, 10081143, 10073477, 
10047983, 10047984


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
High Billirubin (if entered as AE)

High Liver Enzymes (excluding GGT) (if entered as AE)
o
This table will be broken out by presence of liver metastases (yes vs. no) 
additionally

Hand/Foot Syndrom, consisting of the following MedDRA LLT*:
10033552, 10033552, 10070580, 10069640, 10019111, 10048776, 10019126, 
10063069, 10033553, 10054524, 10070580, 10069640, 10019111, 10048776, 
10019126, 10063069, 10033553, 10054524
All tables for TEAE/TESAE, except the one displaying (S)AE by relationship, will also be 
broken out by relationship to drug (Rego/Novo/Both). Relationship to drug in this case is 
defined as:

Related to Rego: relationship to regorafenib = yes AND relationship to nivolumab = 
no

Related to Nivo: relationship to nivolumab = yes AND relationship to regorafenib = 
no

Related to Both: relationship to regorafenib = yes AND relationship to nivolumab = 
yes

Any related: relationship to regorafenib = yes OR relationship to nivolumab = yes
Descriptive summary tables (frequency and percentage of patients, not of events) will be 
presented using the most recent version of MedDRA terminology, for the following:

Overview over treatment-emergent AEs

Treatment-emergent AEs with grade 3, 4, or 5

Treatment-emergent AEs by worst CTCAE grade

Treatment-emergent AEs occurring in at least 5% of patients

Overview over treatment-emergent AEs leading to study drug withdrawal

Treatment-emergent AEs leading to study drug withdrawal by worst CTCAE grade

Treatment-emergent AEs leading to regorafenib dose reduction

Treatment-emergent AEs leading to drug interruption

Treatment-emergent AEs leading to dose reduction and/or drug interruption

Treatment-emergent AEs of importance

Overview over treatment-emergent drug-related AEs

Treatment-emergent drug-related AEs with grades 3, 4, or 5

Treatment-emergent drug-related AEs by worst CTCAE grade

Treatment-emergent drug-related AEs occurring in at least 5% of patients

Overview over treatment-emergent drug-related AEs leading to study drug withdrawal


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
Treatment-emergent drug-related AEs leading to study drug withdrawal by worst 
CTCAE grade

Treatment-emergent drug-related AEs leading to regorafenib dose reduction

Treatment-emergent drug-related AEs leading to drug interruption

Treatment-emergent drug-related AEs leading to dose reduction and/or drug 
interruption
The incidence of pre-treatment AE and non-treatment-emergent AEs during long-term follow-
up will be tabulated. Other non-treatment-emergent AE will be presented by means of a 
subject data listing only.
Overview tables of adverse events will be presented in addition to the frequency tables.
6.5.3
Deaths and Serious Adverse events
Serious adverse events (SAE) will be classified using Version 5 of the National Cancer 
Institute (NCI) Common Terminology Criteria Adverse Event (CTCAE) grading system, and 
MedDRA terminology.

Overview over treatment-emergent SAEs

Treatment-emergent SAEs by worst CTCAE grade

Treatment-emergent SAEs leading to study drug withdrawal

Treatment-emergent SAEs leading to study termination

Treatment-emergent SAEs leading to regorafenib dose reduction

Treatment-emergent SAEs leading to drug interruption

Treatment-emergent SAEs leading to dose reduction and/or drug interruption

Overview over treatment-emergent drug-related SAEs

Treatment-emergent drug-related SAEs by worst CTCAE grade

Listing of treatment-emergent SAEs

Listing of non-treatment-emergent SAEs
The incidence of deaths in the study and especially deaths up to within 30 and 100 days of last 
dose of Regorafenib and Nivolumab respectively will be summarized by cause of death. All 
deaths up to within 30 (100) days of last dose of study drug will be listed by patient with start 
and stop date of study medication, date of death, and cause of death. All deaths beyond 30 
(100) days after last dose of study drug will be displayed in a separate listing.
6.5.4
Pregnancies
All pregnancies reported during the study will be listed.
6.5.5
Clinical laboratory data
Descriptive statistics (number of observations, mean, standard deviation, minimum, median 
and maximum values) will be presented for clinical laboratory tests (hematology, clinical
biochemistry and urinalysis), their changes from baseline (including baseline value), and their 
percent changes from baseline at applicable visits.


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Severity of hematological and biochemical laboratory values will be assessed based on NCI 
CTCAE Version 5.0. CTCAE severity grading for laboratory abnormalities are based on 
applicable laboratory threshold values outlined in NCI CTCAE. It should be noted that in the 
present analysis of those laboratory parameters for which additional clinical information 
potentially can also influence the toxicity grade, this clinical information is in general not 
available and only the laboratory measurements are used for severity assessment.
Any additional specific handling of the NCI CTCAE toxicity grading assignments will be 
noted in the footnotes of the corresponding tables as applicable per the data collection in the 
study.
•
In the event of overlapping CTCAE criteria ranges for specific lab tests, the 
algorithm assigns the worst grade
•
If calcium type is not recorded (i.e. only “calcium” is recorded), then grading is 
done as if the calcium is total calcium.  “Calcium corrected” is computed from 
total calcium and serum albumin (if ≤4.0 g/dl) from the same time point based on 
CTCAE v5.0 guidance. If serum albumin (if ≤4.0 g/dl) from the same time point 
is not available or if “calcium, unspecified” was collected then grading is done as 
if the calcium is ”corrected calcium.”
•
Results with special characters (such as “>” and “<”) are not graded.
The frequency of treatment emergent laboratory abnormalities regarding hematology, 
coagulation panel, clinical chemistry, and urinalysis will be tabulated. Worst grades for 
hematological and biochemical toxicities will be calculated according to CTCAE based on 
laboratory measurements, and will be summarized by NCI CTCAE category and worst grade.
Clinical laboratory toxicities during treatment including a period of 30 days after last dose of 
treatment will be considered as “treatment-emergent” for Regorafenib. The duration for 
Nivolumab will be 100 days.
The last non-missing value before or on the first day of study drug will be retained as 
“baseline” data. If several assessments are performed on the same day (without timing 
information) the average of the values will be considered.
Incidence tables (frequency and percentage of patients) as well as tables with change in NCI 
CTCAE worst grade from baseline will be presented as following:

Hematological and biochemical toxicity during screening (the last evaluation available 
before assignment to treatment is taken into account).

Treatment-emergent hematological and biochemical toxicity.

Treatment-emergent hematological and biochemical toxicities with incidence rate 
above 5% in any treatment arm.

Change in worst grade for hematological and biochemical toxicity from baseline.
The laboratory values will be also categorized into low, normal and high according to their 
reference ranges.
Descriptive statistics will be calculated by time interval. 
Unscheduled laboratory data will be listed (Section 16 of the CSR) only.


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6.5.5.1
Laboratory abnormalities
Incidence tables for the following laboratory abnormalities under Nivolumab treatment will 
be summarized:

ALT or AST > 3 x ULN

ALT or AST > 5 x ULN

ALT or AST > 10 x ULN 

ALR or AST > 20 x ULN

Total bilirubin > 2 x ULN

ALP > 1.5 x ULN

Concurrent (within 1 day after Nivolumab treatment) ALT or AST > 3 x ULN and 
total bilirubin > 2 x ULN

Concurrent (within 30 days after Nivolumab treatment) ALT or AST > 3 x ULN and 
total bilirubin > 2 x ULN

TSH value > ULN and
o
with baseline TSH value <= ULN
o
with at least one FT3/FT4 test value < LLN within 2-week window after the 
abnormal TSH test
o
with all FT3/FT4 test values >= LLN within 2-week window after the 
abnormal TSH test
o
with FT3/FT4 missing within 2-week window after the abnormal TSH test

TSH < LLN and
o
with baseline TSH value >= LLN
o
with at least one FT3/FT4 test value > ULN within 2-week window after the 
abnormal TSH test
o
with all FT3/FT4 test values <= ULN within 2-week window after the 
abnormal TSH test
o
with FT3/FT4 missing within 2-week window after the abnormal TSH test
6.5.6
12-Lead ECG, QTc
Analyses of ECG and QTc will be performed on the SAF population.
Corrected QT (QTc) will be calculated using Bazett’s (QTcB) and Fridericia’s (QTcF) 
formula. If several assessments are performed on the same day (without timing information) 
the average of the values will be considered.
Descriptive statistics including arithmetic mean, SD, median, minimum, and maximum will
be presented for the following ECG parameters: HR, RR, PR, QT, QRS, QTcB and QTcF. 
Parameters will be summarized for actual results and the change from baseline for the safety 
analysis set at each scheduled visit.
The number and percent of patients with absolute QTc interval prolongation or QTc increase 
from baseline will be defined and summarized. The criteria are:


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
QTc prolongation: QTc interval > 450 msec, QTc interval > 480 msec and QTc 
interval > 500 msec.

Increase from baseline in QTc interval: QTc interval increases from baseline > 30 
msec and QTc interval increases from baseline > 60 msec.
The number and percent of patients with new clinically significant abnormalities on ECGs per 
the investigator’s assessment at post-baseline time points will be summarized.
Unscheduled ECG data will be listed (Section 16 of the CSR) only.
6.5.7
ECOG status
The ECOG performance status will be summarized by descriptive statistics tables over time, 
incl. change from baseline. Two sets of tables will be produced, interpreting the score as 
categorical variable (categories 0-5) as well as continuous variable.
6.5.8
Other safety measures
Vital signs (i.e. blood pressure, heart rate, weight and BMI) will be tabulated and summarized 
by visit for observed values and changes from baseline using descriptive statistics, as 
appropriate.
Unscheduled vital signs data will be listed (Section 16 of the CSR) only.
7.
Document history and changes in the planned statistical analysis
This is the first amendment of the SAP.
CCI