Clinical trial NCT04704154
Conditions: Solid Tumors
Keywords: Pancreatic Ductal Adenocarcinoma (PDAC) Head and Neck Squamous Cell Carcinoma (HNSCC) Esophageal Squamous Cell Carcinoma (ESCC) Glioblastoma Multiforme (GBM) Anaplastic Astrocytoma (AA) Biliary Tract Carcinoma (BTC) PD-1 inhibitor nivolumab regorafenib multi-kinase inhibitor
Sponsor: Bayer
Start date: 2021-02-03; Completion date: 2024-03-29
Enrollment: 175 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Researchers are looking for a better way to treat people with solid tumors. Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how it works.

In this trial, the researchers want to learn about regorafenib taken together with nivolumab in a small number of participants with different types of tumors. These include tumors in the head and neck, the esophagus, the pancreas, the brain, and the biliary tract. The biliary tract includes gall bladder and bile ducts.

The trial will include about 200 participants who are at least 18 years old. All of the participants will take 90 mg of regorafenib as a tablet by mouth. The dose of regorafenib can be adjusted up to 120 mg or down to 60 mg by the doctor based on how well a participant tolerates treatment. All of the participants will receive 480 milligrams (mg) of nivolumab through a needle put into a vein (IV infusion).

The participants will take treatments in 4-week periods called cycles. They will take regorafenib once a day for 3 weeks, then stop for 1 week. In each cycle, the participants will receive nivolumab one time. These 4-week cycles will be repeated throughout the trial. The participants can take nivolumab and regorafenib until their cancer gets worse, until they have medical problems, or until they leave the trial. The longest nivolumab can be given is up to 2 years.

During the trial, the doctors will take pictures of the participants' tumors using CT or MRI and will take blood and urine samples. The doctors will also do physical examinations and check the participants' heart health using an electrocardiogram (ECG). They will ask questions about how the participants are feeling and if they have any medical problems.

Detailed description:

Arms: arm 1: Parallel-cohort in adult participants with selected recurrent or metastatic tumors (HNSCC, ESCC, PDAC, BTC, and GBM/AA) who have been previously treated with one or more systemic therapy for the selected tumor indication.
Interventions: intervention 1: Regorafenib, (Stivarga, BAY73-4506) intervention 2: Nivolumab (Opdivo)
Intervention descriptions: intervention 1: Intake orally, starting with 3x 30 mg tablets every day (once daily.) for 21 days of every 28-day cycle (21 days on, 7 days off).

If the starting dose is well tolerated dose can be escalated to 120 mg (4x30 mg tablets). intervention 2: 480 mg administered on Day 1 of each treatment cycle.

Protocol documents:
SAP_002.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A Multi-indication, Single-treatment Arm, Open-label Phase 2 
Study of Regorafenib and Nivolumab in Combination in Patients 
with Recurrent or Metastatic Solid Tumors 
NCT Number: 
NCT04704154 
Document Date: 
12 MAR 2024 
 




CONFIDENTIAL 
Table of Contents 
Statistical Analysis Plan 
BAY 73-4506 I 21136 
Version 3.0 
Page: 2 of9 
Title Page ............................................................................................................................... 1
Version History ..................................................................................................................... 3
1.
Introduction ................................................................................................................... 3 
1.1 
Objectives and Endpoints ............................................................................................ 3 
1.2 
Study Design ................................................................................................................ 3 
2.
Statistical Hypotheses ................................................................................................... 4
3.
Sample Size Determination .......................................................................................... 4
4.
Analysis Sets .................................................................................................................. 4
5.
Statistical Analyses ........................................................................................................ 4
5 .1 
General Considerations ................................................................................................ 4 
5 .2 
Participant Dispositions .............................................................................................. .4 
5.3 
Primary Endpoint(s) Analysis ...................................................................................... 4 
5.3.1 
Definition ofEndpoint(s) ......................................................................................... 4 
5.3.2 
Main Analytical Approach ....................................................................................... 4 
5.3.3 
Sensitivity Analyses ................................................................................................. 5 
5.3.4 
Supplementary Analyses .......................................................................................... 5 
5.4 
Secondary Endpoint(s) Analysis .................................................................................. 5 
5.4.1 
Key/Confirmatory Secondary Endpoint(s) ............................................................... 5 
5.4.2 
Supportive Secondary Endpoint(s) ........................................................................... 5 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis ................................................................. 5 
5.5.1 
Tertiary Endpoint(s) ................................................................................................. 5 
5.6 
(Other) Safety Analyses ............................................................................................... 6 
5.6.1 
Extent of Exposure ................................................................................................... 6 
5.6.2 
Adverse Events ......................................................................................................... 6 
5.6.3 
Additional Safety Assessments ................................................................................ 6 
5.7 
Other Analyses ............................................................................................................. 6 
5.7.1 
Other Variables and/or Parameters ........................................................................... 6 
5. 7 .2
Subgroup Analyses ................................................................................................... 7 
5 .8
Interim Analyses .......................................................................................................... 7 
5 .8.1
Data Monitoring Committee or Other Review Board .............................................. 7 
6.
Supporting Documentation .......................................................................................... 8
6.1 
Appendix 1: List of Abbreviations .............................................................................. 8 
6.2 
Appendix 2: Changes to Protocol-planned Analyses ................................................... 8 
6.3 
Appendix 3: Baseline characteristics and demographics ............................................. 8 
6.4 
Appendix 4: Protocol deviations .................................................................................. 8 
6.5 
Appendix 5: Medical history ....................................................................................... 8 
6.6 
Appendix 6: Prior/concomitant/follow-up medications (including dictionary) ........... 8 
7.
References ...................................................................................................................... 9 




CONFIDENTIAL 
Statistical Analysis Plan 
BAY 73-4506 I 21136 
Version 3.0 
2.
Statistical Hypotheses
Refer to main SAP v2.0, dated 25 JAN 2023. 
3.
Sample Size Determination
Refer to main SAP v2.0, dated 25 JAN 2023. 
4.
Analysis Sets
Refer to main SAP v2.0, dated 25 JAN 2023. 
5.
Statistical Analyses
5.1 
General Considerations 
Refer to main SAP v2.0, dated 25 JAN 2023. 
5.2 
Participant Dispositions 
Page: 4 of9 
The number of participants enrolled and included in each of the analysis populations will be 
tabulated overall, by country and center. A summary table will also be presented for the 
number of participants enrolled and the number and percentage of participants in each of the 
defined populations (i.e. FAS, SAF ... ). 
The number and percentage of participants who started and discontinued treatment, active 
follow-up and long-term follow-up will be given as well as the reason for discontinuation. 
Demographic, baseline characteristics, prior medications and medical history analyses will 
not be presented in the CSR addendum. 
Protocol deviations analyses are defined under Section 6.4. 
Concomitant medications, follow-up medications analyses are defined under Section 6.6. 
5.3 
Primary Endpoint(s) Analysis 
5.3.1 
Definition of Endpoint(s) 
The primary endpoint of this study is ORR. 
Refer to main SAP v2.0, dated 25 JAN 2023. 
5.3.2 
Main Analytical Approach 
ORR will be displayed using frequency counts and percentages as well as 80% two-sided 
Clopper-Pearson confidence intervals, by cohort. 
Summary statistics will be displayed for all best response categories: CR, PR, stable disease 
(SD), progression disease (PD) by radiographic imaging and PD by clinical judgment. 
Frequency counts and percentages with 80% two-sided Clopper-Pearson CI will be displayed. 











Prot_000.pdf: 
 
 
 
CONFIDENTIAL 
Clinical Study Protocol Global Amendment 1 
BAY 73-4506/ 21136 
27 JAN 2021 
 
 
 
 
 
 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A Multi-indication, Single-treatment Arm, Open-label Phase 2 
Study of Regorafenib and Nivolumab in Combination in Patients 
with Recurrent or Metastatic Solid Tumors 
NCT Number: 
NCT04704154 
Document Date: 
27 JAN 2021 


 
 
 
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BAY 73-4506/ 21136 
 
27 JAN 2021 
 
Page 2 of 135 
 
 
 
Title Page 
Protocol Title: 
A Multi-indication, Single-treatment Arm, Open-label Phase 2 
Study of Regorafenib and Nivolumab in Combination in Patients 
with Recurrent or Metastatic Solid Tumors  
Protocol Number: 
21136 Global Amendment 1 
Compound Number: 
BAY 73-4506 
Study Phase:  
Phase 2 
Short Title:  
Multi-indication study of regorafenib plus nivolumab for 
recurrent or metastatic solid tumors 
Sponsor Name and 
Legal Registered 
Address: 
Non-US: Bayer AG, 51368 Leverkusen, Germany  
 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA 
Regulatory Agency 
Identifier Number(s) 
IND: 150865 
Eudra CT: 2020-003359-13 
 
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 
 
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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27 JAN 2021 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment 1 
27 JAN 2021 
Original Protocol 
09 SEP 2020 
Amendment 1 (27 JAN 2021) 
This amendment is considered substantial based on the relevant criteria of the (EU) clinical 
trial legislation. 
Overall Rationale for the Amendment:  
The protocol amendment 01 was triggered by an amendment to nivolumab IB version 19, that 
includes updates to the management guidance for immune-mediated adverse events related to 
nivolumab and to male contraception guidance.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
 
Table 1-2 Schedule of 
activities 
Updated mention of footnotes 
on tumor assessment 
(CT/MRI) visits 
Footnote e – updated to point 
out which AEs are collected 
Table 1-3 Schedule of 
Biomarker Blood Sampling 
Updated footnote 
Schedule of Activities updated to 
more clearly define the timing of the 
CT/MRIs and the collection of AEs 
during follow-up. 
Footnote removed as it does not 
apply to study population. 
4.1.3 Active 
FU 
Added sentence on AE 
documentation after start of 
new anti-cancer treatment 
Wording was updated so only related 
AEs are collected during the follow-
up period once new anti-cancer 
treatment is started. 
4.4 End of 
Study 
Definition 
Additional wording on trial 
stop added. 
To clarify options in case the trial is 
stopped. 
5.1 Inclusion 
Criteria 
Cohort 1 
(HNSCC, IO 
naïve) 
Inclusion criteria number 102 
edited. 
Additional inclusion criteria for stage 
2 participants to clarify previous 
therapies allowed. 
5.1 Inclusion 
Criteria 
Cohort 3 
(ESCC) 
Inclusion criteria number 302 
edited. 
Additional inclusion criteria for stage 
2 participants to clarify previous 
therapies allowed. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
For all cohorts 
Inclusion criteria 9: Updated 
guidance on contraception 
after study intervention 
regarding nivolumab 
Updated guidance regarding male 
contraception based on updated 
nivolumab IB. 
5.2 Exclusion 
Criteria  
For all cohorts 
Exclusion criteria 1: Updated 
definition 
 
Exclusion criteria 12: 
Definition of poorly controlled 
hypertension updated to ‘above 
140/90 mmHg’ 
To clearly specify that participants 
that have known NTRK fusions are 
excluded. 
 
Updated according to most recent 
guidelines and recommendations. 
6 Study 
Intervention 
Definition of light meal added 
Additional text inserted to further 
define light meal. 
6.5.3 
Prohibited 
Prior and 
Concomitant 
Therapies 
Strong UGT1A9 inhibitors 
included as prohibited therapy. 
Updated to remain consistent with 
current regorafenib label. 
6.6.1 Toxicity 
Management 
Table 6-3 Dose Modification/ 
Dose Interruption Guide for 
Regorafenib-Related Toxicities  
 
Table 6-5 Regorafenib Dose 
Modification Guidance: Non-
Immune Toxicities: 
Hypertension 
Tables updated as per HA request. 
6.6.2 Toxicity 
Management 
6.6.2.1 
Note referring to CTCAE v5 
deleted. 
Nivolumab toxicity management 
guidelines were updated to reflect 
incorporation of CTCAE v5 as well 
as changes consistent with updated 
nivolumab immune-mediated AE 
management algorithms. 
Guidance in section 10.9 was updated 
accordingly. 
Table 6-7 updated 
 
 
 
Reference to Nivolumab 
management algorithm added 
Recommended dose modification for 
nivolumab was updated according to 
the newest management algorithms 
for studies, under CTCAE v5. 
Section edited to be consistent with 
newest Nivolumab management 
algorithm. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
6.6.2.2 
Management of 
Immune-
Mediated AEs 
Definition of immune-
mediated AE added 
Make description clearer and more 
precise for the reader. 
7.1 
Discontinuation 
of Study 
Intervention 
Section Withdrawal from 
active FU edited. 
Wording updated to further clarify 
when patients must be withdrawn 
from active FU. 
8 Study 
Assessments 
and Procedures 
Sentence added on trial-
continuity issues. 
To specify possible measures in the 
event of a significant trial-continuity 
issue (e.g. caused by a pandemic). 
8.1 Efficacy 
Assessments 
Use of oral contrasts  
Specification that oral contrast agents 
are required unless inconsistent with 
local regulations. 
10.1.1 
Regulatory and 
Ethical 
Considerations 
Section edited regarding 
amendments.  
Section updated to clarify that 
substantial amendments to the 
protocol require regulatory authority 
approval before implementation. 
10.2 Appendix 
2 
Wording updated  
 
 
Updated Table 10-1 Protocol-
Required Safety Laboratory 
Assessments  
Wording updated to clarify which 
assessments are performed in the 
local laboratory. 
Table footnote updated: Amylase and 
lipase will be part of safety blood test 
conducted in each treatment cycle. 
GGT will be assessed if clinically 
indicated. 
10.6 Appendix 
6 
10.6.3 RANO 
Definitions added and table 
updated. 
Section was updated to improve 
readability and clarify on RANO 
criteria definitions. 
10.9 Appendix 
9 
Update of AE management 
algorithms 
AE management algorithms were all 
updated and apply criteria from NCI-
CTCAE v5. Tables were exchanged 
accordingly. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and clerical 
errors and document 
formatting revisions 
Minor, therefore have not been 
summarized 
A tracked changes version of the document will be provided separately. 
 
 


 
 
 
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Table of Contents 
Title Page ............................................................................................................................... 1 
Protocol Amendment Summary of Changes Table ........................................................... 3 
Table of Contents ................................................................................................................. 7 
Table of Tables ..................................................................................................................... 9 
Table of Figures .................................................................................................................. 10 
1. 
Protocol Summary ...................................................................................................... 11 
1.1 
Synopsis ..................................................................................................................... 11 
1.2 
Schema ....................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) ..................................................................................... 14 
2. 
Introduction ................................................................................................................. 22 
2.1 
Study Rationale .......................................................................................................... 22 
2.2 
Background ................................................................................................................ 22 
2.3 
Benefit/Risk Assessment ........................................................................................... 27 
3. 
Objectives and Endpoints ........................................................................................... 29 
4. 
Study Design ................................................................................................................ 30 
4.1 
Overall Design ........................................................................................................... 30 
4.1.1 
Screening Phase ...................................................................................................... 32 
4.1.2 
Treatment Phase ..................................................................................................... 32 
4.1.3 
Active FU ............................................................................................................... 33 
4.1.4 
Long-Term FU ........................................................................................................ 34 
4.2 
Scientific Rationale for Study Design ....................................................................... 34 
4.3 
Justification for Dose ................................................................................................. 34 
4.4 
End of Study Definition ............................................................................................. 35 
5. 
Study Population ......................................................................................................... 36 
5.1 
Inclusion Criteria ....................................................................................................... 36 
5.2 
Exclusion Criteria ...................................................................................................... 39 
5.3 
Lifestyle Considerations ............................................................................................ 43 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 44 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................................................. 44 
5.4 
Screen Failures ........................................................................................................... 44 
6. 
Study Intervention ...................................................................................................... 44 
6.1 
Study Intervention(s) Administered ........................................................................... 46 
6.2 
Preparation/Handling/Storage/Accountability ........................................................... 46 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 47 
6.4 
Study Intervention Compliance ................................................................................. 47 
6.5 
Concomitant Therapy ................................................................................................ 48 
6.5.1 
Drug-Drug Interactions Relevant for Regorafenib ................................................. 48 
6.5.2 
Permitted Concomitant Therapies .......................................................................... 49 
6.5.3 
Prohibited Prior and Concomitant Therapies ......................................................... 51 
6.5.4 
Documentation of Prior and New Concomitant Therapies .................................... 52 


 
 
 
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6.5.5 
Rescue Medicine..................................................................................................... 52 
6.6 
Dose Modification ..................................................................................................... 52 
6.6.1 
Toxicity Management, Dose Modification and Permanent Discontinuation 
Recommendations for Regorafenib ........................................................................ 53 
6.6.2 
Toxicity Management, Dose Modification and Permanent Discontinuation 
Recommendations for Nivolumab .......................................................................... 56 
6.7 
End of Treatment ....................................................................................................... 60 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...................................................................................... 61 
7.1 
Discontinuation of Study Intervention ....................................................................... 61 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 64 
7.3 
Lost to FU .................................................................................................................. 64 
8. 
Study Assessments and Procedures ........................................................................... 65 
8.1 
Efficacy Assessments ................................................................................................ 65 
8.2 
Safety Assessments .................................................................................................... 70 
8.2.1 
Physical Examinations ............................................................................................ 70 
8.2.2 
Vital Signs .............................................................................................................. 70 
8.2.3 
Electrocardiograms ................................................................................................. 71 
8.2.4 
Clinical Safety Laboratory Assessments ................................................................ 71 
8.2.5 
ECOG Performance Status ..................................................................................... 71 
8.2.6 
Pregnancy Tests ...................................................................................................... 72 
8.2.7 
Baseline Characteristics .......................................................................................... 72 
8.3 
Adverse Events and Serious Adverse Events ............................................................ 73 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information................... 73 
8.3.2 
Method of Detecting AEs and SAEs ...................................................................... 74 
8.3.3 
FU of AEs and SAEs .............................................................................................. 74 
8.3.4 
Regulatory Reporting Requirements for SAEs ...................................................... 74 
8.3.5 
Pregnancy ............................................................................................................... 74 
8.4 
Treatment of Overdose .............................................................................................. 75 
8.5 
Pharmacokinetics ....................................................................................................... 76 
8.6 
Pharmacodynamics .................................................................................................... 76 
8.7 
Genetics ..................................................................................................................... 77 
8.8 
Biomarkers ................................................................................................................. 77 
8.8.1 
Pharmacodynamics Biomarker ............................................................................... 79 
8.8.2 
Biomarkers that may associate with Response ....................................................... 79 
8.8.3 
Other Biomarkers ................................................................................................... 80 
8.9 
Immunogenicity Assessments .................................................................................... 80 
9. 
Statistical Considerations ........................................................................................... 80 
9.1 
Statistical Hypotheses ................................................................................................ 81 
9.2 
Sample Size Determination ....................................................................................... 81 
9.3 
Populations for Analyses ........................................................................................... 82 
9.4 
Statistical Analyses .................................................................................................... 82 
9.4.1 
General Considerations........................................................................................... 82 
9.4.2 
Primary Endpoint(s) ............................................................................................... 83 
9.4.3 
Secondary Endpoint(s) ........................................................................................... 83 
9.4.4 
Tertiary/Exploratory Endpoint(s) ........................................................................... 84 


 
 
 
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9.4.5 
Safety Analyse(s) .................................................................................................... 84 
9.4.6 
Other Analyses ....................................................................................................... 84 
9.5 
Interim Analyses ........................................................................................................ 84 
9.6 
Data Monitoring Committee (DMC) or other Review Board .................................... 84 
10. Supporting Documentation and Operational Considerations ................................ 84 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 84 
10.1.1 Regulatory and Ethical Considerations .................................................................. 84 
10.1.2 Financial Disclosure ............................................................................................... 85 
10.1.3 Informed Consent Process ...................................................................................... 85 
10.1.4 Data Protection ....................................................................................................... 87 
10.1.5 Committees Structure ............................................................................................. 87 
10.1.6 Dissemination of Clinical Study Data .................................................................... 87 
10.1.7 Data Quality Assurance .......................................................................................... 88 
10.1.8 Source Documents .................................................................................................. 89 
10.1.9 Study and Site Start and Closure ............................................................................ 90 
10.1.10 Publication Policy ................................................................................................... 91 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 91 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
FU, and Reporting ...................................................................................................... 93 
10.3.1 Definition of AE ..................................................................................................... 93 
10.3.2 Definition of SAE ................................................................................................... 94 
10.3.3 Recording and FU of AE and/or SAE .................................................................... 95 
10.3.4 Reporting of SAEs .................................................................................................. 97 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 98 
10.5 Appendix 5: Genetics ............................................................................................... 101 
10.6 Appendix 6: Response Evaluation Criteria in Solid Tumors ................................... 101 
10.6.1 RECIST 1.1 .......................................................................................................... 101 
10.6.2 iRECIST ............................................................................................................... 104 
10.6.3 RANO ................................................................................................................... 109 
10.6.4 iRANO .................................................................................................................. 111 
10.7 Appendix 7: New York Heart Association (NYHA) Classification ........................ 114 
10.8 Appendix 8: CYP3A4 Inhibitors and Inducers ........................................................ 114 
10.9 Appendix 9: Guidance for Management of Immune-Related Adverse Events ....... 115 
10.10 Appendix 10: Abbreviations .................................................................................... 123 
10.11 Appendix 11: Protocol Amendment History ........................................................... 128 
11. References .................................................................................................................. 132 
 
Table of Tables 
Table 1–1 Objectives and Endpoints ...................................................................................... 12 
Table 1–2 Schedule of Activities ........................................................................................... 14 
Table 1–3 Schedule of Biomarker Blood Sampling ............................................................... 20 
Table 1–4 Pharmacokinetic and Immunogenicity Sample Collection Plan ........................... 21 
Table 3–1 Objectives and Endpoints ...................................................................................... 29 
Table 6–1 Administration of Study Intervention .................................................................... 46 
Table 6–2 Dose Levels for Regorafenib ................................................................................. 53 
Table 6–3 Dose Modification/Dose Interruption Guide for Regorafenib-Related Toxicities 53 


 
 
 
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Table 6–4 Regorafenib Dose Modification/Dose Interruption Guidance: HFSR/ Palmar-
Plantar Erythrodysesthesia Syndrome ................................................................... 54 
Table 6–5 Regorafenib Dose Modification Guidance: Non-Immune Toxicities: Hypertension
 ............................................................................................................................... 55 
Table 6–6 Dose Modification/Dose Interruption Guide for Regorafenib-related Toxicities: 
Liver Function Test Increases Related to Regorafeniba ........................................ 55 
Table 6–7 Recommended Dose Modification for Nivolumaba .............................................. 57 
Table 8–1 Definitions for ECOG PS Grading ........................................................................ 72 
Table 8–2 Requirements for Tumor Tissue Collection .......................................................... 78 
Table 9–1 Populations for Analyses ....................................................................................... 82 
Table 10–1 Protocol-Required Safety Laboratory Assessments .............................................. 92 
Table 10–2 Highly Effective Contraceptive Methods .............................................................. 99 
Table 10–3 RECIST 1.1 - Time Point Response for participants with target and non-target 
lesions .................................................................................................................. 104 
Table 10–4 Imaging and Treatment after First Radiologic Evidence of PD .......................... 108 
Table 10–5 RANO Response Criteria Incorporating MRI and Clinical Factor ..................... 110 
Table 10–6 RANO and iRANO Criteria ................................................................................ 112 
Table 10–7 New York Heart Association (NYHA) Classification ........................................ 114 
Table 10–8 Overview of CYP3A4 Inducers and Strong CYP3A4 Inhibitors ........................ 115 
Table 10–9 Abbreviations ...................................................................................................... 123 
Table 10–10 Terms and Definitions ....................................................................................... 127 
 
 
Table of Figures 
Figure 1–1 Study Schema ........................................................................................................ 13 
Figure 4–1 Study Design Overview ......................................................................................... 30 
Figure 4–2 Study Schema ........................................................................................................ 31 
Figure 10–1 
iRECIST: Process for Assessment of Disease Progression ............................ 109 
Figure 10–2 
iRANO Treatment Algorithm for the Assessment of Progressive Imaging 
Findings in Patients with Neuro-Oncological Malignancies Undergoing 
Immunotherapy ................................................................................................... 113 
 
 
 


 
 
 
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1. 
Protocol Summary 
1.1 
Synopsis  
Protocol Title:  
A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib in 
Combination with Nivolumab in Patients with Recurrent or Metastatic Solid Tumors 
 
Short Title:  
Multi-indication study of regorafenib plus nivolumab for recurrent or metastatic solid tumors 
 
Rationale:  
Immune checkpoint inhibitors (ICI) have been shown to be effective anticancer therapy and are 
approved as standard treatment in several tumor types. However, approximately 60-70% of 
tumors do not respond to single agent ICI therapy and among the tumors that respond, resistance 
to therapy can develop over time. A high unmet need remains to improve clinical outcomes for 
cancer patients. One such strategy to improve outcomes is combining ICI with a multi-kinase 
inhibitor (MKI) targeting vascular endothelial growth factor (VEGF) which are predicted to 
have complementary anti-tumor effects and potential enhancement of tumor-directed immune 
response. In preclinical and clinical studies, the combination of an ICI and anti-VEGF MKI has 
demonstrated promising results showing enhanced tumor response in different cancers and 
improvement of clinical measures (Khan and Kerbel 2018). 
To explore the potential to enhance anti-tumor response through combining of an ICI with an 
anti-VEGF MKI, this open-label, multi-center Phase 2 study of regorafenib and nivolumab 
aims to evaluate the safety and efficacy of the combination in multiple cohorts of participants 
with selected advanced solid tumors. 
The combination of regorafenib with nivolumab is predicted to enhance tumor-directed 
immune response by relieving immunosuppression through the reduction of tumor associated 
macrophages (TAMs), regulatory T cells (Treg), and expression of programmed cell death 
protein 1 ligand 1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO-1), along with 
inhibition of VEGF signaling. In addition, tumor immunity may be enhanced by the increased 
infiltration of cytotoxic T cells mediated by increased expression of the chemoattractant C-X-
C motif chemokine ligand 10 (CXCL10), the ligand for CXC-motif-chemokine receptor 3 
(CXCR3), which occurs on T cells (data on file).  
Therefore, novel therapies using regorafenib with programmed cell death protein 1 (PD-1) 
antibody, such as nivolumab, present a unique opportunity to address a high unmet need and 
improve clinical outcomes in multiple advanced solid tumor indications.   


 
 
 
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Objectives and Endpoints  
Table 1–1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate efficacy of the regorafenib and 
nivolumab combination by cohort  
• 
ORR per RECIST 1.1a by local assessment for all 
solid tumors except GBM/AA  
• 
ORR per RANOa by local assessment for GBM/AA 
Secondary 
• 
Evaluation of the additional efficacy measures of 
the regorafenib and nivolumab combination  
 
• 
DORa  
• 
DCRa 
• 
PFSa,  
• 
6 months PFSa 
• 
OS 
• 
1yr OS 
• 
To evaluate safety of the combination by cohort 
and overall 
• 
Frequency and severity of AEs per CTCAE v 5.0 
Tertiary/Exploratory 
• 
To characterize the PK and immunogenicity of the 
regorafenib and nivolumab combination 
 
• 
Exposure of regorafenib and nivolumab and 
detection of anti-drug antibodies (ADA) 
(immunogenicity) 
• 
To evaluate the relationship between regorafenib 
exposure and relevant biomarkers for efficacy 
and/or safety 
• 
Retrospective analysis of the relationship 
between regorafenib exposure and biomarker, 
safety and/or efficacy measures 
• 
To assess efficacy of regorafenib and nivolumab 
combination using immune related response 
criteria in solid tumors  
• 
ORR per iRECIST or per iRANO for GBM/AAa 
 
• 
To identify biomarkers in baseline tumor 
materials, blood and/or stool samples that may 
associate with response   
• 
Correlation of biomarkers in tumor, blood or stool 
samples before treatment with other study 
endpoints 
• 
To explore pharmacodynamic effects of 
regorafenib and nivolumab combination on e.g. 
immune environment, signaling pathway activity, 
and downstream processes 
• 
Change from baseline in levels of biomarkers in 
tumor, blood or stool samples 
 
• 
To further investigate the study intervention and 
similar drugs (i.e., mode-of-action-related effects 
and / or safety) and to further investigate patho-
mechanisms deemed relevant to cancer and 
associated health problems 
• 
Various biomarkers (e.g., diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers) 
Abbreviations: AA = Anaplastic astrocytoma; ADA = Anti-drug antibody; AE = Adverse event; CTCAE = Common terminology 
criteria for adverse events; DCR=Disease Control Rate; DOR = Duration of response; GBM = Gliobastoma multiforme; iRANO = 
Immune response assessment in neuro-oncology; iRECIST = Response evaluation criteria in solid tumors for trials testing 
immunotherapeutics; ORR = Objective response rate; OS = Overall survival; PFS = Progression free survival; PK = 
Pharmacokinetics; RANO = Response assessment in neuro-oncology; RECIST 1.1 = Response evaluation criteria in solid 
tumors 1.1  
a) 
The efficacy endpoints will be based on the local Investigator’s assessment. Imaging data on tumor assessment will be 
collected for a potential central review of tumor evaluation by blinded readers.  
 
Overall Design:  
Disclosure Statement: This is a multi-indication, single-treatment arm, open-label Phase 2 
study of regorafenib in combination with nivolumab in participants with recurrent or 
metastatic solid tumors 


 
 
 
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Number of Participants:  
Approximately 286 participants will be screened to achieve up to approximately 200 treated 
participants. For cohort-specific details on treated participants see Figure 1-1. 
Data Monitoring Committee: Not applicable. 
 
1.2 
Schema  
Figure 1–1 
Study Schema 
 
Abbreviations: AA = Anaplastic Astrocytoma; BTC = Biliary Tract Carcinoma; ChT = Chemotherapy; DCR = Disease control 
rate; DOR = Duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESCC = 
Esophageal Squamous Cell Carcinoma; GBM = Glioblastoma Multiforme; HNSCC = Head and Neck Squamous Cell 
Carcinoma; IO = Immune oncology; IV = Intravenous; ORR= Overall Response Rate; OS = Overall survival; PDAC= Pancreatic 
ductal adenocarcinoma; PFS = Progression free survival; PK = Pharmacokinetics; PO = Per oral; q4wk = Every 4 weeks; QD = 
Once daily; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors 1.1; RANO = Response assessment in neuro-
oncology; R/M = Recurrent/Metastatic 
 
 


 
 
 
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1.3 
Schedule of Activities (SoA)  
Table 1–2 
Schedule of Activities 
Procedure 
Screening 
Treatment period 
EoT visit 
Active FUa  
Long-
term 
FU 
Comments 
Cycle1 
Cycle 2 
Cycle ≥3 
 
within 
28 d 
prior to 
first 
dose 
within 
7 d 
prior 
to first 
dose 
D 1 
D 8 
D15 
D22 
D1 
D8 
D15 
D1 
within 14 d after 
permanent study 
treatment 
discontinuation  
Safety FU visit 
30 d after 
permanent study 
treatment 
discontinuation  
Safety FU 
visit  
100 d after 
LD for 
nivolumaba 
Efficacy FU 
visit 
(between 
EoT and 
confirmed 
radiological 
PD)  
every 3 
months 
(phone 
call)  
 
 
acceptable 
deviation (days)   
 
 
± 2 d 
± 2 d 
± 3 d 
 
+ 7 d 
+ 14 d 
± 14 d 
± 14 d 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IxRSb 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
General 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5 
Cancer 
classificationc  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor molecular 
and cellular data 
collection MSI 
status, TMB and 
PD-L1 if available 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.7 
GBM/AA: IDH 
mutation and 
MGMT 
methylation status 
by historical test 
or local test in 
tumor tissue if 
available 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.8.2 


 
 
 
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Procedure 
Screening 
Treatment period 
EoT visit 
Active FUa  
Long-
term 
FU 
Comments 
Cycle1 
Cycle 2 
Cycle ≥3 
 
within 
28 d 
prior to 
first 
dose 
within 
7 d 
prior 
to first 
dose 
D 1 
D 8 
D15 
D22 
D1 
D8 
D15 
D1 
within 14 d after 
permanent study 
treatment 
discontinuation  
Safety FU visit 
30 d after 
permanent study 
treatment 
discontinuation  
Safety FU 
visit  
100 d after 
LD for 
nivolumaba 
Efficacy FU 
visit 
(between 
EoT and 
confirmed 
radiological 
PD)  
every 3 
months 
(phone 
call)  
 
 
acceptable 
deviation (days)   
 
 
± 2 d 
± 2 d 
± 3 d 
 
+ 7 d 
+ 14 d 
± 14 d 
± 14 d 
 
HNSCC 
(oropharyngeal):  
HPV/p16 status 
by historical test 
or local test in 
tumor tissue 
(mandatory)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.8.2 
Primary tumor 
diagnosis using 
complete 
pathological 
report 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-cancer 
treatment 
(therapy, surgery, 
radiotherapy)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination  
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
Section 8.2.1 
Limited physical 
examination  
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
 
Section 8.2.1 
Neurological 
examination for 
GBM/AA  
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
Section 8.2.1 


 
 
 
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Procedure 
Screening 
Treatment period 
EoT visit 
Active FUa  
Long-
term 
FU 
Comments 
Cycle1 
Cycle 2 
Cycle ≥3 
 
within 
28 d 
prior to 
first 
dose 
within 
7 d 
prior 
to first 
dose 
D 1 
D 8 
D15 
D22 
D1 
D8 
D15 
D1 
within 14 d after 
permanent study 
treatment 
discontinuation  
Safety FU visit 
30 d after 
permanent study 
treatment 
discontinuation  
Safety FU 
visit  
100 d after 
LD for 
nivolumaba 
Efficacy FU 
visit 
(between 
EoT and 
confirmed 
radiological 
PD)  
every 3 
months 
(phone 
call)  
 
 
acceptable 
deviation (days)   
 
 
± 2 d 
± 2 d 
± 3 d 
 
+ 7 d 
+ 14 d 
± 14 d 
± 14 d 
 
Relevant medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE reviewe  
X 
X 
==========================================================================→ 
 
 
 
ECOG 
performance 
status 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Section 8.2.5 
Serum pregnancy 
test if applicable 
(WOCBP only)f  
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Section 8.2.6 
Table 10–1 
Serology testing 
for Hepatitis B/C 
and HIV  
X 
If clinically indicated 
 
 
at screening if 
history or 
symptoms of 
Hep B/C or 
HIV 
Clinical chemistry  
expandedg 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Table 10–1 
Clinical chemistry  
limited 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Table 10–1 
Hematology 
expandedg 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Table 10–1 
Hematology 
limited 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Table 10–1 
PT-INR and 
aPTTg 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Table 10–1 


 
 
 
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Procedure 
Screening 
Treatment period 
EoT visit 
Active FUa  
Long-
term 
FU 
Comments 
Cycle1 
Cycle 2 
Cycle ≥3 
 
within 
28 d 
prior to 
first 
dose 
within 
7 d 
prior 
to first 
dose 
D 1 
D 8 
D15 
D22 
D1 
D8 
D15 
D1 
within 14 d after 
permanent study 
treatment 
discontinuation  
Safety FU visit 
30 d after 
permanent study 
treatment 
discontinuation  
Safety FU 
visit  
100 d after 
LD for 
nivolumaba 
Efficacy FU 
visit 
(between 
EoT and 
confirmed 
radiological 
PD)  
every 3 
months 
(phone 
call)  
 
 
acceptable 
deviation (days)   
 
 
± 2 d 
± 2 d 
± 3 d 
 
+ 7 d 
+ 14 d 
± 14 d 
± 14 d 
 
Urine analysis by 
dipstickg 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
  
 
Table 10–1 
Thyroid function 
testingg 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Table 10–1 
12-lead ECGh 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Section 8.2.3 
Vital signs 
(including weight) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Section 8.2.2 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
assessments – 
(CT/MRI)i 
X 
 
 
 
 
 
 
 
 
X 
Xa,i 
Xa,i 
Xa,i 
Xa,i 
 
Section 8.1 
Bone scani 
X 
 
======================== If indicated, see section 8.1 ========================→ 
 
Section 8.1 
Brain scan 
(MRI/CT)i 
X 
 
======================== If indicated, see section 8.1 ========================→ 
 
Section 8.1 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1st subsequent 
anti-cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Study 
intervention 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment: 
Nivolumabj 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Section 6.1 
Study treatment: 
Regorafenibj 
 
 
===============================→ 
3 weeks on/ 1 week off 
 
 
 
 
 
Section 6.1 


 
 
 
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Procedure 
Screening 
Treatment period 
EoT visit 
Active FUa  
Long-
term 
FU 
Comments 
Cycle1 
Cycle 2 
Cycle ≥3 
 
within 
28 d 
prior to 
first 
dose 
within 
7 d 
prior 
to first 
dose 
D 1 
D 8 
D15 
D22 
D1 
D8 
D15 
D1 
within 14 d after 
permanent study 
treatment 
discontinuation  
Safety FU visit 
30 d after 
permanent study 
treatment 
discontinuation  
Safety FU 
visit  
100 d after 
LD for 
nivolumaba 
Efficacy FU 
visit 
(between 
EoT and 
confirmed 
radiological 
PD)  
every 3 
months 
(phone 
call)  
 
 
acceptable 
deviation (days)   
 
 
± 2 d 
± 2 d 
± 3 d 
 
+ 7 d 
+ 14 d 
± 14 d 
± 14 d 
 
Drug 
accountability  
(regorafenib and 
nivolumab)k 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Drug dispensing 
(regorafenib)k  
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Prior/Concomitant 
medications and 
radiotherapy 
review (including 
vaccination) 
X 
X 
===========================================================================→ 
 
 
 
Research 
sample 
collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regorafenib PK 
sample collection 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
see Table 1–4 
Nivolumab PK 
sample collection 
 
 
X 
 
 
 
X 
 
 
X  
 
 
 
 
 
see Table 1–4  
Immunogenicity 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
see Table 1–4 
Biomarker blood 
sampling 
 
for sampling details, see Table 1–3. 
 
 
 
 
see Table 1–3 
Tumor tissue  
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Stool sample 
collectionl  
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 


 
 
 
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Abbreviations: AA =Anaplastic astrocytoma; AE = Adverse event; AJCC = American Joint Committee of Cancer; aPTT = Activated partial thromboplastin time; BTC = Biliary 
tract cancer; C = Cycle; CT = Computed tomography; CTCAE = Common terminology criteria for adverse events; D (d) = Day; ECG = Electro cardiogram; ECOG = Eastern 
Cooperative Oncology Group; EoT = End of treatment; ESCC = Esophageal squamous cell cancer; FU = Follow-up; GBM = Glioblastoma multiforme; GGT = Gamma-
glutamyl transferase; Hep B/C = Hepatitis B/C virus; HIV = Human immunodeficiency virus; HNSCC = Head and neck squamous cell cancer; HPV = Human papilloma virus; 
hr = Hour(s); IDH = Isocitrate dehydrogenase; INR = International normalized ratio; IxRS = Interactive voice/web response system; LD = Last dose; MGMT= O6-
methylguanine DNA methyltransferase; MRI = Magnetic resonance; PDAC = Pancreatic ductal adenocarcinoma; PI/ICF = Participant information/informed consent form); PK 
= Pharmacokinetics; PT = Prothrombin time; WHO = World Health Organization; WOCBP = Women of childbearing potential. 
a. 
Participants discontinuing study treatment without radiological disease progression should continue tumor evaluations (by CT/MRI) if at all possible until radiological 
progression and/or start of first subsequent systemic anti-cancer treatment whichever comes first, or until participant withdraws from study for any reason. During active 
FU, CT/MRI scans will be performed every 12 weeks +/-14d (see Section 8.1). Active FU will either be terminated by the last safety FU visit or thereafter by the last tumor 
assessment or documentation of first subsequent systemic anti-cancer treatment or any criterion for withdrawal is met.  
If nivolumab is permanently discontinued first and the day 100 safety FU visit after nivolumab discontinuation falls into regorafenib treatment period or day 30 safety FU 
period, no separate nivolumab day 100 safety FU visit is necessary as the information gathering and examinations will occur with regorafenib treatment cycle visit, EoT 
visit or day 30 safety FU visit (required after study treatment discontinuation).  
b. 
Contact IxRS to record the following: 1. to register the participant who has signed the PI/ICF 2. the participant is a screening failure (failed to meet the criteria during the 
screening period), 3. on D1 of every treatment cycle in order to register the cycle and to ensure the specific participant drug bottles/vials can be provided for dispensing 
purposes and also in case the participant has discontinued the study treatment (EoT) for any reason. 
c. 
AJCC classification for HNSCC, ESCC, PDAC, BTC, and, WHO classification for GBM/AA. 
d. 
Test results need to be available before start of study treatment. 
e. 
Participants will be followed for intervention-related toxicities until these toxicities resolve, return to baseline or are deemed irreversible. All AEs will be documented for 
30 d + 7 d after study treatment discontinuation or 100 d + 14 d after LD of nivolumab, whatever occurs later. After start of subsequent anti-cancer therapy only study 
intervention-related AEs should be collected. CTCAE v5.0 will be used. 
f. 
A negative pregnancy test must be available within 24 h before the 1st study treatment administration. Monthly pregnancy testing independent of study treatment dosing 
should be conducted as per local regulations where applicable. 
g. 
Need to be performed within 2 days prior to the study treatment administration. For thyroid function tests, results can also be analyzed retrospectively in case the results 
are not immediately available. 
h. 
12-lead ECG to be scheduled at every cycle on D1 until cycle 6, after which ECG can be performed at the discretion of the investigator if clinically indicated. 
i. 
CT/MRI scans performed prior to the participant signing informed consent can be used as baseline scans if they are not older than 28 days from C1D1 and meet the 
requirements outlined in Section 8.1. Scans are to be performed every 8 weeks (± 7 d) through Cycle 8 (or until treatment discontinuation, if treatment discontinuation 
occurs before), afterwards every 12 weeks (± 14 d). See Section 8.1 for further details on the schedule of tumor assessments beyond progression per RECIST 1.1 or 
RANO criteria. For all participants with known bone metastases or clinically suspected of having bone disease, bone scans will be performed as outlined in Section 8.1. 
HNSCC, ESCC, PDAC, BTC participants with neurological symptoms and/or known CNS disease must undergo CT/ MRI scans of the brain as outlined in Section 8.1.  
j. 
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 nivolumab treatment and may 
continue on regorafenib monotherapy. 
k. 
Participants will bring their medication at each visit. Drug accountability of regorafenib will be done on Day 1 of every cycle starting from Cycle 2, and at the EoT visit. 
l. 
Collection of stool can be performed at any time during visit or within ±7 d of the planned visit. 
 


 
 
 
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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 
cycle 
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 
 
Biomarker plasma 
for ctDNA 
 
X 
 
X 
 
X 
X 
X 
X 
Biomarker blood for 
flow cytometry 1 
X 
X 
X 
X 
X 
X 
 
 
X 
Biomarker blood for 
flow cytometry 2 
X 
X 
X 
X 
X 
X 
 
 
X 
Biomarker seruma  
X 
X 
X 
X 
X 
X 
X 
 
X 
Biomarker plasma a 
X 
X 
X 
X 
X 
X 
X 
 
X 
Biomarker blood for 
RNA 
 
X 
X 
X 
 
X 
 
 
X 
Biomarker blood for 
pharmacogenetics 
 
X 
 
 
 
 
 
 
 
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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Table 1–4 
Pharmacokinetic and Immunogenicity Sample Collection Plan 
Sampling 
time 
Regorafenib, M-2 and 
M-5 PK 
Nivolumab PK 
 
Immunogenicity  
C1 D1 
pre-dose and at 0.5 hrb 
and 3-4 hrb after oral 
intake  
pre-infusion and EoIa  
 
pre-infusion 
C1 D8 
pre-dose 
 
 
C1 D15 
pre-dose and 2-4 hrb 
after oral intake 
 
 
C2 D1 
pre-dose and at 0.5 hrb 
and 3-4 hrb after oral 
intake  
pre-infusion  
pre-infusion 
C2 D15 
pre-dose and 2-4 hrb 
after oral intake 
 
 
C5 D1 
 
pre-infusion  
pre-infusion 
C19 D1 
 
pre-infusion 
pre-infusion 
Abbreviations: C = Cycle; D = Day; EoI = End of infusion; hr = Hour(s); PK = Pharmacokinetics  
a) 
Nivolumab pre-dose samples should be taken just prior to start of infusion (preferably within 
30 min). If the infusion is delayed and a pre-dose sample in already collected, there is no need 
to collect an additional pre-dose sample. EoI samples should be taken as close to EoI as 
possible (preferably 2 min prior to EoI) on the contralateral arm (i.e. the arm not used for the 
infusion). If nivolumab is not administered on the scheduled day PK, pre-dose samples should 
be collected. Otherwise PK sampling should always be linked to the nivolumab administration. 
b) 
If regorafenib is not administered on the day of PK sampling, the pre-dose samples will be 
collected, the post-dose samples will not be collected. Pre-dose samples will also not be 
collected if participants have not taken regorafenib on the previous day. However, if 
regorafenib is re-started than PK sampling should resume as scheduled. 


 
 
 
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2. 
Introduction  
2.1 
Study Rationale 
ICIs have been shown to be effective anticancer therapy and are approved as standard treatment 
in several tumor types. However, approximately 60-70% of tumors do not respond to single 
agent ICI therapy and among the tumors that respond, resistance to therapy can develop over 
time. A high unmet need remains to improve clinical outcomes.  
One such strategy to improve outcomes is combining ICI with a MKI targeting VEGF which 
are predicted to have complementary anti-tumor effects and potential enhancement of tumor-
directed immune response. In preclinical and clinical studies, the combination of an ICI and 
anti-VEGF MKI has demonstrated promising results showing enhanced tumor response in 
different cancers and improvement of clinical measures (Khan and Kerbel 2018). 
Recently, combinations of anti PD-1antibodies and MKIs targeting VEGF pathway such as 
axitinib, lenvatinib, regorafenib and cabozantinib have shown encouraging activity in multiple 
solid tumors (Agarwal et al. 2020, Makker et al. 2019, Rini et al. 2019). In pre-clinical tumor 
models of various cancer types (colorectal cancer [CRC], hepatocellular carcinoma [HCC], 
melanoma) the combination of regorafenib and anti-PD-1 drugs was more effective compared 
to either monotherapy (Hoff et al. 2017, Wu et al. 2019). In a Phase 1b trial of Japanese 
patients with advanced microsatellite stable (MSS) colorectal and gastric cancer (GC), the 
combination of regorafenib and nivolumab was safe and demonstrated significant activity 
with confirmed overall response rate (ORR) of 33% and 44%, respectively (Fukuoka et al. 
2020). 
To explore the potential to enhance antitumor response through combining of an ICI with an 
anti-VEGF MKI, this open-label, multi-center Phase 2 study of regorafenib and nivolumab aims 
to evaluate the safety and efficacy of the combination in multiple cohorts of participants with 
selected advanced solid tumors.  
The combination of regorafenib with nivolumab is predicted to improve efficacy through 
complementary anti-tumoral effects and to enhance tumor-directed immune response by 
relieving immunosuppression through the reduction of tumor associated macrophages, Tregs, 
and expression of PD-L1 and IDO-1, along with inhibition of VEGF signaling. In addition, 
tumor immunity may be enhanced by the increased infiltration of cytotoxic T cells mediated by 
increased expression of the chemoattractant CXCL10, the ligand for CXCR3, which occurs on 
T cells (data on file).  
Therefore, novel therapies using regorafenib with PD-1 antibody, such as nivolumab, present 
a unique opportunity to address a high unmet need and improve clinical outcomes in multiple 
advanced solid tumor indications.   
2.2 
Background 
Regorafenib 
Regorafenib (BAY 73-4506) is an oral small molecule tyrosine kinase inhibitor that potently 
blocks multiple protein kinases, including kinases involved in tumour angiogenesis (vascular 
endothelial growth factor receptor (VEGFR1), 2, 3, tyrosine kinase with immunoglobulin and 
epidermal growth factor homology domain 2 (TIE-2), oncogenesis [stem cell factor receptor 
(KIT)], rearranged during transfection (RET), rapidly accelerated fibrosarcoma 1 [RAF1], 


 
 
 
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type B of RAF kinase (BRAF), BRAFV600E), metastasis (VEGFR3, platelet-derived growth 
factor receptor (PDGFR), fibroblast growth factor receptor (FGFR)] and tumour immunity 
[colony-stimulating factor 1 receptor (CSF1R)]. 
In preclinical studies, regorafenib has demonstrated potent antitumor activity as a single agent 
in a broad spectrum of tumour models, including models of head and neck squamous-cell 
carcinoma (HNSCC), glioblastoma multiforme/anaplastic astrocytoma (GBM/AA), pancreatic 
ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) (Daudigeos-Dubus 
et al. 2015, Klinghammer et al. 2015, Wilhelm et al. 2011), likely mediated by its 
anti-angiogenic and anti-proliferative effects. Regorafenib under trade name Stivarga is 
approved for pre-treated advanced CRC, pre-treated advanced gastro-intestinal stromal tumor 
(GIST), and pre-treated advanced hepatocellular carcinoma (HCC).  
Regorafenib under the trade name Stivarga® is currently authorized in 96 countries for 
treatment of mCRC, 93 countries for treatment of GIST, and 86 countries for the treatment of 
HCC.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of regorafenib is 
provided in the most recent Investigator’s Brochure (IB)  
Nivolumab 
Nivolumab (BMS-936558) is a fully human, immunoglobulin (IgG)4 (kappa) isotype 
monoclonal antibody that binds PD-1 on activated immune cells and disrupts engagement of 
the receptor with its ligands (PD-L1) (B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby 
abrogating inhibitory signals and augmenting the host antitumor response.  
Nivolumab under the trade name Opdivo® is approved by the United States (US) Food and 
Drug Administration (FDA) for the treatment of multiple tumor types, unresectable or 
metastatic melanoma, adjuvant treatment of melanoma, metastatic NSCLC, small cell lung 
cancer (SCLC), advanced renal cell carcinoma (RCC), classical Hodgkin lymphoma, 
HNSCC, urothelial carcinoma (UC), microsatellite instability-high or mismatch repair 
deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) and esophageal squamous 
cell carcinoma (ESCC). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the most recent IB. 
Head and Neck Squamous Cell Carcinoma 
Head and neck cancer is the seventh most common cancer worldwide with 890,000 newly 
diagnosed patients each year resulting in 450,000 death annually (Chow 2020). In the US, 
head and neck cancer incidence is estimated to be 65,000 with 15,000 deaths annually. 
HNSCC accounts for more than 90% of head and neck cancers and arises in the oral cavity, 
oropharynx, hypopharynx, and larynx. The two most common risk factors for HNSCC is 
tobacco and alcohol use (Hashibe et al. 2009), but Epstein-Barr virus (EBV) and human 
papilloma virus (HPV) also play a role in the development of carcinomas of the nasopharynx 
and the oropharynx, respectively. HPV infection is known to cause oropharyngeal cancer, 
especially those arising from the tonsils and tongue base but may also be associated with 
other HNSCC cancers as well (Ang et al. 2010, D'Souza et al. 2007). Oropharyngeal cancer 
associated with HPV infection as noted by HPV-positive or p16-positive status have better 
prognosis than those not associated with HPV.  
 


 
 
 
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Immunotherapy either alone or in combination with chemotherapy have improved the survival 
of patients with HNSCC regardless of PD-L1 status and have become part of standard of care 
in 1L and 2L. Despite these advances, patients with non-curative recurrent or metastatic 
disease have a median survival less than 16 months (Rischin et al. 2019) with 1L therapy and 
less than 9 months in the 2L setting, (Cohen et al. 2019, Ferris et al. 2016). Approximately 
36% of HNSCC patients will respond to 1L systemic therapy and less than 13-18% of patients 
respond in the 2L setting when treated with an PD-1 inhibitor (Ferris et al. 2016, Mehra et al. 
2018). With only a minority of patients benefitting from ICI, there is a need to explore 
additional strategies to improve outcomes. 
 
Early results from clinical trial in subjects with advanced HNSCC treated with combination of 
anti-angiogenic MKI and PD-1 inhibitor (lenvatinib and pembrolizumab) suggest potential 
synergistic effect on response compared to the historical results of single agent PD-1 inhibitor 
(Taylor et al. 2020). Whereas clinical trials of single agent nivolumab and pembrolizumab in 
patients with advanced HNSCC showed an ORR of 13% to 18% (Ferris et al. 2016, Mehra et 
al. 2018), the study of the combination of lenvatinib and pembrolizumab resulted in an ORR 
of 46% (Taylor et al. 2020).  
Nivolumab is approved for treatment of recurrent or metastatic HNSCC that are platinum-
resistant based on data showing improved survival compared to treatment with single-agent 
chemotherapy (hazard ratio [HR] 0.70; 97.73% confidence interval [CI], 0.51 to 0.96; P = 
0.01) (Ferris et al. 2016). The median OS for the nivolumab group was 7.5 months (95% CI, 
5.5 to 9.1) and ORR was 13%. The activity of nivolumab as single agent and early clinical 
data from studies of PD-1 inhibitor in combination with an anti-angiogenic MKI suggest 
exploring the potential for combing nivolumab with regorafenib to improve clinical results for 
patients with advanced HNSCC. 
 
Little is known regarding the eﬀectiveness of ICI rechallenge after disease progression 
following initial ICI treatments in HNSCC and other solid tumors. Many previous trials 
involving ICI excluded patients who have received prior ICI. As ICIs have received expanded 
approval for different tumor indications including broader application for initial treatment in 
HNSCC, an unmet need exists to assess whether a rechallenge with an ICI in combination 
with another agent may overcome resistance to initial ICI treatment and improve response. 
There is early indication that a rechallenge with ICI in combination with a MKI may allow 
some solid tumors that have progressed on prior ICI to respond. In the REGONIVO study, 3 
of 7 GC patients who were refractory to previous PD-1–targeted therapy achieved response 
with regorafenib plus nivolumab. The ORR was 42.8% (3 out of 7) for GC patients who 
progressed on prior ICI and 44% (11 out of 25) among all GC patients (Fukuoka, Hara et al. 
2020). Among the 7 responders out of 21 patients with advanced NSCLC, 2 participants who 
progressed on prior ICI therapy achieved responses (1 complete response [CR] and 1 partial 
response [PR]) upon treatment with lenvatinib in combination with pembrolizumab (Taylor et 
al. 2020). These results are encouraging and warrant further study to address whether the 
combination regorafenib with nivolumab can elicit anti-tumor response in patients with 
HNSCC who have progressed on prior ICI therapy. 
Esophageal Squamous Cell Carcinoma 
Esophageal cancer, the sixth most common cause of cancer deaths worldwide, has an 
incidence of 570,000 cases annually (Bray et al. 2018, WHO-IARC 2018). The most common 
subtype globally is ESCC which accounts for 88% of all esophageal cancer (Abnet et al. 


 
 
 
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2018). ESCC occurs most commonly in Asia, Eastern Africa, and South America. The 5-year 
survival rate is 5% for patients diagnosed with metastatic disease (NIH-SEER 2020). In a 
randomized control Phase 3 trial (ATTRACTION-3), nivolumab improved survival versus 
chemotherapy (paclitaxel or docetaxel) (median OS 10.9 months vs 8.4 months, HR 0.77, 
95% CI 0.62-0.96; p=0.019) irrespective of tumor PD-L1 expression in subjects with 
unresectable advanced, recurrent or metastatic ESCC previously treated with 
fluoropyrimidine- and platinum-based chemotherapy (Kato et al. 2019). Treatment with 
nivolumab was associated with an ORR of 19% and a favorable safety profile. Despite this 
progress, a high unmet need remains to explore a combinatorial approach to enhance the anti-
tumor effects of PD-1 inhibition in patients with ESCC.  
 
Pancreatic Duct Adenocarcinoma  
PDAC, a highly lethal cancer associated with poor prognosis, is the seventh leading cause of 
cancer-related deaths worldwide and third leading cause of cancer-related deaths in the US 
(Rawla et al. 2019). Many patients present with advanced disease not eligible for curative 
treatment. Except for a small number of patients who qualify for targeted therapy based on 
selected tumor markers (e.g. MSI-H, tropomyosin receptor kinase [NTRK]) the treatment 
options for patients with non-curative advanced disease, include gemcitabine and 
fluoropyrimidine based chemotherapy regimens that are guided by performance status, 
(Ducreux et al. 2015, NCCN-Pancreatic-Cancer 2020). With these chemotherapy regimens, 
patients have associated hematological, gastrointestinal, and neurological toxicities and the 
overall 5-year survival rate has not improved markedly, remaining less than 10%. Although 
PD-1/PD-L1 inhibitors have shown efficacy in several different tumor indications, clinical 
trials have not shown effectiveness in PDAC (Henriksen et al. 2019). There exists a high 
unmet need to improve therapeutic options that lead to better clinical outcomes for patients 
with PDAC. Several potential mechanisms of pancreatic resistance to ICI exist including 
those related to Tregs and tumor associated macrophages (TAMs) in the tumor 
microenvironment (Skelton et al. 2017). Regorafenib inhibits CSF1R, a receptor which in 
preclinical models of several cancers have been shown to reduce the number of 
immunosuppressive TAMs, thereby facilitating an immune response against tumors (Abou-
Elkacem et al. 2013, Zopf et al. 2016). Pancreatic cancers have been shown to express high 
levels of serum CSF-1, the ligand for CSF1R (Groblewska et al. 2007). These findings form 
the rationale for a combination approach of using an anti-angiogenic agent such as 
regorafenib with CSF1R inhibition in combination with nivolumab to potentially overcome 
resistance to ICI therapy and fulfill the need to improve therapeutic options and clinical 
outcomes for patients with PDAC. 
 
Biliary Tract Cancer 
BTC is a group of rare heterogenous cancer that includes the subtypes intrahepatic 
cholangiocarcinoma (CCA), extrahepatic CCA, and gallbladder cancers (GBC). These 
cancers are more common in Asian countries than Western countries with an incidence age-
standardized rate of 3 per 100,000 in South Korea and 0.66 per 100,000 in the United 
Kingdom (Wang et al. 2020). BTCs accounts for approximately 12,000 new cases and 4,000 
deaths per year in the US (Siegel et al. 2019). Most patients are diagnosed with advanced 
disease and have poor prognosis, with 5-year survival rates of approximately 10% (Everhart 


 
 
 
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and Ruhl 2009, Ghosn et al. 2015). Chemotherapy typically with gemcitabine and cisplatin 
are first-line standard of care for patients with unresectable and metastatic BTC. Despite 
treatment advances, the survival for these patients is typically less than a year (Valle et al. 
2010). Thus, there is a need to search for new and more effective therapeutic options for 
patients this rare and fatal cancer.   
VEGF overexpression has been reported in BTC and appears to be a potential prognostic 
marker (Mobius et al. 2007, Yoshikawa et al. 2008). For this reason, regorafenib has been 
explored in several clinical studies which have shown encouraging efficacy in advanced BTC 
(Kim et al. 2020b, Sun et al. 2019). In a single arm Phase 2 trial of regorafenib in patients 
with advanced/unresectable or metastatic biliary tract cancer who failed at least 1 line of 
systemic chemotherapy, the median progression free survival (PFS) was 15.6 weeks (90% 
confidence interval, 12.9-24.7 weeks), and the median overall survival (OS) was 31.8 weeks 
(90% confidence interval, 13.3-74.3 weeks), with survival rates 40% at 12 months and 32% at 
18 months, and ORR of 11%. Another single arm Phase 2 trial of single agent regorafenib in 
patients with advance BTC who have progressed after at least 1 prior line of therapy, the PFS 
and OS were 3.7 months and 5.4 months respectively, and the ORR was 9.1%. A multi-
institution single arm study of nivolumab in patients with advanced BTC who have 
progressed after at least 1 line of standard of care (SOC) demonstrated, PFS of 3.7 months, 
OS 14.2 months, and ORR of 11% by central independent review (Kim et al. 2020a). The 
encouraging efficacy results from these trials and the tolerable profiles of regorafenib and 
nivolumab as single agent support exploration of the combination of these two agents to 
improve clinical responses for patients with advanced BTC. 
 
Recurrent Glioblastoma and Anaplastic Astrocytoma 
There are more than 300,000 tumors of the brain and central nervous system worldwide each 
year, and approximately 240,000 deaths (Bray et al. 2018). The prognosis for patients 
diagnosed with GBM is poor, with 5-year survival rates of approximately 5% (Tykocki and 
Eltayeb 2018). The SOC for patients with GBM following surgical resection is radiation 
therapy (RT) with concomitant and adjuvant temozolomide (TMZ). Methylation of the 
promoter of the O6-methylguanine-DNA methyltransferase (MGMT) deoxyribonucleic acid 
(DNA)-repair gene is an independent favorable prognostic factor for patients treated with RT 
and TMZ. The standard of care in patients with recurrent GBM is less clear. Bevacizumab is 
approved in the U.S. and Japan for the treatment of recurrent GBM based on PFS but has not 
been shown to improve OS when compared to single agent nitrosourea-based chemotherapy 
(Friedman et al. 2009, Wick et al. 2017) 
GBM is a highly vascularized tumor and is characterized by the expression of VEGF and 
other proangiogenic cytokines (Wong et al. 2009). Regorafenib alone significantly inhibited 
tumor growth in glioma tumor xenografts and antitumor activity was associated with 
decreased vascularization and inhibition of the platelet-derived growth factor receptor 
(PDGFR) pathways (Daudigeos-Dubus et al. 2015) A randomized, controlled Phase 2 trial of 
regorafenib showed OS benefit in a patient with recurrent GBM compared to lomustine (HR 
0.50, 95% CI 0.33–0.75; log-rank p=0∙0009) (Lombardi et al. 2019). Nivolumab was shown 
to have comparable median OS to bevacizumab in a randomized, controlled Phase 3 study of 
patient with first recurrence of GBM. Based on the high unmet need that exists for patients 
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further study to assess the effectiveness of the combination of these two agents is warranted to 
improve outcomes for patients with this fatal tumor.  
2.3 
Benefit/Risk Assessment 
ICIs have been approved for treatment in a broad range of cancers. However, approximately 
60-70% of tumors do not respond to single agent ICI therapy and among the tumors that 
respond, resistance to therapy can develop over time. An approach that combines ICI with 
regorafenib, which blocks multiple protein kinases, including kinases involved in anti-tumor 
pathways including tumour angiogenesis, oncogenesis, metastasis, and immunity (Section 
2.2), has the potential to improve tumor response in patients with advanced cancers. 
 
Combination of regorafenib and nivolumab was evaluated in a Phase 1b trial of Japanese 
patients with advanced proficient mismatch repair (pMMR)/MSS CRC and gastric cancer and 
demonstrated clinically relevant activity greater than that expected from either agent alone 
with confirmed ORR of 33% and median PFS of 7.9 months in CRC and 44% for gastric 
cancer and median PFS 5.6 months (Fukuoka et al. 2020). The combination was well 
tolerated and had a manageable safety profile. In addition, a Phase 1b study combining 
regorafenib with a PD-1 inhibitor pembrolizumab for the treatment of patients with HCC 
without prior systemic therapy demonstrated encouraging anti-tumor activity and no new 
safety signals than what is expected from the safety profile of either drug alone (El-Khoueiry 
et al. 2020, Fukuoka et al. 2020).  
Nivolumab is approved for treatment of recurrent or metastatic HNSCC that are platinum-
resistant and unresectable advanced, recurrent or metastatic ESCC after prior 
fluoropyrimidine- and platinum-based chemotherapy. The therapeutic benefits of nivolumab 
for these indications apply to a minority of patients. Thus, additional strategies are needed to 
allow more patients to benefit from ICI therapy. Encouraging data (as discussed in Section 
2.2) demonstrate that combining a MKI and PD-1 inhibitor may improve anti-tumor response 
over single agent PD-1 inhibitor. In one study, the combination of lenvatinib and 
pembrolizumab lead to an higher response rate (ORR of 46%) than what has been reported 
from trials of single agent PD-1 inhibitors (ORR 13-18%) for the treatment of advanced 
HNSCC (Ferris et al. 2016, Mehra et al. 2018). This clinical data as well as additional data as 
discussed in Section 2.2 suggest that combining a PD-1 inhibitor nivolumab with a MKI such 
as regorafenib has the potential for mechanistic synergy and enhanced the anti-tumor response 
which may lead to improved clinical outcomes. 
Patients with recurrent GBM/AA and BTC typically have median survival of less a year and 
many of these patients fail to respond to therapy or develop progression after initial response.  
Trials of regorafenib or nivolumab as single agents for the treatment of advanced BTC and 
recurrent GBM have demonstrated some encouraging responses (as discussed in Section 2.2). 
These early indications of efficacy form the rationale to further investigate whether 
combining regorafenib and nivolumab can enhanced anti-tumor effects and address the high 
need for better therapeutic options for patients with these fatal cancers. 
Advanced pancreatic cancers are highly lethal due to resistance to many classes of therapy.  
Despite ICI working in a broad range of cancers, PDAC remains fairly resistant to ICI 
therapy.  Several potential mechanisms of PDAC resistance exist.  Preclinical models show 
that regorafenib inhibits CSF1R, a receptor which in several cancers have been shown to 
reduce the number of immunosuppressive TAMs (see Section 2.2). This observation suggests 
that regorafenib has the potential to facilitate an immune response against tumors and to 


 
 
 
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enhance the immune-mediated action of nivolumab (Abou-Elkacem et al. 2013, Zopf et al. 
2016). 
The safety profiles from studies of regorafenib in combination with a PD-1 inhibitor 
(nivolumab or pembrolizumab) have shown that toxicities are consistent with those of 
regorafenib or nivolumab monotherapy (El-Khoueiry et al. 2020, Fukuoka et al. 2020). In the 
Phase 1b REGONIVO study of patients with CRC or GC treated with regorafenib plus 
nivolumab, the common grade ≥3 treatment-related AEs were rash (12%), proteinuria (12%), 
and palmar-plantar erythrodysesthesia (10%). In the Phase 1b study of patients with advanced 
HCC treated with regorafenib plus pembrolizumab, grade ≥3 treatment-related AEs were AST 
increase (20%), lipase increase (17%), hypertension (14%), ALT increase (17%), and 
bilirubin increase (11%). 
Regorafenib has shown in clinical trials a positive benefit-risk across different tumor types, 
including CRC, GIST and HCC. The incidence, severity and relationship of adverse events 
(AEs) were generally similar across dose levels and tumor types. The development of some 
AEs (e.g. diarrhea, hyperbilirubinemia, increase in transaminases, hand foot skin reaction 
[HFSR], rash) are common in regorafenib clinical trials.  
Overall, the safety profile of nivolumab monotherapy as well as in combination with other 
agents is manageable and generally consistent across completed and ongoing clinical trials 
with no maximal tolerated dose (MTD) reached at any dose tested up to 10 mg/kg. Most AEs 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. 
There was no pattern in the incidence, severity, or causality of AEs with respect to nivolumab 
dose level. A pattern of immune-related AEs has been defined. Most high-grade events were 
manageable with the use of corticosteroids or hormone replacement therapy for 
endocrinopathies. Additional details on the safety profile of nivolumab, including results from 
other clinical studies, are also available in the nivolumab IB. 
Potential overlapping side effects of regorafenib and nivolumab such as transaminitis, 
diarrhea, and skin reactions may be possible. Safety will be monitored closely on an ongoing 
basis. 
For patients with advanced or metastatic HNSCC, ESCC, PDAC, BTC, and recurrent 
GBM/AA who have failed systemic 1L therapy, the prognosis is poor. Although ICIs have 
shown benefit in many different tumors, including HNSCC and ESCC, it is common for 
primary and second resistance to occur and limit the therapeutic success of immunotherapy.  
The combination of regorafenib and nivolumab has potential for synergy which can improve 
anti-tumor immune response (as discussed above and Section 2.1 and 2.2). Early data suggest 
that the combination of regorafenib and nivolumab have a manageable safety profile. Taken 
together the safety profile, potential for benefit, and high unmet need for patients with 
advanced HNSCC, ESCC, PDAC, BTC, and recurrent GBM/AA, the overall benefit-risk 
assessment is favorable and supports the conduct of this Phase 2 study. 
 


 
 
 
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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 combination by cohorta  
• 
ORR per RECIST 1.1a by local assessment for 
all solid tumors except GBM/AA  
• 
ORR per RANOa by local assessment for 
GBM/AA 
Secondary 
• 
Evaluation of the additional efficacy measures of 
the regorafenib and nivolumab combination  
 
• 
DORa  
• 
DCRa 
• 
PFSa,  
• 
6 months PFSa 
• 
OS 
• 
1yr OS 
• 
To evaluate safety of the combination by cohort 
and overall 
• 
Frequency and severity of AEs per CTCAE v 
5.0 
Tertiary/Exploratory 
• 
To characterize the PK and immunogenicity of the 
regorafenib and nivolumab combination 
 
• 
Exposure of regorafenib and nivolumab and 
detection of anti-drug antibodies (ADA) 
(immunogenicity) 
• 
To evaluate the relationship between regorafenib 
exposure and relevant biomarkers for efficacy 
and/or safety 
• 
Retrospective analysis of the relationship 
between regorafenib exposure and biomarker, 
safety and/or efficacy measures 
• 
To assess efficacy of regorafenib and nivolumab 
combination using immune related response 
criteria 
• 
ORR per iRECIST or per iRANO for GBM/AAa 
 
• 
To identify biomarkers in baseline tumor 
materials, blood and/or stool samples that may 
associate with response   
• 
Correlation of biomarkers in tumor, blood or 
stool samples before treatment with other 
study endpoints 
• 
To explore pharmacodynamic effects of 
regorafenib and nivolumab combination on e.g. 
immune environment, signaling pathway activity, 
and downstream processes 
• 
Change from baseline in levels of biomarkers 
in tumor, blood or stool samples 
 
• 
To further investigate the study intervention and 
similar drugs (i.e., mode-of-action-related effects 
and / or safety) 
and to further investigate pathomechanisms 
deemed relevant to cancer and associated 
health problems 
• 
Various biomarkers (e.g., diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers) 
Abbreviations: AA = Anaplastic astrocytoma; ADA = Anti-drug antibody; AE = Adverse event; CTCAE = 
Common terminology criteria for adverse events; DCR=Disease Control Rate; DOR = Duration of response; 
GBM = Gliobastoma multiforme; iRECIST = Response evaluation criteria in solid tumors for trials testing 
immunotherapeutics; iRANO = Immune response assessment in neuro-oncology; ORR = Objective response 
rate; OS = Overall survival; PFS = Progression free survival; PK = Pharmacokinetics; RANO = Response 
assessment in neuro-oncology; RECIST 1.1 = Response evaluation criteria in solid tumors 1.1  
a) 
The efficacy endpoints will be based on the local Investigator’s assessment. Imaging data on tumor 
assessment will be collected for a potential retrospective central review of tumor evaluation by blinded 
readers.  
 


 
 
 
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4. 
Study Design 
4.1 
Overall Design 
This study is a multi-center, multi-indication, open-label, single-treatment arm, parallel-cohort 
Phase 2 study of regorafenib in combination with nivolumab in adult participants with selected 
recurrent or metastatic tumors (HNSCC, ESCC, PDAC, BTC, and GBM/AA) who have been 
previously treated with one or more systemic therapy for the selected tumor indication. An 
overview of the study schema is presented in Figure 4–1. 
The study will be conducted at approximately 60 sites in North America, Europe and 
Asia/Pacific. Up to 200 participants who qualify for the study will be treated with regorafenib 
plus nivolumab. 
This study is composed of the following periods: Screening, treatment, active follow-up (FU), 
and long-term follow up. An overview of the study schema is presented in Figure 4–1. 
Figure 4–1 
Study Design Overview 
 
Abbreviations: C = Cycle; FU = Follow-up; LD = Last dose; Q4W = Every 4 weeks; QD = Daily 
a) 
Nivolumab 480 mg using a 30-min i.v. infusion every 4 weeks (Q4W). Regorafenib starting dose 90 mg 
orally every day (QD) for 3 weeks of every 4 weeks (i.e. 21 days on, 7 days off). If starting the dose of 90 
mg is well tolerated (absence of any grade rash/HFSR or other Grade 2 or higher clinically significant 
toxicity. Lab abnormalities of any grade that resolve to ≤G1 within 72 hours are acceptable) the dose can 
be escalated to 120 mg orally daily anytime after C1, starting with C2D1. 
b) 
Mandatory safety FU visit (30 d + 7 d after study treatment discontinuation and 100 d + 14 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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Figure 4–2 
Study Schema 
 
Abbreviations: AA = Anaplastic Astrocytoma; BTC = Biliary Tract Carcinoma; ChT = Chemotherapy; DCR = 
Disease control rate; DOR = Duration of response; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; ESCC = Esophageal Squamous Cell Carcinoma; GBM = Glioblastoma Multiforme; HNSCC 
= Head and Neck Squamous Cell Carcinoma; IO = Immune oncology; IV = Intravenous; ORR= Overall Response 
Rate; OS = Overall survival; PDAC= Pancreatic ductal adenocarcinoma; PFS = Progression free survival; PK = 
Pharmacokinetics; PO = Per oral; q4wk = Every 4 weeks; QD = Once daily; RECIST 1.1 = Response Evaluation 
Criteria In Solid Tumors 1.1; RANO = Response assessment in neuro-oncology; R/M = Recurrent/Metastatic 
 
Each cohort starts with the Stage 1 and may continue to the Stage 2 if sufficient efficacy will 
be observed.  
Stage 1 of the study: 
Tumor based cohorts will recruit as follows: 
• approximately 9 participants will be treated for the HNSCC (IO naïve), ESCC and 
GBM/AA (participants with AA are included only in Stage 2) cohorts 
• approximately 14 participants will be treated for the HNSCC (IO treated) cohort 
• approximately 17 participants will be treated for the PDAC and BTC cohorts 
Stage 2 of the study:  
Tumor based cohorts that pass the pre-defined ORR threshold of the Stage 1 may expand as 
follows: 
• approximately 21 participants will be treated for the HNSCC (IO naïve), ESCC and 
GBM/AA cohorts 
• approximately 6 participants will be treated for the HNSCC (IO treated) cohort 
• approximately 28 participants will be treated for the PDAC and BTC cohorts 
 
Information about the respective Cohort of the participant will be recorded by the investigator 
or delegate in IxRS after signing off the participant information/informed consent form 
(PI/ICF). 


 
 
 
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All participants will be assessed for efficacy and safety during Stage 1 and Stage 2. 
Enrollment may be discontinued for those cohorts that will not pass the pre-defined ORR 
threshold for Stage 1. In addition, the totality of the data, including the duration and depth of 
response and overall risk-benefit assessment may be considered in the decision to terminate or 
continue the expansion after Stage 1. 
 
4.1.1 
Screening Phase 
The screening period for a specific participant will start after signing the ICF and after a specific 
slot has been provided by the Sponsor. Participants will be screened for eligibility up to 28 days 
(d) 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. Recruitment is competitive on study, country and site level. As 
only a few patients will start treatment within one cohort, the participant slot allocation form is 
used to provide a slot for a defined cohort for a specific patient to avoid over-recruitment. 
 
4.1.2 
Treatment Phase 
The start of the treatment period is defined by the first administration of study treatment. The 
length of a cycle is 28 days (plus a potential time window, for acceptable deviation see Section 
1.3 SoA). Participants will be treated with nivolumab intravenously given on Day 1 and 
regorafenib orally every day for 3 weeks of a 4 week 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 90 mg for 21 days of every 28-day cycle (i.e., 21 days on, 7 days off). If the starting 
dose of 90 mg daily is well tolerated (absence of any grade rash/hand foot skin reaction (HFSR) 
or other Grade 2 or higher clinically significant toxicity) the dose can be escalated to 120 mg 
orally daily anytime after Cycle 1, starting with Cycle 2 Day 1. The Sponsor will be 
immediately informed, if the Investigator decides not to escalate the dose to 120 mg on C2D1 
despite meeting the criteria.  
Dose modification guidelines for dose reduction in case of toxicity are detailed in Section 6.6. 
Treatment with individual drugs (regorafenib or nivolumab) may continue on schedule even if 
the other drug is interrupted or permanently discontinued due to toxicity.  
Participants who complete 24 infusions of nivolumab (after approximately 2 years of treatment) 
need to discontinue treatment with nivolumab. Regorafenib monotherapy treatment can be 
continued beyond 2 years until discontinuation criteria are met. 
During the study, participants will undergo evaluations for safety, efficacy, pharmacokinetics 
and tissue and blood for biomarker will be collected.  
Response will be assessed by imaging and participants may continue treatment until 
confirmation of disease progression per response evaluation criteria in solid tumors for trials 
testing immunotherapeutics (iRECIST; Section 10.6.2) or per immune response assessment in 
neuro-oncology (iRANO; Section 10.6.4), unacceptable toxicity or any other protocol defined 
criterion for withdrawal occurs. See Section 8.1 for further details on treatment continuation 
and tumor assessments beyond progression per RECIST 1.1 or RANO criteria. Primary 
endpoint of the study for all cohorts is ORR as measured by RECIST 1.1 or RANO for 
GBM/AA as determined by the investigator. For GBM/AA tumor assessment per RANO will 


 
 
 
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also include use of corticosteroids and neurological status. Imaging data on tumor assessment 
will be collected for a potential central review of tumor evaluation by blinded independent 
readers. 
 
4.1.3 
Active FU 
Safety FU visits: 
A mandatory clinical visit to monitor safety will take place 30 d (window of +7 d) after study 
treatment discontinuation and 100 d (window of +14 d) after the last dose of nivolumab. 
Longer safety FU for nivolumab is required due to the long half-life of the antibody. 
If the study treatment was permanently discontinued after dose interruption/delay of more 
than 28 days (including drug holiday for regorafenib), the safety FU visit should occur within 
14 days of the discontinuation. If the EoT and safety FU visits will be scheduled at the same 
time, the visits can be combined. 
If nivolumab is permanently discontinued first and the day 100 safety follow up visit after 
nivolumab discontinuation falls into regorafenib treatment period or day 30 safety FU period, 
no separate day 100 safety FU visit for nivolumab is necessary as the information gathering 
and examinations will occur with regorafenib treatment cycle visit, EoT visit or day 30 safety 
FU visit.  
Participants who discontinue study intervention due to radiologically confirmed progressive 
disease will terminate the active FU period after the safety FU visits. 
During the safety FU, all AEs will be documented until the start of new anti-cancer 
treatment.  Once new anti-cancer treatment is started, only study intervention related 
AEs should be documented. 
 
Efficacy FU visits: 
For participants who discontinue study treatment without confirmed radiological disease 
progression every effort should be made to continue tumor evaluations (by computed 
tomography [CT]/magnetic resonance imaging [MRI]) until confirmation of radiological 
progression per RECIST 1.1 or RANO and/or start of first subsequent systemic anti-cancer 
treatment whichever comes first, or any other criterion for withdrawal is met. During the 
efficacy FU visits, CT/MRI evaluations will be performed every 12 weeks (+/-14 days). 
Following the occurrence of progression per RECIST 1.1 or RANO during efficacy FU, scans 
for tumor assessments may be obtained to confirm progression as per iRECIST or iRANO as 
detailed in Section 8.1. For GBM/AA tumor assessment per RANO will also include use of 
corticosteroids and neurological status. In addition, study intervention-related toxicity/AE and 
first subsequent anti-cancer therapy will be followed up until completion of the active FU. 
Active FU will either be terminated by the last safety FU visit or thereafter by the last tumor 
assessment or documentation of first subsequent systemic anti-cancer treatment or any 
criterion for withdrawal is met. 
 


 
 
 
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4.1.4 
Long-Term FU 
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 first subsequent anti-cancer therapy at 3-
month intervals (± 14 d) at least for 1 year after starting treatment or until the last participant 
in the study has completed the active safety FU visit, or consent withdrawal or death or lost to 
follow up is reached for the last patient, whichever comes last. 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.  
 
4.2 
Scientific Rationale for Study Design 
This study is a multi-center, multi-indication, open-label, single-treatment arm, parallel-cohort 
Phase 2 study of regorafenib in combination with nivolumab in adult participants with 
selected recurrent or metastatic tumors (HNSCC, ESCC, PDAC, BTC, and GBM/AA) who 
have been previously treated with one or more systemic therapy for the selected tumor 
indication. The open-label, single-treatment arm, multi-indication, parallel-cohort study 
design follows well-established Phase 1b/2 oncology trials, including studies that include 
combinations of a PD-1 inhibitor and a MKI with similar targets and mechanism of action as 
nivolumab and regorafenib (Taylor et al. 2020). This type of study is aimed at allowing for 
efficient evaluation of tumors types that will respond to the combination of a PD-1 inhibitor 
and a MKI.  
Efficacy of each cohort will be examined in 2 stages based on a Sargent 3-outcome design 
with one-sided alpha of 0.1 (false positive rate), beta (false negative rate) of 0.1, power of 
70% and likelihood of futility of 70% when the null hypothesis is true. Details of the 
statistical considerations, hypotheses, and sample size calculations are described in Section 9. 
The rationale for a 2-stage design is intended to allow an interim efficacy assessment based on 
the number participants enrolled in Stage 1 and early termination of a cohort if there is 
insufficient number of responders to meet the pre-defined low boundary for efficacy. 
Considerations were made so that the number of participants in Stage 1 needed for efficacy 
assessment was minimized. The ability to terminate a cohort early based on lack of efficacy 
based on Stage 1 is designed to efficiently assess efficacy while allowing for sufficient 
estimation of antitumor response to the study treatment. 
 
4.3 
Justification for Dose 
Combination of regorafenib and nivolumab was evaluated in a Phase 1b trial of Japanese 
patients with advanced pMMR/MSS CRC and gastric cancer and demonstrated clinically 
relevant activity greater than that expected from either agent alone with confirmed ORR of 
33% and median PFS of 7.9 months in CRC and 44% for gastric cancer and median PFS 5.6 
months (Fukuoka et al. 2020). The combination was well tolerated at regorafenib starting dose 
of 80 mg once daily for 21 days on and 7 days off and nivolumab 3 mg/kg Q2W  
In the dose escalation part of the study, regorafenib doses of 80, 120 or 160 mg were 
administered once daily for 21 days on and 7 days off with intravenous nivolumab 3 mg/kg 
Q2W. Three dose limiting toxicities (DLTs) were observed during dose-escalation with 


 
 
 
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regorafenib 160 mg, including Grade 3 maculopapular rash, colonic perforation and 
proteinuria. There was no DLT observed with 80 mg or 120 mg dose of regorafenib. 
Maximum tolerated dose for the combination based on pre-defined DLT criteria was deemed 
to be 120 mg. In the first 18 patients treated at 120 mg dose of regorafenib in the dose 
expansion cohort, all but one required dose reduction to 80 mg for AEs mostly related to 
frequent Grade 3 skin toxicities. All remaining 18 patients were treated with regorafenib 
starting dose of 80 mg and tolerated treatment well. Grade ≥ 3 treatment related adverse 
events occurred in 20 patients (6 at 80 mg, 11 at 120 mg and 3 at 160mg). The common 
Grade ≥ 3 events (> 10%) were rash (12%), palmar-plantar erythrodysesthesia (10%), and 
proteinuria (12%). None of the patients treated at 80 mg dose had Grade ≥ 3 rash or palmar-
plantar erythrodysesthesia, while 5 events (20%) each were reported at 120 mg dose. Grade ≥ 
3 treatment related adverse events among patients treated at 80 mg dose included 2 events 
each for hypertension, proteinuria and hepatic dysfunction. 
Based on emerging data from ongoing clinical studies (Fukuoka et al. 2020) of regorafenib in 
combination with IO (e.g. nivolumab or pembrolizumab), 80 mg is the currently 
recommended starting dose with the option to escalate to 120 mg in patients who can tolerate 
it. However, a number of patients who start at a dose of 80 mg still require dose reductions 
due to safety/tolerability. With the currently available 40 mg tablet, the only options are to 
reduce to 40 mg QD which is a 50% dose reduction or to 80 mg every other day (QOD) 
which is more difficult for patient compliance and still a 50% dose reduction. Therefore, 
Bayer is proposing a new tablet strength of 30 mg for regorafenib in combination with IO. A 
30 mg tablet would allow for a starting dose of 90 mg QD for the first 21 d of each 28 d cycle. 
Due to the high inter-subject PK variability, a dose of 90 mg is expected to provide very 
similar exposure to the currently recommended combination starting dose of 80 mg. A 30 mg 
tablet also will allow for a dose modification step to 60 mg which is a more conventional 33% 
dose reduction as compared to 50% with the 40 mg tablet. Based on data from the Phase 1 
dose escalation study of regorafenib monotherapy, a dose of 60 mg showed a decrease in 
levels of sVEGFR2 that was in a comparable range to the 120 mg dose. This supports the 
pharmacological activity of a 60 mg dose (Mross et al. 2012). Further details on the 30 mg 
tablet are provided in the IB. 
 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant (LPLV) in the 
study.  
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.  
If the trial is stopped but benefits are observed for patients, further treatment options may be 
discussed and agreed between the investigator, sponsor and the patients and continued 
treatment in a Roll Over Study (ROS) or with commercial supply will be offered. 
 
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. 
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The primary completion of the study is defined by the event when all participants have been 
assessed for response rate (as defined by RECIST 1.1 or RANO) after the last participant has 
been followed for approximately 10 months unless they have discontinued before due to 
progression or any other reason. 
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply 
(unless where specified for specific tumor indication). Reintroduction of the same 
chemotherapy in sequential order and locoregional treatments such as hepatic arterial infusion 
therapy is not considered as a new line of treatment: 
Cohort 1 (HNSCC, IO naïve) 
101 
Cohort 1: Histologically confirmed recurrent or metastatic HNSCC (from any of the 
following primary sites only: oral cavity, oropharynx, hypopharynx and larynx) that is 
not amenable to curative intent surgery or chemoradiation. 
102 
Cohort 1: Progressed on or after 1, 2 or 3 lines of prior systemic therapy for recurrent 
or metastatic disease containing platinum chemotherapy or fluoropyrimidine or 
cetuximab, or a combination of these agents. Patients should receive standard of care 
treatment as initial treatment in accordance with local guidelines unless they are 
intolerant to standard first-line systemic chemotherapy as judged by their treating 
physician. 
• For Stage 2, participants also qualify if they have recurrent disease within 6 
months after the last dose of chemotherapy as part of definitive curative intent 
therapy (including patients who underwent chemoradiation with or without 
surgery).  
103 
Cohort 1: Documented HPV/p16 status for oropharyngeal cancer (historical results are 
acceptable if available).  
104 
Cohort 1: For Stage 2 participants only: Provision of recent tumor tissue 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. 
Cohort 2 (HNSCC, IO treated) 
201 
Cohort 2: Histologically confirmed recurrent or metastatic HNSCC (from any of the 
following primary sites only: oral cavity, oropharynx, hypopharynx and larynx) that is 
not amenable to curative intent surgery or chemoradiation. 
202 
Cohort 2: Progressed on or after 1, 2 or 3 lines of prior systemic therapy for recurrent 
or metastatic disease containing PD-1/PD-L1 inhibitor alone or in combination with 
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Progression on a prior PD-1/PD-L1 inhibitor regimen should meet the following 
criteria: 
• Has received at least 2 doses of an anti-PD-1/PD-L1 mAb.  
• Has demonstrated disease progression after anti-PD-1/PD-L1 therapy as defined by 
RECIST. Confirmation of radiographic progression on prior anti-PD-1/PD-L1 
therapy is required with a scan confirming progression at least 4 weeks after the 
initial progression date. Screening scans can be used as the confirmation of 
progression.  
203 
Cohort 2: Documented HPV/p16 status for oropharyngeal cancer (historical results are 
acceptable if available).  
204 
Cohort 2: Provision of recent tumor tissue 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. 
Cohort 3 (ESCC) 
301 
Cohort 3: Histologically or cytologically confirmed recurrent or metastatic ESCC that 
is not amenable to curative intent surgery or chemoradiation.  
302 
Cohort 3: Progression on or after 1 line of systemic therapy for recurrent or metastatic 
disease with platinum and/or fluoropyrimidine based regimen. 
• For Stage 2, participants also qualify if they have recurrent disease within 6 
months after the last dose of chemotherapy as part of definitive curative intent 
therapy (including patients who underwent chemoradiation with or without 
surgery). 
Cohort 4 (PDAC) 
401 
Cohort 4: Histologically or cytologically confirmed recurrent or metastatic PDAC that 
is not amenable to curative intent surgery 
402 
Cohort 4: Progression on or after 1 or 2 lines of systemic therapy for recurrent or 
metastatic disease with gemcitabine or fluoropyrimidine based regimens 
Cohort 5 (BTC) 
501 
Cohort 5: Histologically or cytologically confirmed recurrent or metastatic BTC, 
namely cholangiocarcinoma (intrahepatic or extrahepatic) or gall bladder cancer, that 
is not amenable to curative intent surgery, transplantation, or ablative therapies. 
502 
Cohort 5: Progression on or after 1 or 2 lines of systemic therapy for recurrent or 
metastatic disease containing gemcitabine or fluoropyrimidine or platinum therapy or 
a combination of these agents 
Cohort 6 (GBM/AA) 
601 
Cohort 6: Histologically or cytologically confirmed Grade IV GBM or Grade III AA 
(World Health Organization [WHO] criteria) established following either a surgical 
resection or biopsy. This includes participants with prior diagnosis of lower grade 
astrocytoma from a biopsy that has been upgraded to a histologically verified 
glioblastoma or anaplastic astrocytoma after a subsequent definitive surgery. AA is 
only allowed in Stage 2. 


 
 
 
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602 
Cohort 6: Unequivocal first progression after surgery followed by radiotherapy and 
temozolomide. Evidence of recurrent disease (RD) should be demonstrated by disease 
progression on biopsy or on MRI based on RANO criteria (using the post-
chemoradiation or post-radiation scan as baseline). 
For all cohorts 
1. Capable of giving signed informed consent, including compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in the 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 age of legal maturity or older on 
day of signing the ICF 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1. 
4. Adequate hematologic and organ function as assessed by the following laboratory tests 
performed within 7 d before start of study treatment: 
• 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 participants with liver involvement of their cancer) 
• Platelet count ≥100,000 /mm3, Hemoglobin (Hb) ≥9 g/dL, white blood cell count 
(WBC) ≥2000/μL absolute neutrophil count (ANC) ≥1500/mm3. Red blood cell 
(pRBC) transfusion is allowed if Hb meets the criteria for at least 14 days after 
transfusion. 
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min (measured or 
calculated using the Cockcroft-Gault formula) 
• Prothrombin time-international normalized ratio (PT-INR) <2.3 and activated 
partial thromboplastin time (aPTT)<1.5 x ULN.  
5. Measurable disease by baseline CT or MRI per RECIST 1.1 criteria for all cohorts except 
GBM/AA. For GBM/AA, participants should have measurable disease as defined by 
RANO criteria at baseline by MRI. Previously irradiated lesions should not be counted as 
target lesions unless there have been demonstrated progression in the lesion since 
radiotherapy before study enrollment and no other lesions are available for selection as 
target lesions  
6. Participants must consent to provide biopsy/tumor tissue of a primary tumor lesion or 
from metastases (e.g. liver, lung) and as defined below: 
• 
Provision of archival tumor tissue sample is mandatory if available.  
• 
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, are mandatory in HNSCC (IO treated) cohort for Stage 1 and 2 and 
in HNSCC (IO naïve) cohort for Stage 2.  
• Recent tumor tissue samples as defined above are mandatory if medically feasible 
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participants in Stage 1 in HNSCC (IO naïve) cohort. For GBM/AA cohorts, recent 
tumor tissue samples are optional. 
7. Anticipated life expectancy greater than 3 months 
8. Be able to swallow and absorb oral tablets 
9. Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception (see Section 10.4) for the duration of study intervention and 7 
months (or 210 days) 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 (see Section 10.4) for the duration of study 
intervention and 4 months (or 120 days) 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.  
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:  
Cohort 1 (HNSCC IO naïve) 
101 
Cohort 1: Histologically confirmed non-squamous, nasopharyngeal, or salivary 
histology of head and neck cancer, or squamous cell carcinoma that originated from 
the skin, or of unknown primary origin. 
102 
Cohort 1: More than 3 prior lines of systemic anticancer therapy for 
recurrent/metastatic cancer 
103 
Cohort 1: Presence of symptomatic central nervous system (CNS) metastases, 
leptomeningeal metastases or spinal cord compression. Previously treated lesions 
should be stable for at least 6 weeks prior to study entry.  
104 
Cohort 1: Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days 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 
105 
Cohort 1: Prior therapy with PD-1/PD-L1 or cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) inhibitors, or any form of immunotherapy to treat cancer.  
Cohort 2 (HNSCC IO treated) 
201 
Cohort 2: Histologically confirmed non-squamous, nasopharyngeal, or salivary 
histology of head and neck cancer, or squamous cell carcinoma that originated from 
the skin, or of unknown primary origin.  
202 
Cohort 2: More than 3 prior lines of systemic anticancer therapy for 
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203 
Cohort 2: Presence of symptomatic CNS metastases, leptomeningeal metastases or 
spinal cord compression. Previously treated lesions should be stable for at least 6 
weeks prior to study entry.  
204 
Cohort 2: Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days 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 
205 
Cohort 2: More than one prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any 
other form of immunotherapy to treat cancer.  
Cohort 3 (ESCC) 
301 
Cohort 3: More than 1 prior line of systemic anticancer therapy for 
recurrent/metastatic cancer 
302 
Cohort 3: Patients with apparent tumor invasion on organs located adjacent to 
the esophageal disease (e.g., the aorta or respiratory tract). 
303 
Cohort 3: Patients who have previously received taxane agents for recurrent/metastatic 
cancer. 
304 
Cohort 3: Presence of symptomatic CNS metastases, leptomeningeal metastases or 
spinal cord compression. Previously treated lesions should be stable for at least 6 
weeks prior to study entry.  
305 
Cohort 3: Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days 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 
306 
Cohort 3: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of 
immunotherapy to treat cancer.  
Cohort 4 (PDAC) 
401 
Cohort 4: More than 2 prior lines of systemic anticancer therapy for 
recurrent/metastatic cancer 
402 
Cohort 4: Presence of symptomatic CNS metastases, leptomeningeal metastases or 
spinal cord compression. Previously treated lesions should be stable for at least 6 
weeks prior to study entry.  
403 
Cohort 4: Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days 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 
404 
Cohort 4: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of 
immunotherapy to treat cancer.  
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501 
Cohort 5: More than 2 prior lines of systemic anticancer therapy for 
recurrent/metastatic cancer 
502 
Cohort 5: Presence of symptomatic CNS metastases, leptomeningeal metastases or 
spinal cord compression. Previously treated lesions should be stable for at least 6 
weeks prior to study entry.  
503 
Cohort 5: Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days 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 
504 
Cohort 5: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of 
immunotherapy to treat cancer.  
Cohort 6 GBM/AA 
601 Cohort 6: Primary tumors localized to the brainstem or spinal cord  
602 Cohort 6: Locally directed therapies administered by injection convection-enhanced 
delivery within 6 months of start of study treatment.  
603 Cohort 6: Presence of diffuse leptomeningeal disease or extracranial disease 
604 Cohort 6: Participants requiring > 4 mg of dexamethasone or biologic equivalent per 
day to control symptoms related to brain tumor and cerebral edema within 21 days of 
starting study treatment. Also excluded are participants who have a condition (other 
than symptoms related to brain tumor and cerebral edema) requiring systemic treatment 
with either corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days 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. 
605 Cohort 6: Major ongoing safety issues following surgery (e.g. infection requiring 
intravenous [IV]) antibiotics) 
606 Cohort 6: CNS hemorrhage of Grade >1 on baseline MRI scan, unless subsequently 
documented to have resolved  
607 Cohort 6: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of 
immunotherapy to treat cancer.  
For all cohorts 
1. Participants who have known dMMR/MSI-H cancers or NTRK fusions  
2. Prior therapy with regorafenib  
3. Uncontrolled hypercalcemia (e.g. causing signs and symptoms putting the participant at 
risk as judged by the investigator) 
4. Uncontrolled pleural effusions (e.g. causing signs and symptoms putting the participant at 
risk as judged by the investigator) 
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6. Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is 
shorter) of the first dose of study treatment 
7. Previous radiotherapy is acceptable under the following conditions: 
• Therapy completed more than 4 weeks before the baseline (at screening) scan. 
• Palliative radiotherapy for bone metastases or soft tissue lesions is allowed and 
should be completed > 7 days prior to baseline scan. 
• Participants must have recovered from all therapy-related toxicities to Grade < 1. 
• If the site of previous radiotherapy is the only site of disease, it should show 
evidence of disease progression. 
8. Participants having 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, platinum-induced neurotoxicity, and endocrine disorders due to prior IO 
treatment that are well controlled).  
9. Participants who have permanent discontinuation of PD-1/PD-L1 therapy due to toxicity.  
10. Arterial thrombotic or embolic events such as cerebrovascular accident (including 
transient ischemic attacks) within 6 months before the start of study treatment. Active 
pulmonary emboli or deep vein thrombosis that are significant or not adequately 
controlled on anticoagulation regimen as per investigator’s judgement 
11. History of cardiac disorders as defined by: 
• Congestive heart failure ≥ New York Heart Association (NYHA) class 2  
• 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 
• Uncontrolled cardiac arrhythmias (e.g. not well controlled on medications or 
causing signs and symptoms putting the participant at risk as judged by the 
investigator) 
12. Poorly controlled hypertension, defined as a blood pressure consistently above 140/90 
mmHg despite optimal medical management 
13. Persistent proteinuria of NCI-CTCAE Grade 3 or higher. 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 
14. Major surgical procedure or significant traumatic injury within 28 days before start of 
study treatment. Note: If participants received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to starting 
therapy. Central line placement and minor invasive biopsy are not considered major 
surgery  
15. Non-healing wound, non-healing ulcer, or non-healing bone fracture 
16. Participants with evidence or history of any bleeding diathesis, irrespective of severity 
17. Any hemorrhage or bleeding event ≥ NCI-CTCAE Grade 3 within 28 days prior to the 
start of study treatment  


 
 
 
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18. 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 
19. 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 
20. History of (non-infectious) pneumonitis that required steroids, current pneumonitis or 
interstitial lung disease  
21. Participants with previous malignancies (except superficial esophageal cancer, 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 informed consent signature and no additional therapy is 
required or anticipated to be required during the study period 
22. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (for 
doses >10 mg daily prednisone equivalent) or any other form of immunosuppressive 
therapy 
23. Active infection > NCI-CTCAE Grade 2  
24. Positive test (from historical data or tested during screening) for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 
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 
(except for participants on anti-viral therapy for HBV with a viral load < 100 IU/mL), or 
Hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid [RNA] 
negative)  
26. Pregnancy or breast feeding 
27. Psychological, familial, or sociological condition potentially hampering compliance with 
the study protocol 
28. Previous treatment with live vaccine within 30 days of planned start of study treatment 
(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 
30. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial or interfere with the participation for the full 
duration of the trial 
31. Participants with a current or past history of interstitial lung disease or pulmonary fibrosis 
diagnosed based on imaging or clinical findings. 
 
5.3 
Lifestyle Considerations 
 


 
 
 
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5.3.1 
Meals and Dietary Restrictions 
For details please refer to Section 6. 
 
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 treatment. 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, 
date of informed consent, inclusion/exclusion criteria with at least one of them failed, the 
reason for premature discontinuation, cancer classification), and any serious AE (SAE) 
information. 
Individuals who do not meet the criteria for participation in this study 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. All expired 
tests/assessments must be repeated to fall within the protocol-defined time window as 
specified in SoA and the investigator should ensure that the repeated screening procedures do 
not expose the patient to unjustifiable health risks. 
The screening failure will be registered in Interactive Voice/Web Response System (IxRS) to 
close the participant identification number (PID). Re-screening will start by signing a new 
informed consent form, even if the content was not changed after the patient’s previous 
screening, and being assigned a new PID via IxRS.  
6. 
Study Intervention 
Study intervention is defined as any investigational intervention intended to be administered to 
a study participant according to the study protocol. 
A cycle will be defined as 28 days (plus a potential time window, for acceptable deviation see 
Section 1.3 SoA) regardless of interruptions. Accordingly, a new cycle will start, even if one or 
both study drugs are interrupted.  
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 IV infusion every 4 weeks (Q4W)  
Regorafenib will be given orally every day for 3 weeks of each cycle. Each treatment cycle will 
be 28 d in duration. Regorafenib will be given as 30 mg tablets QD for 3 weeks of every 4 
weeks (i.e., 3 weeks on, 1 week off) as a starting dose of 90 mg. If starting dose of 90 mg daily 
is well tolerated (absence of any grade rash/HFSR or other Grade 2 or higher clinically 
significant toxicity; lab abnormalities of any grade that resolve to ≤Grade 1 within 72 hours are 
acceptable) dose can be escalated to 120 mg orally daily anytime after Cycle 1 starting with 
C2D1. Sponsor should be informed immediately, if the Investigator decides to not escalate the 
dose to 120 mg despite meeting the criteria.  


 
 
 
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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. A light meal contains less than 600 calories and 
less than 30% fat. 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 of pre-dose PK all blood samples will be collected at the clinic prior to the morning 
dose of regorafenib. When participants are dosed at the site, they will receive regorafenib 
directly from the Investigator or designee. 
Participants will continue treatment until any treatment discontinuation criteria apply as 
specified in Section 7.1.  
Treatment with individual drugs (regorafenib or nivolumab) may continue on schedule even if 
the other drug is interrupted or permanently discontinued due to toxicity. 
Participants who complete 24 infusions of nivolumab (after approximately 2 years of treatment) 
need to discontinue nivolumab treatment. Regorafenib treatment can be continued until clinical 
or radiological disease progression or unacceptable toxicity.  
Treatment beyond radiological progression is possible. See Section 8.1 for additional details. 
In order to continue treatment after initial documentation of disease progression as per  
RECIST 1.1 or RANO, participant must be re-consented. Re-consent also covers a potential 
treatment continuation with regorafenib after confirmed radiological progression (according to 
iRECIST or iRANO). 
 


 
 
 
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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 (mAB), biologic 
Dose Formulation 
tablet 
solution for infusion 
Unit Dose 
Strengths 
30 mg / tablet 
100 mg / 10 mL vial (10 mg/mL) 
Dosage Levels 
3x 30 mg tablets every day (q.d.) for 21 
days of every 28-day cycle (21 days on, 7 
days off) as a starting dose of 90 mg. 
If the starting dose is well tolerated dose 
should be escalated to 120 mg (4x30 mg 
tablets) starting with C2D1. 
480 mg (5x100 mg / 10 mL vials) on D1 
of each cycle 
Route of 
Administration 
oral 
i.v. infusion 
Use 
experimental 
experimental 
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 21 tablets 
Regorafenib 30 mg and a 3 g desiccant per 
bottle. 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. 
Current/Former 
Name(s) or Alias 
(es) 
Stivarga / BAY 73-4506 
Opdivo® 
Abbreviations: IMP = Investigational medicinal product; i.v. = Intravenous; mAB = Monoclonal antibody; 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 30 mg tablets in bottles and the nivolumab 100 mg / 10 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 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 participant. Beyond 
that, no special precautions are required, when handling the study intervention. 
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 


 
 
 
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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, 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 cycles must be assigned by 
the IxRS for tracking and accountability purposes. 
 
Participant Identification 
After a participant has signed the PI/ICF, the participant identification number will be 
provided to the Investigators through the IxRS. Participants will be identified by a 9-digit PID 
number consisting of: 
Digits 1 to 5 = Unique center number 
Digits 6 to 7 = Indication (cohort) identifier and study stage 
Digits 8 to 9 = Current patient number within the center and indication (cohort) 
 
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 regorafenib pharmacokinetics (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 (see Table 1–4). 
When participants self-administer regorafenib at home, compliance with regorafenib will be 
assessed at each D1 of a cycle. 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. 
6.5 
Concomitant Therapy 
6.5.1 
Drug-Drug Interactions Relevant for Regorafenib 
6.5.1.1 
Inhibitors / Inducers of CYP3A4 
Administration of ketoconazole (400 mg for 18 d), a strong cytochrome p450 (CYP)3A4 
inhibitor, with a single dose of regorafenib (160 mg on D5) resulted in an increase in mean 
exposure (area under the plasma concentration time curve [AUC]) of regorafenib of 
approximately 33%, and a decrease in mean exposure of the active metabolites, M 2 and M 5, 
of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of 
CYP3A4 activity (Section 10.8) as their influence on the steady state exposure of regorafenib 
and its metabolites has not been studied. 
Administration of rifampicin (600 mg for 9 d), a strong CYP3A4 inducer, with a single dose 
of regorafenib (160 mg on D7) resulted in a reduction in AUC of regorafenib of 
approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M 5, 
and no change in exposure of active metabolite M 2. Other CYP3A4 inducers (Section 10.8) 
may also increase metabolism of regorafenib. Inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product, with no or minimal potential to 
induce CYP3A4 should be considered.  
Section 10.8 provides an overview of the most commonly used strong CYP3A4 inhibitors and 
CYP3A4 inducers) that should be avoided during the study. 
6.5.1.2 
 UGT1A1 and UGT1A9 Substrates  
In vitro data indicate that regorafenib as well as its active metabolites M-2 inhibit 
glucuronidation mediated by UDP-glucuronosyltransferase 1-1 (UGT1)A1 and UGT1A9 
whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady 
state.  
Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted 
in an increase of approximately 44% in mean exposure (AUC) of SN-38, a substrate of 
UGT1A1 and an active metabolite of irinotecan. An increase in mean exposure (AUC) of 
irinotecan of approximately 28% was also observed. This indicates that co-administration of 
regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. The 
clinical significance is unknown and is dependent on the substrate. 
6.5.1.3 
 Breast Cancer Resistance Protein and P-glycoprotein Substrates 
Administration of regorafenib (160 mg for 14 d) prior to administration of a single dose of 
rosuvastatin (5 mg), a breast cancer resistance protein (BCRP) substrate, resulted in a 3.9-fold 
increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax. This 
indicates that co-administration of regorafenib may increase the plasma concentrations of 
other concomitant BCRP substrates (e.g., methotrexate, fluvastatin, atorvastatin). Therefore, it 
is recommended to monitor participants closely for signs and symptoms of increased exposure 
to BCRP substrates.  


 
 
 
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6.5.1.4 
 CYP Isoform-Selective Substrates 
A CYP probe substrate study in cancer participants was conducted to evaluate the effect of 
regorafenib on the pharmacokinetics of CYP2C9 substrate warfarin (10 mg), CYP2C19 
substrate omeprazole (40 mg), CYP3A4 substrate midazolam (2 mg) and CYP2C8 substrate 
rosiglitazone (4 mg) and to provide information about potential changes in exposure of these 
substrates when administered with regorafenib. 
Overall, the PK data suggest that regorafenib may be given concomitantly with substrates of 
CYP3A4, CYP2C8, CYP2C9, and CYP2C19 without the expectation of a clinically 
meaningful drug interaction. 
6.5.1.5 
 Antibiotics 
The concentration-time profile indicates that regorafenib and its metabolites may undergo 
enterohepatic circulation. Co-administration with neomycin, a poorly absorbed antimicrobial 
agent used for eradicating the gastrointestinal microflora (which may interfere with the 
enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure. There was 
an approximately 80% decrease in the exposure of the active metabolites M-2 and M-5. 
Effects of other antibiotics have not been studied. The clinical significance of the neomycin 
effect and potential interactions with other antibiotics is unknown, but may result in a 
decreased efficacy of regorafenib. 
6.5.1.6 
 Bile Salt-Sequestering Agents 
Bile salt-sequestering agents may interact with regorafenib by forming insoluble complexes 
which may impact absorption (or reabsorption), thus resulting in potentially decreased 
exposure. The clinical significance of these potential interactions is unknown, but may result 
in a decreased efficacy of regorafenib.  
 
6.5.2 
Permitted Concomitant Therapies 
All concomitant medications (including start / stop dates, total daily dose, and indication) must 
be recorded in the participant’s source documentation and in the eCRF. 
a) Treatment with non-conventional therapies (e.g., acupuncture) and vitamin/mineral 
supplements is acceptable provided that they do not interfere with the study endpoints, in 
the opinion of the Investigator.  
b) Administration of contrast media for protocol-specified radiological procedures (CT 
scan or MRI) does not need to be reported on the concomitant medication eCRF page, 
unless there is an AE related to the contrast medium injection (e.g. allergic reaction). 
c) Participants who are therapeutically treated with low molecular weight heparin or novel 
oral anticoagulants (NOACs) such as dabigatran or rivaroxaban will be allowed to 
participate provided that no prior evidence of underlying abnormality in coagulation 
parameters exists.  
d) Participants may receive palliative or supportive care for any underlying illness (e.g.: anti-
emetics, anti-diarrheal, IV fluids). 
e) Bisphosphonates and/or receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitor therapies (such as denosumab) for bone metastases may be continued if 


 
 
 
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treatment with an agent from one of these two classes was initiated prior to signing 
informed consent. Bisphosphonates and/or RANKL inhibitor therapies cannot be 
initiated after informed consent has been signed, unless in the opinion of the 
Investigator, the participant does not have PD.  
f) Hematopoietic colony stimulating growth factors such as granulocyte colony stimulating 
factor (G-CSF) and other hematopoietic growth factors may be used during the study in 
the management of acute toxicity such as febrile neutropenia when clinically indicated 
or at the discretion of the Investigator; however, they may not be substituted for a 
required dose reduction or used prophylactically. Participants taking chronic 
erythropoietin are permitted. 
g) Participants are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement 
steroid doses >10 mg daily prednisone are permitted in the absence of active 
autoimmune disease. 
h) A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye 
allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted 
i) Radiotherapy: 
○ Palliative radiotherapy during the study is allowed for local pain control after 
individual benefit-risk assessment provided that: 
▪ In the opinion of the Investigator, the participant does not have PD, 
▪ No more than 25% of the participant’s bone marrow is irradiated 
▪ The radiation treatment field may not include a target lesion by RECIST 1.1.  
○ Nivolumab should be withheld for at least 1 week before, during and 1 week after 
radiation. Participants should be closely monitored for any potential toxicity during 
and after receiving radiotherapy, and AE should resolve to Grade ≤1 prior to 
resuming therapy. Regorafenib may only be continued during palliative 
radiotherapy after an individual benefit-risk assessment. The Investigator should 
consult the Sponsor 
j) Analgesics 
k) Nutritional support 
l) Other medications that the Investigator deems to be medically necessary. 
Major surgery should only be performed during the study period if, in the opinion of the 
Investigator and after careful individual benefit/risk assessment (taking into account the 
potential wound healing complications that have been described with all anti-VEGF drugs), 
the surgery will be beneficial for the participant (except surgery for symptom management or 
palliative tumor control). 
It is recommended to stop regorafenib treatment at least two weeks before scheduled major 
surgery. Central line placement and minor invasive biopsy are not considered major surgery. 
The decision to resume regorafenib after major surgery should be no sooner than two weeks 
after major surgery and be based on clinical judgment of adequate wound healing. Patients 
should be placed back on study therapy within 4 weeks of the scheduled interruption of 


 
 
 
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regorafenib. The appropriate interval of time between minor procedure (biopsy) and 
regorafenib treatment required to minimize the risk of impaired wound healing and bleeding 
has not been determined. Treatment with regorafenib may be interrupted at least 24 hours 
before the procedure and the decision to reinitiate regorafenib treatment should be based upon 
a clinical assessment of satisfactory wound healing and recovery from the procedure.  
6.5.3 
Prohibited Prior and Concomitant Therapies 
Patients are prohibited from receiving the following therapies during the course of the study: 
a) Disease-specific anti-neoplastic therapies, including kinase inhibitors, immunotherapy, 
chemotherapy, hormonal therapy, non-palliative radiation therapy or experimental 
therapies other than regorafenib and nivolumab are not allowed. 
b) Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care. Use of marijuana 
and its derivatives for treatment of symptoms related to cancer or cancer treatment are 
permitted if obtained by medical prescription or if its use (even without a medical 
prescription) has been legalized locally. 
c) Surgery for symptom management or tumor control. 
d) Concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 (listed 
in Section 10.8) are not permitted for 2 weeks prior to start of study intervention or 
during the study. 
e) Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted during 
the study.  
f) Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found 
in multivitamins, including prenatal multivitamins, biotin supplements, and dietary 
supplements for hair, skin, and nail growth at levels that may interfere with laboratory 
tests. 
g) Investigational anti-neoplastic chemo/hormonal/immunotherapy. 
h) Any live/attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio 
and measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose 
(LD) of nivolumab. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed.  
i) Immunosuppressive agents and immunosuppressive doses of systemic corticosteroids 
(except as stated in Section 6.5.2 regarding permitted therapies and to treat a drug-
related adverse event). 
j) Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and 
niflumic acid) during regorafenib treatment should be avoided, as their influence on the 
steady-state exposure of regorafenib and its metabolites has not been studied. 
 


 
 
 
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6.5.4 
 
Documentation of Prior and New Concomitant Therapies 
All medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that may affect efficacy, toxicity or taken for any concurrent 
medical conditions at the time of enrollment or during the study must be recorded along with: 
a) Reason for use 
b) Dates of administration including start and end dates 
c) Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
6.5.5 
Rescue Medicine 
Not applicable for this study intervention 
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, 
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. The 
length of a cycle is 28 days (plus a potential time window, for acceptable deviation see 
Section 1.3 SoA). 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. 
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 dependent on 
resumption of nivolumab 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. 
A cycle will be defined as 28 days regardless of interruptions. 
• In case of interruption regorafenib is allowed to be re-started during the cycle within 
day 1 and day 21, regorafenib should not be restarted in the off week. Missed doses of 
regorafenib will not be replaced in the off week.  
• For nivolumab dosing occurs on day 1 of every cycle  
• Per protocol dose reduction or increase of nivolumab is not allowed  


 
 
 
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6.6.1 
Toxicity Management, Dose Modification and Permanent 
Discontinuation 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 Levels for Regorafenib 
Dose Level 
Daily Regorafenib (21 
days on, 7 days off) 
Daily Regorafenib (21 days on, 7 
days off from cycle 2 onwards if 
escalation if feasible) 
Dose Level 0  
90 mg   
120 mg 
Dose Level -1  
60 mg 
90 mg 
Dose Level -2 
NA  
60 mga 
Abbreviations: NA = Not applicable   
a) 
If reductions are required resulting in regorafenib daily dose of less than 60 mg, then regorafenib will be 
permanently discontinued. 
 
Table 6–3 
Dose Modification/Dose Interruption Guide for Regorafenib-Related 
Toxicities 
CTCAE 
Grade 
Occurrences 
Dose Interruption 
Dose modification (when resuming 
treatment) 
Grade 0-2c 
Any 
No change  
No change 
Grade 3c 
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 4c 
Any  
-  
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 60 mg, then 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. Participants requiring a delay of >4 
weeks should discontinue regorafenib treatment. However, continuation of regorafenib may be 
considered if, in the investigator's opinion, the participant may continue to benefit from the regorafenib 
treatment, and after consultation with Sponsor. 
c) 
Discontinuation is required for severe bleeding necessitating urgent medical intervention, gastrointestinal 
perforation or fistula of any grade and posterior reversible encephalopathy syndrome (PRES) of any 
grade. 
 
 


 
 
 
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Table 6–4 
Regorafenib Dose Modification/Dose Interruption Guidance: HFSR/ 
Palmar-Plantar Erythrodysesthesia Syndrome 
Skin toxicity 
grade (CTCAE) 
Occurrence 
Dose Interruption 
Dose modification (when 
resuming treatment) 
Grade 1 
Any 
Maintain dose level and institute 
supportive measures 
immediately for symptomatic 
relief 
No Change 
Grade 2 
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 
 
Grade 3 
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 60 mg, then 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. Participants requiring a delay of >4 
weeks should discontinue regorafenib treatment. However, continuation of regorafenib may be 
considered if, in the investigator's opinion, the participant 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 HYPERTENSION 
Grade 1 
No change.  
Consider increased BP 
monitoring 
Grade 2 
If symptomatic, hold until symptoms resolve and 
diastolic BP ≤ 90 mmHg. Treat with anti-
hypertensive medications 
At restart, continue at the 
same dose level 
Grade 3 
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 
Grade 4b 
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 60 mg, then 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. Regorafenib cannot be interrupted for 
more than 28 consecutive days including the drug holidays. However, continuation of regorafenib may be 
considered if, in the investigator's opinion, the participant may continue to benefit from the regorafenib 
treatment, and after consultation with Sponsor. 
b) This includes hypertensive crisis per CTCAE v 5.  
 
Table 6–6 
Dose Modification/Dose Interruption Guide for Regorafenib-related 
Toxicities: Liver Function Test Increases Related to Regorafeniba 
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) 
AST and/or ALT > 20 x ULN  
Any 
Discontinue  
  


 
 
 
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Increases in AST/ALT/Bilirubin 
 Occurrence 
Dose Interruption 
Dose Modification (when 
resuming treatment) 
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. 
 
6.6.2 
Toxicity Management, Dose Modification and Permanent 
Discontinuation Recommendations for Nivolumab 
There will be no dose reductions for nivolumab. Recommendations for nivolumab delay and 
discontinuation are provided (Table 6–7) when the Investigator attributes toxicity event to 
nivolumab either alone or in combination with regorafenib. In situations where clear 
attribution cannot be made to an individual drug (regorafenib or nivolumab), a more 
conservative dose modification approach should be used for both drugs (Section 6.6).  
Resumption of nivolumab dosing is not dependent on resumption of regorafenib 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. Further details 
regarding resumption of nivolumab are specified in Section 6.6.2.1. 
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 (Section 6.6.2.2).  
Interrupt or slow the rate of infusion in participants with mild or moderate (Grade 1-2) 
infusion reactions. Discontinue nivolumab in participants with severe or life-threatening 
infusion reactions (Grade 3-4). Additional information is in Section 6.6.2.3. 
.  


 
 
 
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Table 6–7 
Recommended Dose Modification for Nivolumaba 
Adverse Reaction 
Severity (CTCAE v5) 
Dose Modification 
Colitis 
Grade 2 diarrhea or colitis  
Withhold doseb  
Grade 3 diarrhea or colitis  
Withhold doseb  
Grade 4 diarrhea or colitis  
Permanently 
discontinue  
Pneumonitis  
Grade 2 pneumonitis  
Withhold doseb  
Grade 3 or 4 pneumonitis  
Permanently 
discontinue  
Hepatitis/non-hepatocellular 
carcinoma 
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  
Withhold doseb  
AST or ALT more than 5 times the 
ULN or total bilirubin more than 3 
times the ULN  
Permanently 
discontinuec  
Hypophysitis/ Hypopituitarism  
Grade 1-3 hypophysitis that is also 
associated with corresponding 
abnormal lab and/or pituitary scan 
Withhold doseb  
Grade 4  
Permanently 
discontinue  
Hyperthyroidism or Hypothyroidism 
Grade 2 or 3 
Withhold dosed 
Grade 4 
Withhold dose or 
permanently 
discontinue 
Adrenal Insufficiency  
Grade 2 adrenal insufficiency  
Withhold doseb  
Grade 3 or 4 adrenal insufficiency  
Permanently 
discontinuee 
Hyperglycemia  
Grade  2 or 3 hyperglycemia 
requiring initiation or change in daily 
management 
Withhold doseb  
Grade 4 hyperglycemia  
Permanently 
discontinue  
Nephritis and Renal Dysfunction  
Serum creatinine more than 1.5 and 
up to 6 times the ULN  
Withhold doseb  
Serum creatinine more than 6 times 
the ULN  
Permanently 
discontinue  
Skin 
Grade 2 rash covering >30% BSA or 
3 rash or suspected SJS, TEN or 
DRESS  
Withhold doseb  
Grade 4 rash or confirmed SJS, 
TEN or DRESS  
Permanently 
discontinue  
Myasthenia gravis, Guillain-Barre 
syndrome, treatment-related myelitis, 
or encephalitis 
Any grade 
 
Permanently 
discontinue  
Neurological adverse reaction (other 
than Guillain-Barre syndrome, 
myasthenia gravis, encephalitis, or 
myelitis) 
Grade 2 
Withhold doseb 
Grade 3 or 4 
Permanently 
discontinue 
Other 
Other Grade 3 adverse reaction:  
First occurrence  
Recurrence of same Grade 3 AR 
 
Withhold doseb 
Permanently 
discontinue 


 
 
 
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Life-threatening or Grade 4 AR  
Permanently 
discontinue  
Grade 2 myocarditis 
Withhold doseb 
Grade 3 or higher myocarditis  
Permanently 
discontinue  
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks  
Permanently 
discontinue  
Persistent Grade 2 or 3 ARs lasting 
12 weeks or longer  
Permanently 
discontinue  
Abbreviations: ALT = Alanine aminotransferase; AR = Adverse reaction; AST = Aspartate aminotransferase; 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; SJS = Stevens-
Johnson syndrome; TEN = Toxic epidermal necrolysis; DRESS = Drug Reaction with Eosinophilia and 
Systemic Symptoms; ULN = Upper limit of normal 
a) 
For additional management recommendations, please see Appendix 9: Guidance for Management of 
Immune-Related Adverse Events Section 10.9. 
b) 
Resume treatment when adverse reaction improves to Grade 0 or 1 (see further details in Section 
6.6.2.1). 
c) 
In most cases of AST or ALT > 5 x ULN, study treatment will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the investigator and the Medical 
Monitor/ designee must occur and approval from Medical Monitor prior to resuming therapy. 
d) 
Dosing may resume if endocrinopathy resolves to be asymptomatic, or is adequately 
controlled with only physiologic hormone replacement or other medical management. 
e) 
If adrenal insufficiency resolves or is adequately controlled with physiologic hormone 
replacement, participant may not require discontinuation of study drug. Mandatory 
discussion with and approval from the Medical Monitor needed prior to resuming therapy. 
 
 
Nivolumab Treatment – Permanent Discontinuation 
In addition to nivolumab treatment discontinuation specified in Table 6–7, the following 
criteria of discontinuation are as follow: 
a) Patients who complete 24 infusions of nivolumab (after approximately 2 years of 
treatment) 
b) In the scenario when AST or ALT elevation fulfills the criteria of discontinuation and the 
investigator judges there is a possible favorable benefit/risk profile that warrants 
continuation of nivolumab treatment, a discussion between the investigator and the 
Sponsor must occur.  
c) Any event that leads to delay in dosing lasting >10 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
• Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed.  
• Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Sponsor.  
d) 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. 


 
 
 
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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.  
 
6.6.2.1 
Criteria to Resume Nivolumab Treatment 
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 at D1 of a next planned cycle.  
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve to 
Grade  1 or baseline value (please refer to Appendix 9: Guidance for Management of 
Immune-Related Adverse Events), with the following exceptions: 
Participants may resume treatment in the presence of Grade 2 fatigue 
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. 
 
6.6.2.2 
Management of Immune-Mediated AEs 
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 case report form. 
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, cardiac toxicity and renal toxicity. These adverse event management 
algorithms are included in Section 10.9. 
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 
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. 
6.6.2.3 
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, 


 
 
 
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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 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 
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 
End of Treatment 
At the EoT for each individual participant, further therapeutic options with drugs other than 
regorafenib and/or nivolumab are at the discretion of the Investigator.  


 
 
 
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An EoT visit will be performed within 14 days after permanent discontinuation of study 
treatment. Note: If the study treatment was permanently discontinued after dose interruption 
of more than 28 days (including drug holiday for regorafenib), the active FU visit should also 
occur within 14 days of discontinuation. If the EoT and active FU visits will be scheduled at 
the same time, the visits can be combined. 
 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
General procedures 
Discontinuation of one study drug does not constitute withdrawal from study treatment 
period. Permanent discontinuation of both study drugs (regorafenib and nivolumab) 
constitutes withdrawal from treatment period of the study. Withdrawal from treatment period 
(all study drugs are discontinued) does not constitute withdrawal from the study. Patients who 
withdraw from study treatment period for any reason should complete the active safety FU 
visit and should be encouraged to remain on the study for FU of primary, secondary and other 
objectives (i.e. continue in the active FU and long-term FU periods). Patients are expected to 
participate in the FU unless they explicitly object. Withdrawal of consent to treatment should 
be documented in the patient’s medical record. If the patient does not wish to be followed up 
further, this additional consent withdrawal for FU must also be documented. 
The criteria for withdrawal from the study are listed in Section 7.2, and the criteria for 
permanent discontinuation of each study drug are listed in Section 6.6.1 for regorafenib and  
in Section 6.6.2 for nivolumab. 
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 from study, no further study related procedures 
will be allowed. The patient will not suffer any disadvantage as a result.  
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.  
All patients who discontinue due to AEs should be followed up until they recover or stabilize, 
and the subsequent outcome is recorded. If any participant dies during treatment, or within 30 
d + 7 d after the last dose of regorafenib if a patient was on regorafenib monotherapy or within 
100 d + 14 d after the last dose of regorafenib/nivolumab combination treatment or nivolumab 
monotherapy, 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 both, regorafenib and nivolumab, if any of the following 
occurs: 


 
 
 
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• At their own request. 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. 
• Confirmed PD as per iRECIST or iRANO criteria; however, treatment may be 
continued provided that the patient derives ongoing clinical benefit as determined by 
the treating physician (Participants who complete 24 infusions of nivolumab [after 
approximately 
2 years 
of 
treatment] 
need 
to 
discontinue 
nivolumab 
treatment. Regorafenib monotherapy treatment can be continued beyond 2 years until 
discontinuation criteria are met). 
• Clinical progression (every effort should be made to obtain radiological confirmation 
of 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 
degree. 
• Severe allergic reactions, such as exfoliate erythroderma, anaphylaxis, or vascular 
collapse. 
• Start of subsequent systemic anti-cancer treatment. 
• Substantial non-compliance with the requirements of the study. 
• If all study drugs (regorafenib and nivolumab) have to be permanently discontinued. 
Requirements for discontinuation of individual study drugs are described in Section 
6.6.1 for regorafenib and in Section 6.6.2 for nivolumab.  
• 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 FU 
• 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. 


 
 
 
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• Withdrawal of nivolumab only:  
o Patients who experience a delay of > 10 weeks to receive the subsequent 
nivolumab infusion due to treatment related toxicity (see exceptions in Section 
6.6.1) 
▪ Dosing delays to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed.  
▪ Dosing delays lasting > 10 weeks from the previous dose that occur for 
non-drug-related reasons may be allowed if approved by the Medical 
Monitor (or designee). 
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 6.6.1. 
Withdrawal from active FU 
Participants must be withdrawn from active FU if any of the following occurs: 
• At their own request. 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 per iRECIST or iRANO (Participants who discontinue 
study intervention due to confirmed radiological PD per iRECIST or iRANO will 
terminate the active FU period after the safety FU visits are completed 
• Start of subsequent systemic anti-cancer treatment after the safety FU visits are 
completed 
• Development of a second primary malignancy that requires a different treatment after 
the safety FU visits are completed 
• Substantial non-compliance with the requirements of the study 
• Withdrawal of consent to active FU visits 
• 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 


 
 
 
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Participants MAY be withdrawn from both, regorafenib and nivolumab, for the following 
reasons: 
• At the specific request of the sponsor and in liaison with the investigator (e.g., obvious 
non-compliance, safety concerns). 
• Discontinuation of study intervention for toxicity should be considered by the 
Investigator when a participant meets one of the conditions outlined in Section 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 (QT interval corrected for heart rate F [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 review 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 
Participant Discontinuation/Withdrawal from the Study 
For details on participant discontinuation and withdrawal from the study please refer to 
section 7.1. 
7.3 
Lost to FU 
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 
study visit: 
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. 


 
 
 
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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA table (Section 1.3). 
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 
(Section 1.3), 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 (Section 1.3). 
• In the event of a significant trial-continuity issue (e.g. caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring 
may be implemented by the sponsor or the investigator, as per local health authority / 
ethics requirements. 
 
8.1 
Efficacy Assessments 
For HNSCC (IO-naïve), HNSCC (IO-treated), ESCC, PDAC and BTC, RECIST 1.1 (Section 
10.6.1) and iRECIST (Section 10.6.2) criteria will be used to determine the efficacy. iRECIST 
will be used to make treatment-related decisions beyond initial RECIST 1.1 progression. 
 
For GBM/AA, tumor response and efficacy variables will be evaluated using the RANO 
(Section 10.6.3) and iRANO criteria (Section 10.6.4). iRANO will also be used to make 
treatment-related decisions beyond initial progression for GBM/AA. 
 
Imaging acquisitions: 
The following anatomic coverage is required: 
• HNSCC (IO-naïve and IO-treated): At screening, neck, chest, abdominal and pelvic 
CT with oral and intravenous (IV) contrast. During treatment and follow-up, neck and 
chest CT with oral and IV contrast should be performed. Abdominal and pelvic scans 
should be done if disease is present at screening. Otherwise, abdominal and pelvic 
scans may be done as clinically indicated if disease was absent at screening. For 
HNSCC, the anatomic coverage for the neck scan should typically include from the 
base of the skull to the base of the neck. The reconstructed slice thickness for this 


 
 
 
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anatomic coverage is highly recommended to be ≤ 3 mm. For the CT scans of the 
chest, abdomen and pelvis, reconstructed slice thickness should be ≤ 5 mm. 
• ESCC: Neck, chest, abdominal and pelvic CT with oral and IV contrast.  
• PDAC, BTC: CT of chest, abdomen and pelvis with oral and IV contrast. 
• GBM/AA: Brain MRI with and without IV gadolinium-based contrast agent. 
 
When intravenous and oral agents are required per protocol, oral contrast agents may be 
omitted if the requirement for oral contrast administration is inconsistent with local 
regulations. 
 
HNSCC, ESCC, PDAC, BTC participants with known or suspected CNS tumor lesions 
should undergo contrast enhanced MRI (preferred)/CT scans of the brain. Participants with 
new brain metastases on screening scan are excluded. Participants with known CNS tumor 
lesions on screening scan should have stable lesions for at least 6 weeks, confirmed by 
comparison to prior brain MRI/CT scans. If CNS lesion stability is confirmed at screening, 
participants are eligible to undergo study treatment and brain MRI/CT should be repeated at 
every tumor assessment time point on study. If any participants develop CNS symptoms 
during the study, brain MRI/CT should be performed if clinically indicated.  
For all cohorts, the anatomic coverage should further include any other anatomic areas of 
known or suspected disease at baseline and throughout the study. 
 
The slice thickness for CT and MRI is strongly recommended to be ≤ 5mm without gap. MRI 
should be performed instead of CT when institutional policy does not recommend the use of 
CT or there is a contraindication to iodinated CT contrast. It is recommended, that when MRI 
is used instead of CT, MRI of the abdomen and pelvis (and neck, when applicable) should be 
performed with a gadolinium-based contrast agent. However, the chest should still be 
assessed with a CT scan (without contrast if contrast allergy exists). MRI of the chest can be 
performed in extenuating circumstances (e.g. local health regulations). 
 
Whole-body bone scans with both anterior and posterior projection using a technetium-99m 
phosphonate tracer (methylene diphosphonate [MDP], hydroxymethylene diphosphonate 
[HMDP], hydroxyethylene diphosphonate [HDP], or 2,3-dicarboxypropane-1,1-
diphosphonate [DPD]) will be performed within 28 days prior to the start of study treatment 
to establish baseline presence or absence of bone lesions for all participants with known bone 
metastases or clinically suspected of having bone disease. Bone scans should be repeated 
when CR or PR is identified in the CT/MRI assessments to confirm the absence of new bone 
lesion(s) disease or when progression in bone is suspected. 
 
For primary brain tumors (GBM/AA), MRI of the brain should be performed with and 
without a gadolinium-based contrast agent. Recommended sequences are the following: pre-
contrast axial 3D T1, axial T2 fluid-attenuated inversion recovery (FLAIR) and axial 
diffusion-weighted imaging (DWI); post-contrast sequences are an axial T2 and a 3D T1. 
Slice thickness should typically be ≤ 5mm without a gap (1mm is optimal for 3D T1 and 3mm 
for T2, FLAIR and DWI).  
 


 
 
 
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For consistency, the same imaging modality and equivalent technique (e.g. slice thickness, 
field of view, contrast agent, bone scan radiotracer, magnet strength) should be used for all 
scans across all time points (including baseline scans) performed on an individual participant.    
 
Imaging time-points: 
The time-points for CT, MRI and bone scans, if applicable, are described in the SoA (Section 
1.3). Baseline radiological tumor assessments will be conducted within 28 days before C1D1.  
 
Scans performed prior to the participant signing informed consent may be used for baseline 
tumor assessments provided: 
• CT/MRI scans were conducted within 28 days of C1D1 
• Bone scans were conducted within 42 days of C1D1 
• There has been no intervening therapy between the scans and C1D1 
• The scans meet the imaging requirements of this protocol (Section 8.1) 
 
Tumor assessments during the treatment period will occur every 8 weeks (± 7 days) through 
Cycle 8 (or until treatment discontinuation, if treatment discontinuation occurs before) and 
every 12 weeks (± 14 days) thereafter during the treatment period until initial criteria for 
disease progression are met. When disease progression occurs, tumor assessments should 
follow the iRECIST (Section 10.6.2) or iRANO timing (Section 10.6.4) as described below. 
 
Tumor assessment will be repeated at the EoT visit or safety follow-up visit if not performed 
within 12 weeks since the most recent tumor assessment. For participants who discontinue 
study treatment without radiological disease progression, every effort should be made to 
perform CT/MRI tumor assessments every 12 weeks (± 14 days) during active-FU until 
radiological progression of the disease occurs or the start of a new anti-cancer treatment. The 
schedule of tumor assessments beyond unconfirmed progression per RECIST 1.1 or RANO 
during the active FU is described below. 
 
Tumor response assessments for all participants except those with GBM/AA: 
The primary endpoint for efficacy assessment is ORR measured by RECIST 1.1 (Section 
10.6.1) as determined by local assessment. ORR measured by iRECIST (Section 10.6.2) will 
also be included as an exploratory endpoint. Tumor response using RECIST 1.1 criteria will 
continue until disease progression (PD) occurs. The minimum time interval required between 
two tumor assessments for determination of stable disease is 6 weeks per RECIST 1.1. 
CT/MRI scans for confirmation of PR or CR should be performed no sooner than 4 weeks 
after the initial scan demonstrating PR or CR. 
 
Please note that chest X-rays should not be used at baseline in lieu of chest CT assessments. 
However, if an unequivocal new tumor lesion(s) is identified on at a chest X-ray during the 
study and that lesion which was not present on the most recent prior CT chest assessment, this 
chest X-ray is acceptable as imaging evidence for PD. FDG PET/CT scans may be used to 
complement CT or MRI scans for the assessment of progression (e.g., for the detection of new 
lesions) as described in the RECIST 1.1 criteria (Eisenhauer et al. 2009). Changes in FDG 
uptake in known lesions should not be used to define a positive response or progression. The 
low dose or attenuation correction CT portions of a combined PET/CT are of limited use in 
anatomically based efficacy assessments and it is therefore suggested that they should not be 


 
 
 
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substituted for dedicated diagnostic contrast enhanced CT scans for anatomically based 
RECIST 1.1 measurements. However, if a site can document that the CT performed as part of 
a PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then 
the CT portion of the PET/CT can be used for response assessments. 
 
NOTE: Lesions selected as target (measurable) lesions per RECIST 1.1 should not be 
biopsied. Additional guidance will be provided to the site on decisions about performing 
biopsies on potential target lesions when only one potential target lesion exists at baseline. 
 
For treatment beyond RECIST 1.1 progression: 
For participants who show evidence of PD by RECIST 1.1, the Investigator may decide to 
continue a participant on study treatment using the iRECIST guidelines (Section 10.6.2) if the 
participant signs a new consent for continuation of treatment beyond initial documentation of 
disease progression and if the following features are fulfilled:  
• No worsening of performance status has occurred 
• No clinically relevant increases in disease-related symptoms 
• No requirement for intensified management of disease-related symptoms exists 
• Absence of tumor progression at critical anatomical sites that cannot be managed by 
protocol−allowed medical interventions 
 
For participants who continue treatment beyond unconfirmed progressive disease (iUPD), the 
next imaging assessment should be performed ≥ 4 weeks and no longer than 8 weeks later. 
Participants should discontinue study treatment upon confirmed progression per iRECIST 
(iCPD). During the treatment phase, if immune complete response (iCR), immune partial 
response (iPR) or immune stable disease (iSD) is determined following iUPD, imaging 
assessments should continue as originally planned (8 weeks (± 7 days) through Cycle 8 (or 
until treatment discontinuation, if treatment discontinuation occurs before) and every 12 
weeks (± 14 days) thereafter). During active FU, tumor assessments should also be performed 
≥ 4 weeks and no longer than 8 weeks later following any determination of iUPD until 
determination of iCR, iPR, iSD or until iCPD occurs. 
 
NOTE: If a participant has iCPD, but the participant is achieving a clinically meaningful 
benefit, an exception to continue treatment and tumor assessments until clinical disease 
progression may be considered following consultation with the sponsor. 
 
Tumor response assessments for participants with GBM/AA: 
The primary endpoint for efficacy assessment is ORR measured by RANO (Section 10.6.3) as 
determined by local assessment. ORR measured by iRANO (Section 10.6.4) will also be 
included as an exploratory endpoint. Tumor response using RANO criteria will continue until 
initial disease progression is detected. Both CR and PR responses should be confirmed ≥ 4 
weeks later. If PR or CR is not confirmed, response will be considered only SD. If PD occurs 
beyond 6 months after initiation of treatment, the participant should be discontinued from 
treatment. For any participant deemed clinically unstable (provided that their decline is 
attributable to the disease and not comorbid events or changes in medication), the investigator 
should discontinue the participant from study treatment at site-assessed first radiologic 
evidence of PD without need for repeat tumor imaging for confirmation of PD and regardless 
of whether the PD occurs within the first 6 months after initiation of study treatment. For 


 
 
 
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these participants, the date of progression is the date the patient developed substantial 
neurological decline attributable to their underlying tumor. 
 
For treatment beyond initial RANO progression: 
When a participant has an initial unconfirmed PD by RANO that is within the first 6 months 
of starting treatment, the investigator may consider treating past this unconfirmed PD using 
iRANO criteria (Section 10.6.4) if the participant is clinically stable according to the 
following criteria: 
• No decline in ECOG PS  
• No clinically relevant increase in symptoms related to the participant’s cancer 
• No requirement for intensified management of disease related symptoms, including 
increased analgesia, radiation, or other palliative care 
If it is decided that the participant may continue treatment, the participant must be re-
consented for continuation of treatment beyond initial RANO-based unconfirmed disease 
progression. 
Treatment may continue for 12 weeks as long as no significant clinical decline unrelated to 
comorbid event or concurrent medication occurs. Participants who develop substantial clinical 
decline at any time, should be classified as having progressive disease with the date of disease 
progression back-dated to the first date that the patient met criteria for radiographic 
progression. For these participants, treatment should be discontinued. If progression is not 
confirmed, the participant may continue treatment with brain imaging every 12 weeks (± 14 
days) in the absence of increased corticosteroid dosing. Note: Unscheduled brain MRI within 
this 12-week treatment period may be done as medically appropriate at the discretion of the 
investigator. If PD is assessed and judged by the investigator to be true disease progression 
rather than pseudoprogression due to immunotherapy, the participant should discontinue 
treatment. During active FU, within 6 months of initiation of treatment, tumor assessments 
should also be performed every 12 weeks (± 14 days) until confirmation of progressive 
disease, so long as the participant is clinically stable as defined above and no other therapy 
has been initiated. Confirmation of progressive disease is not necessary during active FU 
beyond 6 months after initiation of treatment. 
 
The doses and duration of use of corticosteroids should be limited to the minimum amount 
needed to control neurologic symptoms. Participants who need increased corticosteroid use 
within 2 weeks of MRI assessment relative to the dose taken at the time of the previous 
assessment, cannot be classified as having a CR, PR, or SD and should be classified as non-
evaluable at that timepoint. Conversely, patients who decrease corticosteroid use within 2 
weeks of MRI assessment relative to the dose taken at the time of the previous assessment 
cannot be classified as having PD and should be classified as non-evaluable. 
 
Image scan collection: 
All imaging scans (coded with study participant number and in digital DICOM format for 
CT/MRIs) as well as imaging-related adjunctive data (e.g. dose of contrast) will be 
prospectively collected and stored at an imaging core laboratory designated by the sponsor in 
the event that an independent central review of the scans is warranted.  
 


 
 
 
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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 IBs 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 (Section 1.3).  
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 study 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. Planned time points for all safety 
assessments are provided in the SoA. 
8.2.1 
Physical Examinations 
For physical examinations please refer to Section 1.3 (SoA). 
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.   
A limited physical exam is based on symptom-directed findings or 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. 
For GBM and AA, neurologic examinations (via Neurologic Assessment in Neuro-Oncology 
(NANO) Scale) in addition to the physical examinations will be performed that will include 
assessments of mental status and neurologic functions (motor and sensory systems, cranial 
nerves, reflexes, or other symptom-directed findings as clinically indicated). 
 
8.2.2 
Vital Signs 
Body temperature, heart rate, blood pressure, height (only at screening) and weight 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). 


 
 
 
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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. 
8.2.3 
Electrocardiograms 
12-lead ECG will be locally obtained as outlined in the SoA (Section 1.3) 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. 
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard ICH 
criteria for an SAE (see SAE definition in Section 10.3.2). 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 d (active FU period after study treatment discontinuation) 
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 SoA (see 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-disease 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 and safety FU. 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: 
• Year of birth and age 
• Gender 
• Race, if legally allowed 
• Ethnicity, if legally allowed 
• Child bearing 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 (and sub-location if 
applicable) of the primary tumor, histology, tumor stage at study entry, date of 
diagnosis of first metastasis, presence of liver and/or lung metastasis. Date of most 
recent progression/relapse, prior cancer therapies.  


 
 
 
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• Tumor mutational burden (TMB) (if available) and PD-L1 expression (if available), 
MSI status (if available). 
• All medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the participant within the 
screening period 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 symptoms 
should be recorded as AEs. 
AEs should be assessed in terms of their seriousness, intensity (according to NCI-CTCAE, 
v5.0), and relationship to the study drugs, or other treatment. 
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 
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 informed consent form (ICF) until 
the end of active safety FU visits at the time points specified in the SoA (Section 1.3).  
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 


 
 
 
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reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
 
8.3.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
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 
FU of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to FU (as defined in 
Section 7.3). 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. 
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. 


 
 
 
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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. Participants 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: 
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. 


 
 
 
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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. 
8.5 
Pharmacokinetics 
In all participants enrolled, sparse pharmacokinetic samples will be collected for 
determination of regorafenib and its metabolites M-2 and M-5 (in plasma) and nivolumab (in 
serum) as specified in Table 1–4.  
Deviations from planned sampling time intervals will not be considered as protocol deviations. 
However, omission of samples other than specified in the PK sampling Table 1–4 will be 
considered a protocol deviation. The date and clock time of each sample as well as dates and 
times of the regorafenib administration and start and stop times of nivolumab infusion will be 
recorded in the eCRF as PK estimates will be based on the sampling times relative to dosing 
times. 
For regorafenib, meal intake time should be collected on PK sampling days together with the 
dosing time. 
Samples may be collected irrespective of any dose modifications during the treatment cycle. If 
regorafenib is not administered on the day of PK sampling, the pre-dose samples will be 
collected, the post-dose samples will not be collected. Pre-dose samples will also not be 
collected if participants have not taken regorafenib on the previous day. However, if regorafenib 
is re-started than PK sampling should resume as scheduled. Pre-dose samples will also not be 
collected if participants have not taken regorafenib on the previous day. However, if regorafenib 
is re-started than PK sampling should resume as scheduled 
The regorafenib dose that separates the pre- and post-dose sample needs to be taken under 
supervision and the time of dosing should be recorded.  
Regorafenib data from this study will be pooled with data from other clinical studies for 
pharmacometric analysis. The nivolumab serum concentration may be analyzed using a 
previously developed population PK model to determine measures of individual exposure. 
Model determined exposures of regorafenib and/or nivolumab may be used for exposure 
response analyses of selected measures of efficacy, safety or biomarker changes. The results of 
population PK and exposure response analyses will be reported separately from the overall 
study results. 
The PK analysis will be performed using validated analytical methods.  Exploratory 
measurements of other moieties may be performed, if needed. 
Instructions for the collection, processing, storage and shipment of PK samples will be provided 
separately by the sponsor (e.g., sample handling sheets or laboratory manual). 
8.6 
Pharmacodynamics  
Pharmacodynamic biomarkers will be evaluated in this study and are described in Section 8.8. 


 
 
 
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8.7 
Genetics 
Pharmacogenetic analyses except whole genome sequencing will be part of the biomarker 
investigations in this study. See Section 8.8 for details.  
 
8.8 
Biomarkers 
Biomarker investigations in the current study will include pharmacodynamic biomarker 
assessments and assessments of biomarkers that may associate with efficacy and/or safety. 
Both genetic as well as non-genetic biomarkers will be investigated. Genetic investigations 
may be of any kind (including whole exome sequencing and RNA sequencing), except for 
whole genome sequencing. 
All biomarker analyses are covered by the main study informed consent. No separate consent 
is required as no whole genome sequencing will be performed. The investigator will assess if 
tumor specimen acquisition is medically feasible. 
Timing:  
The following samples for biomarker research are required and will be collected from all 
participants as specified in the SoA (Table 1–2) and schedule of Biomarker Blood Sampling 
(Table 1–3). 
For details regarding tumor tissue collection please refer to the below specification: 
At screening: 
• Archival tumour tissue sample is mandatory if available for all cohorts.  
o HNSCC IO treated cohort: the archival tissue shall be preferably before IO 
treatment if available. 
AND 
• Provision of recent tumor tissues (defined as an archival biopsy not older than 180 day 
and after last anti-tumor treatment; or a new biopsy) are 
o mandatory for all participants in HNSCC (IO treated) in Stage 1 and 2 
o mandatory for HNSCC (IO naïve) in Stage 2 
o mandatory if medically feasible (as judged by the Investigator) for all participants 
in the ESCC, PDAC, and BTC cohorts and for participants in Stage 1 of the 
HNSCC (IO naïve) cohort. 
o Optional for GBM/AA cohort and should only be considered if tumor is accessible 
and biopsy is deemed safe by the Investigator 
C2D8 (+7 days):  
• In Stage 1: mandatory if medically feasible (as judged by the Investigator) for all 
participants in HNSCC (IO treated); optional for all other cohorts  
• In Stage 2: mandatory if medically feasible (as judged by the Investigator) for all 
participants in all cohorts except the GBM/AA cohort. For the GBM/AA cohort, 
tumor tissue collection is optional and should only be considered if tumor is accessible 
and biopsy is deemed safe by the Investigator. 
EoT: 
• Optional for all cohorts. 


 
 
 
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Table 8–2 
Requirements for Tumor Tissue Collection 
 
HNSCC IO 
Naïve 
Stage 1 
HNSCC IO 
naïve 
Stage 2 
HNSCC IO 
treated 
Stage 1+2 
ESCC 
 
Stage 1+2 
PDAC 
 
Stage 1+2 
BTC 
 
Stage 1+2 
GBM/AA 
 
Stage 1+2 
Archival 
tumor 
tissue  
Mandatory 
if available 
Mandatory 
if available 
Mandatory 
if available, 
preferably 
before IO 
treatment 
Mandatory 
if available 
Mandatory 
if available 
Mandatory 
if available 
Mandatory 
if available 
Recent 
tumor 
tissuesa 
Mandatory 
if medically 
feasible 
Mandatory 
Mandatory 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Optional 
C2D8  
Stage 1 
participants 
Optional 
NA 
Mandatory 
if medically 
feasible 
Optional 
Optional 
Optional 
Optional 
C2D8  
Stage 2 
participants  
NA 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Mandatory 
if medically 
feasible 
Optional 
EoT  
Optional 
Optional 
Optional 
Optional 
Optional 
Optional 
Optional 
Abbreviations: AA= Anaplastic astrocytoma; BTC = Biliary Tract Carcinoma; C = Cycle; D = Day; EoT = End of 
treatment; ESCC = Esophageal squamous cell carcinoma, HNSCC = Head and neck squamous cell cancer; IO 
= Immune oncology; NA = not applicable; PDAC= Pancreatic ductal adenocarcinoma 
a) 
archival biopsy not older than 180 day and after last anti-tumor treatment; or a new biopsy 
Note: Medically feasible as judged by the Investigator 
 
Additional samples may be collected at additional time points during the study if warranted 
and agreed upon between the investigator and the sponsor. Sampling time points might also 
be moved or removed. 
Medical history information – if any additional molecular information about the tumor was 
collected in the course of treatment prior to entry of the participant in the study, the results 
may be collected in order to include this data in biomarker analyses. 
Sample handling and storage:  
Tumor tissue requirement for archival tissue: Formalin-fixed paraffin-embedded block or 
minimum of 20 slides if available. Less slides are acceptable if provision of a block or 20 
slides is not feasible. 
Tumor tissue requirement for recent tissue at baseline, C2D8 and EoT tissue: Formalin-fixed 
paraffin-embedded block or minimum of 20 slides, obtained from core needle biopsy, punch 
biopsy, excisional biopsy or surgical specimen. Fine needle aspirates or other cytology 
samples are not acceptable. 
Details on the collection, processing, shipment and storage of samples will be provided in 
separate documents (e.g., sample handling sheets or lab manual). Samples may be stored for a 
maximum of 15 years (or according to local regulations) following the end of the study at a 
facility selected by the sponsor to enable further analyses. 
Reporting:  
Some of the results of biomarker investigations may be reported separately (e.g., in a 
biomarker evaluation report). 


 
 
 
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8.8.1 
Pharmacodynamics Biomarker 
Pharmacodynamics biomarker will be evaluated in samples collected before and during 
treatment to investigate the impact of regorafenib and nivolumab on these biomarkers and 
may be correlated with safety and/or efficacy. Tissue-based pharmacodynamics biomarker 
evaluations will be conducted in available paired tumor biopsies (recent tumor tissues at 
screening and on-treatment/EoT tumor biopsy).  
Candidate pharmacodynamics biomarkers may include (but are not limited to): 
• Intra-tumor PD biomarkers such as immune cell infiltrations (e.g. effector T cells 
[Teff], Treg, marcophages), expression of immune genes/signatures, and/or parameters 
in the regorafenib targeted pathways in paired tumor biopsies (pre- and on-treatment) 
• Quantification and characterization of immune cell populations in blood (e.g. T cells, 
Myeloid-Derived Suppressor Cells [MDSC], etc.) analyzed e.g., by flow-cytometry 
• Systemic levels of immune mediators (e.g., cytokines, chemokines) from serum or 
plasma and tumor markers from circulating tumor deoxyribonucleic acid (ctDNA) 
• Plasma proteins of interest for regorafenib (e.g., TIE-1, sVEGFR1, sVEGFR2, VEGF, 
angiopoietin 1 [Ang1])  
• Circulating miRNA  
• Composition of gut microbiome by e.g., bacterial taxonomy profiling in stool sample  
8.8.2 
Biomarkers that may associate with Response 
Baseline candidate biomarkers will be evaluated for correlation with the response to treatment 
(to identify possible “predictive biomarkers”). Samples from tumor materials, blood and stool 
will retrospectively be analyzed.  
Candidate biomarkers from baseline samples that may associate with response may include 
(but are not limited to): 
• Tumor immune status (e.g., PD-L1 expression, immune gene expression profiles, 
immune cell infiltration e.g. Teff, Treg, macrophages) at baseline 
• Expression of parameters of interest for regorafenib (e.g., ligands of targeted receptor 
tyrosine kinases) in baseline tumor materials 
• Baseline TMB/ tumor mutations (e.g. B2M, JAK1/2/3) as detected in tumor and/or 
ctDNA 
• Baseline immune cell populations in blood and baseline systemic levels of immune 
mediators (e.g., cytokines/chemokines)   
• Germline genetic variants in genes of interest (e.g., cc-chemokine ligands CCL4 and 
CCL3, cc-chemokine receptor 5 (CCR5)) 
• Baseline circulating miRNA markers  
• MGMT methylation status and IDH mutation status (GBM/AA only) 
• HPV/p16 (oropharyngeal HNSCC only) 
• Baseline composition of gut microbiome by e.g., bacterial taxonomy profiling in stool 
sample  
 


 
 
 
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8.8.3 
Other Biomarkers 
In addition to the biomarkers described above, further biomarkers related to the mode of 
action or the safety of regorafenib and nivolumab and similar drugs may be examined. The 
same applies to further biomarkers deemed relevant to cancer and associated health problems. 
These investigations may include e.g., diagnostic testing, potentially predictive, safety, 
pharmacodynamics or monitoring biomarkers. 
8.9 
Immunogenicity Assessments 
Blood (serum) samples will be collected from all participants treated with nivolumab for 
analysis of anti-drug-antibodies (ADAs) and neutralizing antibodies (NABs) in Cycles 1, 2, 5 
and 19, pre-infusion (Table 1–4). 
Serum samples will be screened for ADAs and the titer of confirmed positive samples will be 
reported. Other analyses may be performed to verify the stability of ADAs and/or further 
characterize the immunogenicity of nivolumab. 
The detection and characterization of ADAs will be performed using a validated assay method. 
ADAs may be further characterized and/or evaluated for their ability to neutralize the activity 
of nivolumab.  
Instructions for the collection, processing, storage and shipment of immunogenicity samples 
will be provided separately by the Sponsor (e.g., sample handling sheets or laboratory manual). 
9. 
Statistical Considerations 
This is a single arm, open-label Phase 2 study with ORR per RECIST1.1 per local assessment 
for all solid tumors except GBM/AA or RANO per local assessment for GBM/AA as primary 
endpoint.  
Each cohort will be examined in 2 stages based on a Sargent 3-outcome design (Sargent et al. 
2001) with one-sided alpha of 0.1 (false positive rate), beta (false negative rate) of 0.1, power 
of 70% and likelihood of futility of 70% when the null hypothesis is true. At the end of Stage 
2, 3 outcomes are possible based on 2 efficacy boundaries. The first outcome is considered 
negative if there is an insufficient number of responders to pass the pre-defined low boundary 
for efficacy. The second outcome is considered a positive outcome if the number of 
responders meets or surpasses the pre-defined target boundary for efficacy. The third outcome 
is a result in which the number of responders lies between the two boundaries and is 
considered inconclusive for declaring a positive outcome based on the pre-defined target. 
If Stage 1 does not show the targeted level of activity after 2 tumor assessments, recruitment 
into Stage 2 may be discontinued. In addition, the totality of the data, including the duration 
and depth of response and overall risk-benefit assessment may be considered in the decision 
to terminate or continue the expansion after Stage 1. The complete cohort of participants from 
Stage 1 and Stage 2 will be tested at the one-sided alpha of 0.1. A one-sided exact binomial 
test will be conducted to test the hypotheses.  
All participants treated will be included in the evaluation of response rate, not treated 
participants will be replaced. Any treated participant who does not qualify as a responder 
according to the tumor assessment criteria will be considered as non-responder.   
 


 
 
 
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9.1 
Statistical Hypotheses 
The underlying hypotheses to be tested in this study are 
 
HNSCC (IO naïve): H0: ORRCombination ≤ 15% versus H1: ORRCombination ≥ 30%  
 
HNSCC (IO treated): H0: ORRCombination ≤ 5% versus H1: ORRCombination ≥ 19%  
 
ESCC: H0: ORRCombination ≤ 15% versus H1: ORRCombination ≥ 30%  
 
PDAC: H0: ORRCombination ≤ 10% versus H1: ORRCombination ≥ 20%  
 
BTC: H0: ORRCombination ≤ 10% versus H1: ORRCombination ≥ 20%  
 
GBM/AA: H0: ORRCombination ≤ 15% versus H1: ORRCombination ≥30%  
 
9.2 
Sample Size Determination 
Cohort: HNSCC (IO naïve), ESCC and GBM/AA 
In Stage 1, a total of 9 participants should be targeted for each cohort. To target 30% of ORR 
at least 1 responder out of the 9 participants is needed per cohort.  
In Stage 2, per cohort, 21 additional participants should be added in order to target 30 
participants. If 8 or more out of the 30 participants respond, the cohort is considered as 
showing a positive outcome. If 5 or less out of the 30 participants respond, the cohort is 
considered as showing a negative outcome. If 6 or 7 participants respond, outcome is 
inconclusive. 
 
Cohort: HNSCC (IO treated)  
 In Stage 1, a total of 14 participants should be targeted in the cohort. To target 19% of ORR 
at least 1 responder out of the 14 participants is needed.  
In Stage 2, 6 additional participants should be added in order to target 20 participants. If 3 or 
more out of the 20 participants respond, the cohort is considered as showing a positive 
outcome. If 1 or less out of the 20 participants respond, the cohort is considered as showing a 
negative outcome. If 2 participants respond, outcome is inconclusive. 
 
Cohort: PDAC and BTC 
 In Stage 1, a total of 17 participants should be targeted in the cohort. To target 20% of ORR 
at least 1 responder out of the 17 participants is needed.  
In Stage 2, 28 additional participants should be added in order to target 45 participants. If 8 or 
more out of the 45 participants respond, the cohort is considered as showing a positive 
outcome. If 5 or less out of the 45 participants respond, the cohort is considered as showing a 
negative outcome. If 6 or 7 participants respond, outcome is inconclusive. 
 


 
 
 
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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 (full analysis set) 
All participants who have received any dose of study intervention  
SAF (safety analysis set) 
All participants who have received any dose of study intervention  
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 (at baseline and during the treatment or FU 
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; FU = Follow-up; ICF = Informed 
consent form; IMS = Immunogenicity analysis set; PK = Pharmacokinetics; n-PKS = Nivolumab PK 
analysis set; r-PKS =Regorafenib PK analysis set; SAF = Safety analysis set 
 
As the safety analysis set (SAF) equals the full analysis set (FAS), all analyses related to 
safety will be performed on the Full 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 statistical analysis plan will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and secondary 
endpoints. 
 
9.4.1 
General Considerations 
All analyses will be conducted at one-sided type-I error level of 10% or two-sided type-I error 
level of 20% respectively. A one-sided exact binomial test will be conducted in the Stage 2 to 
test the primary endpoint. Confidence intervals will be presented for selected variables. 
 


 
 
 
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9.4.2 
Primary Endpoint(s) 
The primary endpoint of the study is ORR defined as the proportion of participants with best 
overall response of confirmed CR or partial response (PR). ORR is based on RECIST 1.1. for 
all solid tumors by local assessment and for the GBM/AA cohort ORR is based on RANO by 
local assessment. Participants for whom best overall tumor response is not CR or PR, as well 
as participants without any post-baseline tumor assessment will be considered non-
responders. 
The primary endpoint is ORR based on RECIST 1.1 or RANO as assessed by the investigator. 
The primary efficacy variable will be analyzed per cohort. The primary analysis will be done 
on the Full Analysis Set.  
Methods used will include frequency tables (with the ORR table also including all “Best 
overall response” categories) as well as 80% two-sided Clopper-Pearson confidence intervals 
and the results of an exact binomial test. 
 
9.4.3 
 Secondary Endpoint(s) 
The secondary efficacy endpoints in this study are Duration of Response (DOR), Disease 
Control Rate (DCR), PFS, 6 month PFS, according to RECIST 1.1 or RANO and additionally 
OS and 1 year OS in the Stage 2.  
DOR (for PR and CR) is defined as the time (in days) from the first documented objective 
response of PR or CR, whichever is noted earlier, to first documented objective disease 
progression or death (if death occurs before progression is documented). DOR will be defined 
for responders only, i.e. participants with a CR or PR. The actual dates the tumor scans were 
performed will be used for this calculation. DOR for participants who have not progressed or 
died at the time of analysis will be censored at the date of their last tumor evaluation. 
PFS is defined as the time (in days) from start of study intervention to the date of first 
objectively documented PD or death from any cause (if no progression is documented). The 
actual date of tumor assessments will be used for this calculation. PFS for participants without 
PD or death at the time of analysis will be censored at the date of their last tumor evaluation. 
PFS for participants who have neither tumor assessments nor death after baseline will be 
censored at Day 1. 
OS is defined as the time (in days) from start of study intervention to the date of death due to 
any cause. If a participant is not known to have died, then OS will be censored at the date of 
last known date participant alive. If a participant is lost to FU before any assessment after 
assignment to study intervention, this participant will be censored at Day 1. 
Safety is also considered as secondary endpoint. For details please refers to Section 9.4.5. 
The secondary efficacy endpoints will be based on investigator assessments. Analyses will be 
done on the Full Analysis Set per cohort. 
For analyses of the secondary endpoints, proportion-based efficacy variables will be using 
frequency tables as well as 80% 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 80% two-sided confidence interval 


 
 
 
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9.4.4 
Tertiary/Exploratory Endpoint(s) 
All other endpoints will be analyzed by means of descriptive statistics using frequency tables 
for response endpoints and summary statistics for continuous endpoints. Further analyses will 
be described in the SAP. 
For further information on PK and biomarkers refer to Section 9.4.6. 
9.4.5 
Safety Analyse(s) 
All safety analyses will be done on the Safety Analysis Set as defined in Table 9–1, analysis 
will be done by cohort and overall. 
The incidence of treatment-emergent adverse events (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 or other measured values will be summarized in frequency tables. 
Where applicable, laboratory measurements will be summarized by severity, cohort, and 
changes in severity from baseline to worst post-baseline value. Laboratory data considered as 
AE will be graded according to CTCAE v. 5.0, if applicable. 
 
9.4.6 
Other Analyses  
PK, pharmacodynamic, and biomarker exploratory analyses will be described in a separate 
statistical analysis plan finalized before database release. The population PK analysis and 
pharmacodynamic analyses will be presented separately from the main clinical study report 
(CSR). 
9.5 
Interim Analyses  
At stage 1, an interim futility analysis for response rate will be conducted per cohort based on 
patients in the full analysis set (FAS). The evaluation will be based on a clean database of 
Stage 1 with cut-off date when the last participant of the respective cohort has had the chance 
to complete 4 cycles of treatment. 
At Stage 2, response rates will be analyzed per cohort based on the FAS. Data read out is 
planned after the last participant of the respective cohort has had the chance to complete 4 
cycles of treatment. 
9.6 
Data Monitoring Committee (DMC) or other Review Board 
Not applicable. 
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: 


 
 
 
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• 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, Investigator Brochure, 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 and require 
regulatory authority approval. 
• Any amendments to the protocol will require IRB/IEC and regulatory authority 
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 
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.  


 
 
 
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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 
and answer all questions regarding the study 
Participants will be informed that their participation is voluntary. Participants 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 
required, in the patient’s note/file of the medical institution. 
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. 
Participants who are rescreened are required to sign a new ICF. For details with regard to 
rescreening please refer to Section 5.4. 
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.  
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/RANO, participant must be re-consented. Re-consent also covers a potential 


 
 
 
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treatment continuation with regorafenib after confirmed radiological progression (according 
to iRECIST/iRANO) until clinical progression. 
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. 
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 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 
transferred. 
• The participant must be informed that his/her personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant 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 


 
 
 
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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 2, 3 and 4 
and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after January 01, 2014 as necessary for conducting legitimate research.  
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 
 
10.1.7 
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 
electronically signing the eCRF. 
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. 


 
 
 
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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 
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 


 
 
 
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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. The sponsor has the right to close 
this study (or, if applicable, individual segments thereof [e.g. treatment arms; dose steps; 
centers]) at any time, which may be due but not limited to the following reasons. 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 
• 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 participant 
and should assure appropriate participant therapy and/or FU. 


 
 
 
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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 (except PK, immunogenicity, tumor tissue, 
stool sample and items mentioned in 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. 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 
expanded 
 
• Platelet count  
• Hemoglobin 
 
WBC count with differential: 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Hematology 
limited  
 
• 
Platelet count  
• 
Hemoglobin 
• 
WBC count 
 
Chemistry panel 
expanded 
 
• BUN or Urea 
• Creatinine and 
eGFR a 
• Lipase  
• LDH 
• Albumin 
 
• Potassium 
• Sodium 
• Chloride 
• Amylase  
•  Phosphate 
• AST/SGOT 
• ALT/SGPT 
• Total protein 
• Total calcium, 
calcium 
ionized or 
adjusted 
• Uric acid 
• Magnesium 
• Total and direct bilirubin 
•  ALP 
• Glucose (fasting or non-fasting 
according to local standards) 
• GGT b 
 
 
Chemistry panel 
limited  
 
 
• AST/SGOT 
• ALT/SGPT 
• Total and direct bilirubin 
• Glucose (fasting or non-fasting 
according to local standards) 
 
Routine 
Urinalysisa 
• 
Dipstick: pH, glucose, protein, blood, ketones,  
• 
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.  
• 
Microscopic examination (if blood or protein is abnormal) 
Coagulation 
• PT-INR 
• aPTT 
Thyroid 
• FT3 
• FT4 
• TSH 
Pregnancy Test  
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)  
• A negative pregnancy test must be available within 24 hr before the 1st study 
treatment administration. Monthly pregnancy testing independent of study treatment 
dosing should be conducted as per local regulations where applicable. 
Abbreviations: ALT = Alanine aminotransferase; ALP = Alkaline phosphatase; aPTT = Activated partial 
thromboplastin time; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; eGFR = Estimated 
glomerular filtration rate; FT3 = Free triiodothyronine; FT4 = Free thyroxine; GGT = Gamma-glutamyl 
transferase; hCG = Human chorionic gonadotropin; LDH = Lactic dehydrogenase; PT-INR = Prothrombin 
time-international normalized ratio; SGOT = Serum glutamic-oxaloacetic transaminase; SGPT = Serum 
glutamic-pyruvic transaminase; TSH = Thyroid stimulating hormone; WBC = White blood cell count   
a) 
Cockcroft Gault formula for GFR:  
a. 
 
b) 
GGT will be assessed if clinically indicated.  
 
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, FU, 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 signature of the ICF 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” 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. 


 
 
 
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Events NOT Meeting the AE Definition 
• The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (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 


 
 
 
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may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
10.3.3 
Recording and FU 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 CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. 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 CRO/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 intensity of AEs should be documented using the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). 
The intensity of AEs is classified according to the following categories for events not 
listed in the CTCAE v.5.0: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL (ADL: Activities of Daily Living; instrumental 
ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.). 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (Self-care ADL refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden). 


 
 
 
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• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the Sponsor. 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 the 
Sponsor. 
• 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. 
 
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 the Sponsor 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 postmortem findings 
including histopathology 


 
 
 
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FU of AEs and SAEs 
• New or updated information will be recorded in the originally completed case 
report form (CRF). 
• The investigator will submit any updated SAE data to Bayer within 24 hours of 
receipt of the information. 
10.3.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting a SAE to the Sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the Sponsor by telephone. 
• Contacts for SAE reporting can be found in the Investigator file. 
 
SAE Reporting to the Sponsor via Paper CRF 
• Confidential email (pdf) transmission of the SAE paper CRF is the preferred 
method to transmit this information to the Sponsor. Facsimile transmission should 
be the second choice. 
• In rare circumstances and in the absence of email and 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 CRF pages within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in the Investigator file. 
 
 


 
 
 
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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). 
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 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.  
• 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. 
 
Fertile Man 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy 
Contraception Guidance: 
The investigator or a designated associate is requested to advise the patient how to achieve 
highly effective birth control 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following (as applicable) during the protocol-defined time frame in Section 
5.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 


 
 
 
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• Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 10–2 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration [during the protocol-defined time frame]  
• Refrain from donating sperm for the duration of the study and for a period after study 
completion or the last dose of study treatment as specified in Section 5.1. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10–
2 and during the protocol-defined time frame in Section 5.1. 
 
Table 10–2 Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods of Low User Dependencya  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
• 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be 
used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.  


 
 
 
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Pregnancy Testing 
Highly sensitive serum testing is mandatory if required by local regulations or ethics 
committees, or to resolve an indeterminate test or to confirm a positive urine test. 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive [serum] pregnancy test. 
• 
Additional pregnancy testing should be performed at monthly intervals, during the 
treatment period and at safety FU after the last dose of study treatment as specified in 
Section 1.3 (SoA) and as required locally. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected. 
 
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 treatment. 
• 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 the Sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.  
Female Participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents of the neonate, unless local 
law or specific circumstances of the respective case allow otherwise, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  


 
 
 
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• Any post-study pregnancy related SAE considered reasonably related to the study 
treatment 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 treatment or be withdrawn from the study.  
10.5 
Appendix 5: Genetics 
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study. See Section 8.8 for details. 
 
10.6 
Appendix 6: Response Evaluation Criteria in Solid Tumors  
For participants with HNSCC, ESCC, PDAC, and BTC, response and progression will be 
evaluated using the RECIST 1.1 (Eisenhauer et al. 2009) as well as the modified iRECIST 
guidelines for immune-based therapeutics (Seymour et al. 2017).  
For participants with GBM/AA, response and progression will be evaluated using the RANO 
(Wen et al. 2010) and the iRANO criteria (Okada et al. 2015). 
10.6.1 
RECIST 1.1 
Definition of Measurable disease:  
• Soft tissue/ visceral tumor lesions: Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of 10 mm by CT scan.  If scans with slice thicknesses greater than 5mm 
are used, the minimum size should be twice the slice thickness. 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (for CT scan 
slice thickness of 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed. 
Non-measurable disease 
All other lesions are considered non-measurable. This includes small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) and also 
truly non-measurable lesions, such as: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung. 
Bone lesions, cystic lesions and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Lytic bone lesions, with an identifiable soft-tissue component, (e.g., lytic bone lesions 
in renal cell carcinoma) evaluated by CT or MRI can be considered as measurable 
lesions if the soft-tissue component otherwise meets the definition of measurability 
• Blastic bone lesions are considered as non-measurable 


 
 
 
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Cystic lesions: 
• Lesions that meet radiographic criteria for simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable) 
• “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 participants, these should be preferably selected for assessment 
Lesions with prior local treatment: 
• 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 prior to 
baseline. 
Target lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where participants have only 1 or 2 organ sites involved a maximum of 2 
and 4 lesions respectively will be recorded). Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance 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 as noted above, only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective change in the measurable dimension of the disease. 
Non-target lesions 
All other lesions (or sites of disease) including pathological lymph nodes (with short axis 
≥ 10 mm and < 15 mm) not considered as target should 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’ (more details to 
follow). Please note that some non- target lesions may actually be measurable, but if they 
were chosen to be followed as non-target lesions, they should be assessed only qualitatively. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
Best Response: The best overall response for a participant is the best response recorded from 
the start of the study intervention until the end of treatment or A-FU, if applicable, taking into 
account any requirement for confirmation. 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. 
Complete Response (CR): Disappearance of all non-nodal target and non-target lesions. Any 
pathological lymph nodes (whether target or non-target) must have decreased in size to have a 


 
 
 
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short axis of < 10 mm. In addition, there must be normalization of any applicable tumor 
marker. 
Since lymph nodes are normal body structures, it is not expected that they disappear. Lymph 
nodes identified as target lesions should always have the 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 lymph node is defined as normal when having 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. 
In participants with a bone/brain scan at baseline, a repeat bone/brain scan must be done at 
confirmation of response to ensure there is no bone progression before claiming PR or CR. 
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): Persistence of 
one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal 
limits. 
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). In 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. 
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. 
The above text descriptions of the visit/time point response are logically equivalent to  
Table 10–3 below. 
 


 
 
 
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Table 10–3 RECIST 1.1 - Time Point Response for participants with target and non-
target lesions 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall Time 
Point Response 
Best Response for this 
category also requires 
CR 
CR 
No 
CR 
- 
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 
documented at least 6 weeks from 
treatment allocation  
Not all 
evaluated 
Non-PD 
No 
NE 
- 
PD 
Any 
Yes or No 
PD 
- 
Any 
PD 
Yes or No 
PD 
- 
Any 
Any 
Yes 
PD 
- 
Abbreviations: C=Cycle; CR = Complete response; D=Day; NE = Not evaluated; PD = Progressive disease; 
PR = Partial response; SD = Stable disease. 
 
Participants with a global deterioration of health status requiring discontinuation of 
intervention without objective 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 intervention. 
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. 
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 intervention 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).  When SD is believed to be best response, it must also 
meet the protocol specified minimum time of 6 weeks from baseline. 
10.6.2 
iRECIST 
iRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response 
seen with immunotherapeutic drugs (Table 10–4). Responses assigned using iRECIST criteria 
will have an “i” prefix. 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 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 


 
 
 
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Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1, the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
and response is evaluated using iRECIST for participant management (see Table 10–4 and 
Figure 10–1).  
Regarding the decision to treat past PD (based on RECIST 1.1), the Investigator should 
consider the participant’s clinical stability, which includes the following:  
• No decline in ECOG PS  
• No clinically relevant increase in symptoms related to patient’s cancer 
• No requirement for intensified management of disease related symptoms, including 
increased analgesia, radiation, or other palliative care 
For any participant deemed clinically unstable, the Investigator should discontinue the 
participant from study treatment at site-assessed first radiologic evidence of PD without need 
for 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 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
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 1.1 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 iRECIST assessments, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of the 
underlying cause of progression. At this visit, target and non-target lesions identified at 
baseline by RECIST 1.1 will be assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target 
(NLT). 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 (NLNT). 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging for iRECIST, the participant will be classified as progression 
confirmed (with an overall response of iCPD), or as showing persistent unconfirmed 


 
 
 
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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 1.1 
• 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 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
1. None of the progression-confirming factors identified above occurs AND 
2. The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
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 
threshold.  
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. 


 
 
 
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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 (iCPD) via iRECIST, 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. 
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. 


 
 
 
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Additional details about iRECIST are provided in the iRECIST publication (Seymour et al. 
2017). 
 
Table 10–4 Imaging and Treatment after First Radiologic Evidence of PD 
Tumor Assessment 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic evidence 
of PD by RECIST 1.1  
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 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 
every 8 weeks (±7 d) 
according to the 
imaging schedule 
through Cycle 8 (or 
until treatment 
discontinuation, if 
treatment 
discontinuation 
occurs before) and 
12 weeks (±14 d) 
thereafter  
Abbreviations: D/d = day(s); iCPD = iRECIST Confirmed progressive disease; iCR = iRECIST complete response; 
iRECIST = Response Evaluation Criteria in Solid Tumors 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 1.1 = Response Evaluation Criteria in Solid Tumors 1.1 
 


 
 
 
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Figure 10–1 iRECIST: Process for Assessment of Disease Progression 
 
iRECIST = Immune response evaluation criteria in solid tumors; PD = Progressive disease 
 
10.6.3 
RANO 
The RANO criteria (Wen et al. 2010) were developed to evaluate efficacy of investigational 
agents in glioblastoma clinical trials and have been more broadly utilized for lower grade 
primary CNS malignancies. These criteria were developed in part to address issues faced 
when assessing some lesions based on MacDonald criteria, particularly lesions with central 
necrosis and with a T2 component. 
 
 


 
 
 
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RANO RESPONSE CRITERIA SUMMARY: 
 
Table 10–5 RANO Response Criteria Incorporating MRI and Clinical Factor 
Response 
Category 
Criteria 
CR 
Requires all of the following: 
• 
Disappearance of all measurable and non-measurable enhancing disease 
sustained for at least 4 weeks* 
• 
Stable or improved non-enhancing T2/FLAIR lesions 
• 
No new lesions 
• 
Clinically stable or improved with no reliance on corticosteroids (except for 
physiological replacement) 
PR 
Requires all of the following: 
• 
≥ 50% decrease from baseline in the SPPD of all measurable enhancing 
lesions sustained for at least 4 weeks* 
• 
No progression of non-measurable disease 
• 
Stable or improved non-enhancing T2/FLAIR lesions 
• 
No new lesions 
• 
Clinically stable or improved, with stable or reduced corticosteroids 
compared to baseline 
PD 
Defined by any of the following: 
• 
≥ 25% increase in SPPD of enhancing lesions compared with the smallest 
tumor measurement obtained either at baseline (if no decrease) or best 
response despite stable or increasing steroid dose 
• 
Significant increase in non-enhancing T2/FLAIR lesions compared with 
baseline scan or best response after initiation of therapy not attributable to 
other non-tumor causes 
• 
Any new lesions 
• 
Clinical deterioration not attributable to other non-tumor causes and not due 
to steroid decrease 
• 
Failure to return for evaluation as a result of death or deteriorating condition 
• 
Clear progression of nonmeasurable disease 
SD 
Requires all of the following: 
• 
Does not meet other criteria for response or progression 
• 
Stable non-enhancing T2/FLAIR lesions 
• 
Clinically stable with stable or reduced corticosteroids compared to baseline 
NOTE: In the event the corticosteroid dose is increased for new symptoms and 
signs without confirmation of disease progression, and subsequent follow-up 
imaging shows that this increase in corticosteroids was required because of 
disease progression, the last scan considered to show stable disease will be 
that when the corticosteroid dose was equivalent to the baseline dose 
Abbreviations: CR = Complete response; T2/FLAIR = T2-weighted fluid-attenuated inversion recovery; MRI = 
magnetic resonance imaging; PD = progressive disease; PR = Partial response; RANO = Response 
Assessment in Neuro-Oncology; SD = Stable disease; SPPD = Sum of products of perpendicular diameters. 
* In the absence of a confirming scan 4 weeks later, this response will be considered only stable disease. 


 
 
 
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A measurable lesion is evaluated by contrast-enhancing MRI and: 
• Has clearly defined margins 
• Is visible on two or more axial slices, preferably < 5 mm thick 
• Has two perpendicular diameters of at least 10 mm if slice thickness is < 5 mm (or 2 × 
slice thickness if > 5 mm) 
• Does not measure a cystic cavity 
Non-measurable lesions are those that do not fit the criteria above, and specifically lesions 
that are cystic, necrotic, or include a surgical cavity should not be considered measurable. 
Measurements are calculated by summing the products of perpendicular diameters of all 
measurable enhancing lesions. 
All patients must have at least one measurable lesion as defined by RANO to enroll in the 
study. 
If there are multiple contrast-enhancing lesions, a minimum of the two largest lesions should 
be measured. However, emphasis should be placed on selecting lesions that allow 
reproducible repeated measurements. For patients who have multiple lesions for which only 
one or two are increasing in size, the enlarging lesions should be considered the target lesions 
for evaluation of response. 
 
10.6.4 
iRANO 
The iRANO criteria (Okada et al. 2015) were issued to aid the interpretation of imaging 
changes in patients with cancer undergoing immunotherapy. The key component of the 
iRANO criteria is specific additional guidance for the determination of progressive disease in 
patients with neuro-oncological malignancies undergoing immunotherapy. 
 
iRANO criteria: 
The iRANO guidelines incorporate criteria previously defined by the RANO working 
committee to define complete response, partial response, minor response, stable disease, 
progressive disease, and non-evaluable disease for patients with malignant glioma, low-grade 
glioma, and brain metastases (Table 10–6). 


 
 
 
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Table 10–6 RANO and iRANO Criteria 
 
Malignant glioma 
Low-grade glioma 
Brain metastases 
CR 
Disappearance of all 
enhancing disease for ≥ 4 
weeks; no new lesions; 
stable or improved 
T2/FLAIR; no more than 
physiological steroids; 
clinically stable or improved 
Disappearance of all 
enhancing and T2/FLAIR 
disease for ≥ 4 weeks; no 
new lesions; no more than 
physiological steroids; 
clinically stable or improved 
Disappearance of all 
enhancing target and non-
target lesions for ≥ 4 
weeks; no new lesions; no 
steroids; clinically stable or 
improved 
PR 
≥ 50% decrease in the sum 
of biperpendicular 
diameters of enhancing 
disease for ≥ 4 weeks; no 
new lesions; stable or 
improved T2/FLAIR; stable 
or decreased steroid dose; 
clinically stable or improved 
≥ 50% decrease in the sum 
of biperpendicular diameter 
of T2/FLAIR disease for ≥ 4 
weeks; no new lesions; 
stable or decreased steroid 
dose; clinically stable or 
improved 
≥ 30% decrease in sum of 
longest diameters of target 
lesions for ≥ 4 weeks; no 
new lesions; stable or 
decreased steroid dose; 
clinically stable or improved 
MR 
N/A 
25-49% decrease in the sum 
of biperpendicular diameters 
of T2/FLAIR disease for ≥ 4 
weeks; no new lesions; 
clinically stable or improved 
N/A 
SD 
Does not qualify for 
complete response, partial 
response, or progressive 
disease; no new lesions; 
stable or improved 
T2/FLAIR; stable or 
decreased steroid dose; 
clinically stable or improved 
Does not qualify for complete 
response, partial response, 
or progressive disease; no 
new lesions; stable or 
improved T2/FLAIR; stable or 
decreased steroid dose; 
clinically stable or improved 
Does not qualify for 
complete response, partial 
response, or progressive 
disease 
PD 
≥ 25% increase in the sum 
of biperpendicular 
diameters of enhancing 
disease; or new lesions; or 
substantial worsened 
T2/FLAIR; or substantial 
decline 
≥ 25% increase in the sum of 
biperpendicular diameters of 
T2/FLAIR disease; or new 
lesions; or substantial clinical 
decline 
≥ 20% increase in the sum 
of longest diameters of 
target lesions; or 
unequivocal progression of 
enhancing non-target 
lesions; or new lesions; or 
substantial clinical decline 
Abbreviations: CR = Complete response; FLAIR=fluid-attenuated inversion recovery; iRANO=immunotherapy 
Response Assessment in Neuro-Oncology; MR = Minor response; N/A=not applicable; PD = Progressive 
disease; PR = Partial response; SD = Stable disease. 
 
In patients who have imaging findings that meet RANO criteria for progressive disease within 
6 months of starting immunotherapy, including the development of new lesions, confirmation 
of radiographic progression on follow-up imaging before defining the patient as 
nonresponsive to treatment might be needed, provided that the patient does not have new or 
substantially worse neurological deficits. Such patients might be allowed a window of 3 
months before confirming disease progression with the scan that first showed initial 
progressive changes as the new reference scan for comparison with subsequent imaging 
studies. 
 
If RANO criteria for progressive disease are met on the follow-up scan 3 months later, non-
responsiveness to treatment should be assumed, and the date of progressive disease should be 
back-dated to the initial date when it was first identified (Table 10–6). Patients who develop 


 
 
 
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substantial new or worsened neurological deficits not due to comorbid events or a change in 
co-administered medication at anytime within the 3-month follow-up window should be 
designated as non-responsive to treatment and should discontinue immunotherapy. For these 
patients, the date of actual tumor progression should also be back-dated to the date when 
radiographic progressive disease was initially identified. 
 
If radiographic findings at the 3-month follow-up meet RANO criteria for stable disease, 
partial response, or complete response compared with the original scan meeting criteria for 
progression, and no new or worsened neurological deficits are identified, such patients should 
be deemed as deriving clinical benefit from therapy and allowed to continue treatment. 
Patients who develop worsening radiographic findings compared with the pretreatment 
baseline scan more than 6 months from starting immunotherapy are expected to have a low 
likelihood of ultimately deriving clinical benefit and should be regarded as non-responsive to 
treatment with a recommendation to discontinue therapy. 
The iRANO treatment algorithm is summarized in Figure 10–2. 
 
Figure 10–2 iRANO Treatment Algorithm for the Assessment of Progressive Imaging 
Findings in Patients with Neuro-Oncological Malignancies Undergoing 
Immunotherapy 
 
  
Corticosteroids: 


 
 
 
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Patients with brain tumors frequently develop peritumoral edema needing treatment with 
corticosteroids. Dexamethasone is the most commonly used corticosteroid. In addition to the 
systemic side-effects, dexamethasone can have profound effects on contrast enhancement for 
neuroimaging studies and on the immune system, including T cells, dendritic cells and natural 
killer cells. Therefore, dexamethasone doses and duration of therapy should be limited to the 
minimum amount needed to control neurologic symptoms. If pseudoprogression occurs 
during the course of treatment, higher doses of corticosteroids might be necessary to control 
symptoms. 
Of note, patients who need increased corticosteroid use within 2 weeks of MRI assessment 
relative to the dose taken at the time of the previous assessment, cannot be classified as 
having a complete response, partial response, or stable disease and should be classified as 
non-evaluable at that timepoint. Conversely, patients who decrease corticosteroid use within 2 
weeks of MRI assessment relative to the dose taken at the time of the previous assessment 
cannot be classified as having progressive disease and should be classified as non-evaluable. 
 
10.7 
Appendix 7: 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 10–7 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. 
 
10.8 
Appendix 8: CYP3A4 Inhibitors and Inducers 
CYP3A4 inducers and inhibitors  
Table 10–8 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.  


 
 
 
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Table 10–8 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 10–8 were identified using the 
Bayer-World Health Organization’s Drug Dictionary (WHO-DD) and Bayer drug groupings 
for CYP3A4 inducers and CYP3A4 inhibitors. 
 
10.9 
Appendix 9: Guidance for Management of Immune-Related Adverse 
Events 
The following AE management algorithms apply criteria from NCI-CTCAE v5 
 
 
 


 
 
 
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10.10 
Appendix 10: Abbreviations 
Table 10–9 Abbreviations 
AA 
Anaplastic astrocytoma 
ADA 
Anti-drug-antibodies 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AIDS 
Acquired human immunodeficiency virus 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count 
Ang1 
Angiopoietin 1 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
BP 
Blood pressure 
BRAF 
Proto-oncogene BRAF, type B of RAF 
BCRP 
Breast cancer resistance protein 
BDM 
Bi-dimensional measurements 
BTC 
Biliary tract carcinoma 
BTIP 
Brain tumor imaging protocol 
BUN 
Blood urea nitrogen 
C 
Cycle 
CCA 
Cholangiocarcinoma  
CCL 
cc-chemokine ligand 
CCR 
cc-chemokine receptor 
ChT 
Chemotherapy 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
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 
CXCL10 
C-X-C motif chemokine ligand 10 
CXCR3 
CXC-motif-chemokine receptor 3 
CYP 
Cytochrome P450 
D / (d) 
Day(s) 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
dMMR 
Mismatch repair deficient 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 


 
 
 
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DPD 
Hydroxy ethylene diphosphonate 
DWI 
Diffusion-weighted imaging 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EoI 
End of infusion 
EoT 
End of treatment 
ESCC 
Esophageal Squamous Cell Carcinoma 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor 
FPFV 
First patient first visit 
FSH 
Follicle stimulating hormone 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
FU 
Follow-up 
G 
Grade 
GBC 
Gallbladder cancers 
GBM 
Glioblastoma multiforme 
GC 
Gastric cancer 
GCP 
Good clinical practice 
G-CSF 
Granulocyte colony stimulating factor 
GGT 
Gamma-glutamyl transferase 
GIST 
Gastrointestinal stroma tumor 
Hb 
Hemoglobin 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDP 
2,3-dicarboxypropane-1,1-diphosphonate 
Hep B/C 
Hepatitis B/C 
Hg 
Mercury 
HFSR 
Hand foot skin reaction 
HIV 
Human immunodeficiency virus 
HMDP 
Hydroxy methylene diphosphonate 
HNSCC 
Head and neck squamous-cell carcinoma 
HPV 
Human papilloma virus 
hr 
Hour(s) 
HR 
Hazard ratio 
HRT 
Hormonal replacement therapy 
IB 
Investigators brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
ICI 
Immune checkpoint inhibitor 
IDH 
Isocitrate dehydrogenase 


 
 
 
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IDO-1 
Indoleamine 2, 3-dioxygenase 1 
IEC 
Independent ethics committees 
IgG 
Immunoglobulin 
IMAE 
Immune-mediated adverse event 
IMP 
Investigational medicinal product 
IMS 
Immunogenicity analysis set 
INR 
International normalized ratio 
IO 
Immunoncology 
iRANO 
immune response assessment in neuro-oncology 
IRB 
Institutional review board 
iRECIST 
Response evaluation criteria in solid tumors for trials testing 
immunotherapeutics 
IV / i.v. 
Intravenous 
IxRS 
Interactive voice/web response system 
KIT 
Stem cell factor receptor 
LD 
Last dose 
LDH 
Lactic dehydrogenase 
LPLV 
Last patient last visit 
mAB 
Monoclonal antibody 
mCRC 
Metastatic colorectal cancer 
MDP 
Methylene diphosphonate 
MDSC 
Myeloid-derived suppressor cells 
MGMT 
O6-methylguanine DNA methyltransferase 
MKI 
Multi kinase inhibitor 
MMR 
Measles, mumps, rubella 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
MSI-H 
Microsatellite instable-high  
MSS 
Microsatellite stable 
MTD 
Maximal tolerated dose 
NA 
Not applicable 
NAB 
Neutralizing antibodies 
NCI 
National Cancer Institute 
NIMP 
Non-investigational medicinal product 
NLNT 
New lesions – non target 
NLT 
New lesions - target 
n-PKS 
Nivolumab PK analysis set 
NSCLC 
Non-small cell lung cancer 
NTRK 
Tropomyosine receptor kinase 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PDAC 
Pancreatic ductal adenocarcinoma 
PDGFR 
Platelet-derived growth factor receptor 
PD-L1/2 
Programmed cell death protein 1 ligand 1/2 
PFS 
Progression free survival 
PID 
Participant identification number 


 
 
 
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PI/ICF 
Participant information/informed consent form 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetics analysis set 
pMMR 
Proficient mismatch repair 
PO 
Per oral (route of administration) 
PR 
Partial Response 
PR-interval 
PR-interval in ECG 
PS 
Performance status 
PsP 
Pseudoprogression 
PsR 
Pseudoresponse 
PT 
Prothrombin time 
PT-INR 
Prothrombin time – international normalized ratio 
Q2/4W 
Every two/four weeks 
QD / q.d. 
Quaque die (once daily) 
QRS 
QRS interval in ECG 
QT 
QT interval in ECG 
QTcF 
QT interval corrected for heart rate F 
RAF-1 
rapidly accelerated fibrosarcoma 1 
RANKL 
Nuclear factor kappa-B ligand 
RANO 
Response assessment in neuro-oncology 
RBC 
Red blood cell count 
RCC 
Renal cell cancer 
RD 
Recurrent disease 
RECIST 
Response evaluation criteria in solid tumors 
RET 
Rearranged during transfection 
R/M 
Recurrent / metastatic 
RNA 
Ribonucleic acid 
ROS 
Roll over study 
r-PKS 
Regorafenib PK analysis set 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
SAS Institute, Cary, North Carolina, USA 
SCLC 
Small Cell Lung Cancer 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase  
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of Activities 
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reactions 
TAM 
Tumor associated macrophage 
TEAE 
Treatment-emergent adverse event 
Teff 
Effector T cell(s) 
TIE-2 
Tyrosine kinase with immunoglobulin and epidermal growth factor homology 
domain 2 
TMB 
Tumor mutational burden 
TMZ 
Temozolomide 
Treg 
Regulatory T cell(s) 


 
 
 
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TSH 
Thyroid stimulating hormone 
UC 
Urothelial carcinoma 
UGT1 
UDP-glucuronosyltransferase 1-1 
ULN 
Upper limit of normal 
UPD 
Unconfirmed progressive disease 
US 
United States 
VEGF 
Vascular endothelial growth factor  
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell count 
WHO 
World Health Organization 
WHO-DD 
World Health Organization’s Drug Dictionary 
WOCBP 
Woman of childbearing potential 
 
 
Table 10–10 Terms and Definitions 
Fluoropyrimidine 
comprises 5-fluorouracil and capecitabine 
RAVE 
Clinical data recording and management software 
 
 
 


 
 
 
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 1 (27 JAN 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The protocol amendment 01 was triggered by an amendment to nivolumab IB version 19, that 
includes updates to the management guidance for immune-mediated adverse events related to 
nivolumab and to male contraception guidance.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
 
Table 1-2 Schedule of 
activities 
Updated mention of footnotes 
on tumor assessment 
(CT/MRI) visits 
Footnote e – updated to point 
out which AEs are collected 
Table 1-3 Schedule of 
Biomarker Blood Sampling 
Updated footnote 
Schedule of Activities updated to 
more clearly define the timing of the 
CT/MRIs and the collection of AEs 
during follow-up. 
Footnote removed as it does not 
apply to study population. 
4.1.3 Active 
FU 
Added sentence on AE 
documentation after start of 
new anti-cancer treatment 
Wording was updated so only related 
AEs are collected during the follow-
up period once new anti-cancer 
treatment is started. 
4.4 End of 
Study 
Definition 
Additional wording on trial 
stop added. 
To clarify options in case the trial is 
stopped. 
5.1 Inclusion 
Criteria 
Cohort 1 
(HNSCC, IO 
naïve) 
Inclusion criteria number 102 
edited. 
Additional inclusion criteria for stage 
2 participants to clarify previous 
therapies allowed. 
5.1 Inclusion 
Criteria 
Cohort 3 
(ESCC) 
Inclusion criteria number 302 
edited. 
Additional inclusion criteria for stage 
2 participants to clarify previous 
therapies allowed. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
For all cohorts 
Inclusion criteria 9: Updated 
guidance on contraception 
after study intervention 
regarding nivolumab 
Updated guidance regarding male 
contraception based on updated 
nivolumab IB. 
5.2 Exclusion 
Criteria 
For all cohorts 
Exclusion criteria 1: Updated 
definition  
 
 
Exclusion criteria 12: 
Definition of poorly controlled 
hypertension updated to ‘above 
140/90 mmHg’ 
To clearly specify that participants 
that have known NTRK fusions are 
excluded. 
 
Updated according to most recent 
guidelines and recommendations. 
6 Study 
Intervention 
Definition of light meal added 
Additional text inserted to further 
define light meal. 
6.5.3 
Prohibited 
Prior and 
Concomitant 
Therapies 
Strong UGT1A9 inhibitors 
included as prohibited therapy. 
Updated to remain consistent with 
current regorafenib label. 
6.6.1 Toxicity 
Management 
Table 6-3 Dose Modification/ 
Dose Interruption Guide for 
Regorafenib-Related Toxicities  
 
Table 6-5 Regorafenib Dose 
Modification Guidance: Non-
Immune Toxicities: 
Hypertension 
Tables updated as per HA request. 
6.6.2 Toxicity 
Management 
6.6.2.1 
Note referring to CTCAE v5 
deleted. 
Nivolumab toxicity management 
guidelines were updated to reflect 
incorporation of CTCAE v5 as well 
as changes consistent with updated 
nivolumab immune-mediated AE 
management algorithms. 
Guidance in section 10.9 was updated 
accordingly. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Table 6-7 updated 
 
 
 
Reference to Nivolumab 
management algorithm added 
Recommended dose modification for 
nivolumab was updated according to 
the newest management algorithms 
for studies, under CTCAE v5. 
Section edited to be consistent with 
newest Nivolumab management 
algorithm. 
6.6.2.2 
Management of 
Immune-
Mediated AEs 
Definition of immune-
mediated AE added 
Make description clearer and more 
precise for the reader. 
7.1 
Discontinuation 
of Study 
Intervention 
Section Withdrawal from 
active FU edited. 
Wording updated to further clarify 
when patients must be withdrawn 
from active FU. 
8 Study 
Assessments 
and Procedures 
Sentence added on trial-
continuity issues. 
To specify possible measures in the 
event of a significant trial-continuity 
issue (e.g. caused by a pandemic). 
8.1 Efficacy 
Assessments 
Use of oral contrasts  
Specification that oral contrast agents 
are required unless inconsistent with 
local regulations. 
10.1.1 
Regulatory and 
Ethical 
Considerations 
Section edited regarding 
amendments.  
Section updated to clarify that 
substantial amendments to the 
protocol require regulatory authority 
approval before implementation. 
10.2 Appendix 
2 
Wording updated  
 
 
Updated Table 10-1 Protocol-
Required Safety Laboratory 
Assessments  
Wording updated to clarify which 
assessments are performed in the 
local laboratory. 
Table footnote updated: Amylase and 
lipase will be part of safety blood test 
conducted in each treatment cycle. 
GGT will be assessed if clinically 
indicated. 


 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
10.6 Appendix 
6 
10.6.3 RANO 
Definitions added and table 
updated. 
Section was updated to improve 
readability and clarify on RANO 
criteria definitions. 
10.9 Appendix 
9 
Update of AE management 
algorithms 
AE management algorithms were all 
updated and apply criteria from NCI-
CTCAE v5. Tables were exchanged 
accordingly. 
Throughout 
Minor editorial and clerical 
errors and document 
formatting revisions 
Minor, therefore have not been 
summarized 
A tracked changes version of the document will be provided separately. 
 
 


 
 
 
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