Clinical trial NCT04696055
Conditions: Hepatocellular Carcinoma
Keywords: Advanced or metastatic hepatocellular carcinoma (HCC) Liver cancer
Sponsor: Bayer
Start date: 2021-02-03; Completion date: 2024-04-23
Enrollment: 95 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Researchers are looking for a better way to treat people diagnosed with liver cancer which may have spread to nearby tissue and is unlikely to be cured or controlled with treatment (advanced metastatic hepatocellular carcinoma, HCC). 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 will learn more about the trial treatment, regorafenib, in a small number of participants. They will study the results when the trial treatment is taken with another cancer treatment called pembrolizumab.

There will be 2 parts to this trial. The part 1 (pilot phase) will include about 52 men and women. The part 2 (expansion phase) will include about 67 men and women. All of the participants will have HCC and will be aged 18 years or older. All of the participants will have tried other treatments that did not help their HCC. These other treatments (PD-1/PD-L1 Immune Checkpoint Inhibitors) are designed to work by stopping the activity of certain proteins in the immune system thought to play a role in HCC.

During both parts of the trial, the participants will take regorafenib and receive pembrolizumab. In the pilot phase, there will be 2 groups of participants. The group that each participant joins will be based on the treatment they already received for their HCC. The researchers will review the results in each group to learn if regorafenib and pembrolizumab are helping one group of participants more than others. Outcome of this review will determine the population to be treated in the expansion phase.

Detailed description:

Arms: arm 1: Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.
Interventions: intervention 1: Pembrolizumab intervention 2: Regorafenib (Stivarga, BAY73-4506)
Intervention descriptions: intervention 1: Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W). intervention 2: Regorafenib to be given orally (p.o.) at a starting dose of 90 mg QD for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily is well tolerated the dose should be escalated to 120 mg starting after the first 4-week cycle of regorafenib.

Protocol documents:
SAP_002.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
An Open-Label Study of Regorafenib in Combination with 
Pembrolizumab in Patients with Advanced or Metastatic 
Hepatocellular Carcinoma (HCC) after PD-1/PD-L1 Immune 
Checkpoint Inhibitors 
NCT Number: 
NCT04696055 
Document Date: 
18 APR 2024 
 
 


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Title Page 
Protocol Title: An Open-Label Study of Regorafenib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Hepatocellular Carcinoma (HCC) after PD-1/PD-L1 
Immune Checkpoint Inhibitors 
Protocol Number: 21469 
Compound Number: BAY 73-4506 
Short Title: Pilot study of Regorafenib plus Pembrolizumab in advanced HCC patients who 
have been previously treated with PD-1/PD-L1 Immune Checkpoint Inhibitors  
Sponsor Name: Non-US: Bayer AG 
US territory: Bayer HealthCare Pharmaceuticals Inc. 
Legal Registered Address: Non-US: 51368 Leverkusen, Germany  
US territory: 100 Bayer Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA 
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND: 
07564 
EudraCT: 
2020-003555-16 
 
 
Date:  18 Apr 2024 
Version: 3.0 
 
 
 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate signature document. 


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Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Version History ..................................................................................................................... 3 
1. 
Introduction ................................................................................................................... 3 
1.1 
Objectives and Endpoints ............................................................................................ 4 
1.2 
Study Design ................................................................................................................ 4 
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 of Endpoint(s) ......................................................................................... 4 
5.3.2 
Main Analytical Approach ....................................................................................... 5 
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) ........................................................................... 6 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis ................................................................. 6 
5.5.1 
Definition of Endpoint(s) ......................................................................................... 6 
5.5.2 
Main Analytical Approach ....................................................................................... 6 
5.6 
Other Safety Analyses ................................................................................................. 6 
5.6.1 
Extent of Exposure ................................................................................................... 6 
5.6.2 
Adverse Events ......................................................................................................... 7 
5.6.3 
Additional Safety Assessments ................................................................................ 7 
5.7 
Other Analyses ............................................................................................................. 7 
5.7.1 
Other Variables and/or Parameters ........................................................................... 7 
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 .......................................................................................... 7 
6.1 
Appendix 1: List of Abbreviations .............................................................................. 7 
6.2 
Appendix 2: Changes to Protocol-planned Analyses................................................... 8 
6.3 
Appendix 3: Baseline Population Characteristics ........................................................ 8 
6.4 
Appendix 4: COVID-19 Related Findings .................................................................. 8 
7. 
References ...................................................................................................................... 8 
 


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Version History 
This Statistical Analysis Plan (SAP) for study 21469 is based on the protocol version 1.0 
dated 20 AUG 2020 [1], the global amendment 1 to the protocol dated 08 JUN 2021 and the 
SAP version 1.0 and 2.0 
SAP 
Version 
Date 
Change 
Rationale 
1.0 
23 NOV 2020 
Not Applicable 
Original version 
2.0 
12 JUN 2022 
Adaptations for 
analysis of 
primary 
completion 
Recruitment prematurely stopped, affecting 
analysis of primary completion 
3.0 
31 OCT 2023 
Adaptations for  
final analysis 
 
1. 
Introduction 
This clinical study aims to evaluate the efficacy and safety of Regorafenib in combination 
with Pembrolizumab for the treatment of advanced Hepatocellular Carcinoma (HCC) in adult 
participants who have been previously treated with PD-1/PD-L1 immune checkpoint inhibitor 
in monotherapy or combinations regimens. 
Treatment of advanced HCC remains an area of high unmet need in second line (2L). 
Until 2020, only two oral multi-kinase inhibitors (MKIs), Sorafenib and Levantinib, were the 
approved first line (1L) systemic treatments for advanced HCC.  In May 2020, the Food and 
Drug Administration approved the combination of Atezolizumab, a PD-L1 checkpoint 
inhibitor, and Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth 
factor, as a frontline treatment for patients with unresectable HCC and additional phase 2 and 
3 clinical trials with immune checkpoint inhibitors in monotherapy and combination regimens 
also targeting the 1L setting are ongoing. 
For 2L the best regimen is not well established, and all the current options were approved for 
the patients who were previously treated with MKI. Therefore, an ongoing high-unmet 
medical need remains for patients with unresectable HCC who progressed or did not tolerate 
these novel immunotherapy agents. 
Regorafenib is a MKI and is the first systemic treatment shown to provide a survival benefit 
in HCC patients progressing on Sorafenib treatment [2] . Regorafenib is approved for 2L 
HCC treatment and has shown a comparable level of clinical benefit in the 2L setting as 
observed with Sorafenib as first-line therapy. Pembrolizumab, an anti-PD1 antibody, is 
approved for the treatment of patients with HCC previously treated with Sorafenib [3] . 
Targeting both the antiangiogenic and immune checkpoint pathways may provide synergistic 
anti-tumor activity. 
This SAP further describes the final analysis of the study outlined in the study protocol. 
Table, figure and listing specifications are contained in a separate document. 


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1.1 
Objectives and Endpoints 
 
Refer to main SAP v2.0, dated 12 JUN 2022  
1.2 
Study Design 
Refer to main SAP v2.0, dated 12 JUN 2022  
 
2. 
Statistical Hypotheses 
Refer to main SAP v2.0, dated 12 JUN 2022. 
 
3. 
Sample Size Determination 
Refer to main SAP v2.0, dated 12 JUN 2022. 
 
4. 
Analysis Sets 
Refer to main SAP v2.0, dated 12 JUN 2022.  
 
5. 
Statistical Analyses 
5.1 
General Considerations 
Refer to main SAP v2.0, dated 12JUN 2022. 
 
5.2 
Participant Dispositions 
The number of participants enrolled and included in each of the analysis populations will be 
tabulated. The reasons for participants excluded from each of the participants populations will 
also be tabulated. 
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. 
Protocol deviations will be summarized by country and trial unit. 
5.3 
Primary Endpoint(s) Analysis 
5.3.1 
Definition of Endpoint(s) 
The primary endpoint of this study is ORR per RECIST 1.1 by central assessment and was 
first analyzed after all participants met the criteria for primary completion. 
ORR is defined as the proportion of participants with best overall response of confirmed 
complete response (CR) or partial response (PR). 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. 


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5.3.2 
Main Analytical Approach 
 
Refer to main SAP v2.0, dated 12JUN 2022. 
5.3.3 
Sensitivity Analyses 
Not applicable. 
5.3.4 
Supplementary Analyses 
Not applicable. 
5.4 
Secondary Endpoint(s) Analysis 
5.4.1 
Key/Confirmatory Secondary Endpoint(s) 
Refer to main SAP v2.0, dated 12JUN 2022. 
5.4.1.1 
Definition of Endpoint(s) 
Refer to main SAP v2.0, dated 12JUN 2022. 
5.4.1.2 
Main Analytical Approach 
DOR based on RECIST 1.1 
DOR will be listed. 
ORR based on RECIST 1.1 
Refer to main SAP v2.0, dated 12JUN 2022. 
Safety analysis 
AEs will be classified using the NCI CTCAE grading system, version 5.0, and the most recent 
version of the Medical Dictionary for Regulatory Activities (MedDRA) terminology. A listing 
of Pre-treatment AEs will be provided. Descriptive summary tables will be presented for the 
following: 
x TEAEs by worst CTCAE grade (all and occurring in at least 5% of participants) 
x TEAEs related to any study interventions  
x TEAESI 
x TEAEs resulting in the discontinuation (of any study intervention; of Regorafenib; of 
Pembrolizumab; and of both study interventions) 
x TEAEs resulting in dose interruption (of any study intervention; of Regorafenib; of 
Pembrolizumab; and of both study interventions) 
SAEs will be classified using the most recent version of the NCI CTCAE grading system, 
version 5.0, and the most recent version of the MedDRA terminology. 
The following descriptive summary tables will be presented: 
x Treatment-emergent SAEs 
x Treatment-emergent SAEs related to any study interventions 


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The incidence of deaths in the study will be summarized by cause of death. All deaths within 
start of treatment and 30 days of last dose of study medication and between 30 days post 
permanent treatment discontinuation and 90 days after last infusion of Pembrolizumab will be 
listed by participant with last dose, start and stop date of study medication, date of death, and 
cause of death. All deaths before treatment and beyond 30 days after last dose of study 
intervention will be displayed in separate listings. 
5.4.1.3 
Sensitivity Analyses 
Not applicable. 
5.4.1.4 
Supplementary Analyses 
Not applicable. 
5.4.2 
Supportive Secondary Endpoint(s) 
Not applicable. 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
Refer to main SAP v2.0, dated 12JUN 2022. 
5.5.1 
Definition of Endpoint(s) 
Refer to main SAP v2.0, dated 12JUN 2022. 
5.5.2 
 Main Analytical Approach 
Exploratory efficacy endpoints 
Overall survival (OS) and progression free survival (PFS) will be analyzed by means of 
descriptive statistics using frequency tables for response endpoints and summary statistics for 
continuous endpoints. 
TTE variables will be summarized descriptively using summary statistics, Kaplan Meier 
methodology and plots, as well as median estimates based on Greenwood’s formula, 
including 95% two-sided confidence intervals. 
PFS rates and OS rates will be given for the time points 6, 12, 18 and 24 months, if at least 
one participant has reached this time point. 
5.6 
Other Safety Analyses 
5.6.1 
Extent of Exposure 
The treatment duration, the number of applications and the dosages of the study interventions, 
as well as the dose modifications will be summarized using descriptive statistics and 
frequency tables. Additionally, a swimmer plot for the time on study treatment will be 
provided. 
The dose of Pembrolizumab will be calculated using the formula: 
݀݋ݏ݁ሾ݉݃ሿൌ
௔௖௧௨௔௟ௗ௢௦௘௣௘௥௔ௗ௠௜௡௜௦௧௥௔௧௜௢௡ሾ௠௚ሿൈ௩௢௟௨௠௘௔௖௧௨௔௟௟௬௔ௗ௠௜௡௜௦௧௘௥௘ௗሾ௠௟ሿ
௩௢௟௨௠௘௣௥௜௢௥௧௢௜௡௙௨௦௜௢௡ሾ௠௟ሿ
  
The actual dose per day for both study interventions will be calculated using the formula: 


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ݐ݋ݐ݈ܽ݈݀ܽ݅ݕ݀݋ݏ݁ሾ݉݃ሿൌݐ݋ݐ݈ܽܽ݉݋ݑ݊ݐ݋݂݀݋ݏ݁ሾ݉݃ሿ
݀ܽݕݏ݋݊ݐݎ݁ܽݐ݉݁݊ݐ
 
 
5.6.2 
Adverse Events 
AEs are described in Section 5.4. 
5.6.3 
Additional Safety Assessments  
Refer to main SAP v2.0, dated 12JUN 2022. 
5.7 
Other Analyses 
5.7.1 
Other Variables and/or Parameters 
Percentage reduction from baseline in target lesion 
Percentage reduction from baseline will be calculated using the formula 
ܴ݁݀ݑܿݐ݅݋݊݂ݎ݋݉ܾܽݏ݈݁݅݊݁ሾΨሿൌݐݑ݉݋ݎݏ݅ݖ݁ܽݐܾܽݏ݈݁݅݊݁ሾܿ݉ሿെݐݑ݉݋ݎݏ݅ݖ݁ሾܿ݉ሿ
ݐݑ݉݋ݎݏ݅ݖ݁ܽݐܾܽݏ݈݁݅݊݁ሾܿ݉ሿ
ൈͳͲͲ 
Percentage reduction from baseline in target lesion will be analyzed separately using central 
and investigator assessment. A spider plot will be provided. 
Maximum percentage reduction from baseline in target lesion 
Best percentage reduction from baseline in target lesion is defined as the maximum of the 
percentage reduction from baseline in target lesion from all tumor assessments. The analysis 
will be conducted separately using central and investigator assessment. 
Best percentage reduction from baseline will be listed. A waterfall plot will be provided.  
In the waterfall plot showing the best percentage reduction for central assessment adjudicated 
values and values without adjudication flag will be regarded. Values with adjudication flag=N 
will be disregarded. 
5.7.2 
Subgroup Analyses 
Not applicable. 
5.8 
Interim Analyses  
Not applicable. 
5.8.1 
Data Monitoring Committee or Other Review Board 
Not applicable. 
6. 
Supporting Documentation 
6.1 
Appendix 1: List of Abbreviations 
Abbreviation 
Definition 
1L 
First line 
2L 
Second line 
AE 
Adverse event 


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AESI 
Adverse event of special interest 
CR 
Complete response 
CTCAE 
Common Terminology Criteria Adverse Event 
DOR 
Duration of response 
HCC 
Hepatocellular carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MKI 
Multi-kinase inhibitors 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PFS 
Progression free survival 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
TTE 
Time to event 
6.2 
Appendix 2: Changes to Protocol-planned Analyses 
Not applicable. 
6.3 
Appendix 3: Baseline Population Characteristics 
Refer to main SAP v2.0 dated 12 JUN 2022. 
6.4 
Appendix 4: COVID-19 Related Findings 
Refer to main SAP v2.0 dated 12 JUN 2022. 
7. 
References 
[1] Clinical Study Protocol No. 734506 / 21469, Version 1.0, dated 20 AUG 2020 
[2] Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for 
patients with hepatocellular carcinoma who progressed on sorafenib treatment 
(RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet. 
2017 Jan 7; 389(10064):56-66 
[3] Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab 
in patients with advanced hepatocellular carcinoma previously treated with sorafenib 
(KEYNOTE-224): a non-randomised, open-label phase 2 trial [published correction 
appears in Lancet Oncol. 2018 Sep;19(9):e440], Lancet Oncol. 2018 Jul;19(7):940-52. 
For further references refer to main SAP v2.0, dated 12 JUN 2022. 

Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
An Open-Label Study of Regorafenib in Combination with 
Pembrolizumab in Patients with Advanced or Metastatic 
Hepatocellular Carcinoma (HCC) after PD-1/PD-L1 Immune 
Checkpoint Inhibitors 
NCT Number: 
NCT04696055  
Document Date: 
08-Jun-2021 
 


CONFIDENTIAL
Clinical Study Protocol Global Amendment 1
BAY 73-4506 / 21469
08 JUN 2021
Title Page
Protocol Title: An Open-Label Study of Regorafenib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Hepatocellular Carcinoma (HCC) after 
PD-1/PD-L1 Immune Checkpoint Inhibitors 
Protocol Number: 21469 Global Amendment 1
Compound: BAY 73-4506
Study Phase: 2
Short Title: Pilot study of regorafenib plus pembrolizumab in advanced HCC patients who 
have been previously treated with PD-1/PD-L1 Immune Checkpoint Inhibitors
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: 075642
EudraCT: 2020-003555-16
Medical Monitor Name and Contact Information: Will be provided separately 
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 Trial Master File 
(TMF) and is available on request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.


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Clinical Study Protocol Global Amendment 1
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08 JUN 2021
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY
Document
Date
Global Amendment 1
08 JUN 2021
Original Protocol
20 AUG 2020
Amendment 1 (08 JUN 2021)
This amendment is considered substantial based on the relevant criteria of the European 
Union (EU) clinical trial legislation.
Overall Rationale for the Amendment:
The changes implemented in this protocol amendment are primarily due to health authority 
requests. 
Section Number
and Name
Description of Change
Brief Rationale
Health Authority requests
2.1 Study Rationale
Modified text regarding recent approval for 
atezolizumab/bevacizumab and 
nivolumab/ipilimumab
Clarification of meaning
2.3.2 Benefit 
Assessment; and 
11 References
Updated DOR information from the phase 
IB/II trial of lenvatinib plus pembrolizumab,
and new reference cited
Correction of information cited
5.1 Inclusion 
Criteria; and 10.4.2 
Contraception
Clarified duration of contraception use
Align with wording of 
Investigator’s Brochure (IB)
5.2 Exclusion 
criteria
Changed the definition of uncontrolled 
hypertension to systolic blood pressure of 
≥140 mmHg, diastolic blood pressure of ≥90 
mmHg
Updated definition of 
uncontrolled hypertension
5.2 Exclusion 
criteria
Added gastrointestinal perforation or fistula
Align with wording of 
regorafenib Summary of 
product characteristics 
(SmPC)
5.2 Exclusion 
criteria; and 6.5.3 
Prohibited Prior and 
Concomitant 
Therapies
Excluded patients using strong 
UGT1A9 inhibitors within 2 weeks 
prior to starting study intervention, and 
added a recommendation to avoid co-
administration of strong UGT1A9 
inhibitors during regorafenib treatment
6.6 Dose 
Modification 
(Table 6–3)
Added guidance for regorafenib for Grade 3 
and Grade 4 non-hematologic toxicities for 
current evidence of gastrointestinal 
perforation or fistula, and cardiac ischemia 
and/or infarction
6.6.2 Dose 
Modification and 
Management of 
Liver Toxicity (Table 
6–5)
Added guidance for monitoring liver 
toxicities for regorafenib for ALT/AST 
elevations; aligned AST/ALT values in text 
and table
Align with wording of 
regorafenib SmPC


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Section Number
and Name
Description of Change
Brief Rationale
10.2 Appendix 2: 
Clinical Laboratory 
Tests (Table 10–2)
Updated to mandate an amylase 
assessment in Panel A laboratory tests
6.6.3 Dose 
Modification and 
Toxicity 
Management for 
Immune-related 
AEs Associated 
with 
Pembrolizumab 
(Table 6–7)
Added guidance for Grade 3 irAEs that 
require discontinuation from 
pembrolizumab. Added guidance for 
neurological toxicities and exfoliative 
dermatologic conditions. Updated guidance 
for all other irAEs as well as myocarditis. 
Added footnote for T1DM, G3/4 
hypophysitis, G3/4 and hyperthyroidism. 
Added grading guidance for nephritis and 
renal function. Specified that discontinuation 
is permanent.
Align with wording of 
pembrolizumab SmPC and 
due to an update of 
pembrolizumab IB; dose 
modification guidelines for 
irAEs associated with 
pembrolizumab were updated
6.6.2.1 Hepatic 
Events of Clinical 
Interest (Table 6–6); 
and 10.2 Appendix 2: 
Clinical Laboratory 
Tests (Table 10–3)
Added HCV serotyping if genotyping is not 
available for HCV infection and 
recurrence/flare
Increase flexibility in HCV 
assessments
Other changes (unrelated to health authority requests)
1.1 Synopsis;     4.1 
Overall Design; and 
5.1 Inclusion 
Criteria
Added that Cohort 1 includes participants 
treated with atezolizumab plus bevacizumab
only, and specified that all participants must 
have had only one prior line of systemic
immunotherapy treatment with a PD-1/PD-
L1 mAb
Clarification of meaning
1.3.1 Schedule of 
Activities   (Table 1–
1); and 10.2 
Appendix 2: Clinical 
Laboratory Tests 
(Table 10–1)
Added optional Panel A laboratory 
assessment on W1D1
Panel A tests are to be 
performed within 7 days of the 
first study intervention
(W1D1). If the tests were 
performed in screening but >7 
days before W1D1, the tests 
would need to be performed 
again on W1D1 to have
updated tests and ensure 
patient eligibility
1.3.1 Schedule of 
Activities   (Table 1–
1); and 8.2.2 Vital 
Signs 
Added flexibility to the relative timing of 
collection of vital signs and ECG; removed 
vital signs assessment in screening within 
28 days prior to the first dose
To support best practices at 
hospitals and facilities; not 
necessary to collect vital signs 
twice during screening
1.3.3 
Pharmacokinetic 
and 
Immunogenicity 
Sampling 
(Table 1–3)
Replaced “extension” with “expansion” in 
the table footnotes
Consistency throughout the 
protocol


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Section Number
and Name
Description of Change
Brief Rationale
2.1 Study 
Rationale; 2.2.1 
Hepatocellular 
Carcinoma; 2.2.4 
Combination of 
Regorafenib and 
Anti-PD-1 Antibody;
2.3.2 Benefit 
Assessment; 4.3 
Justification for 
Dose; and
11 References
Updated results for Phase 1b study 19497; 
updated overall survival results data and 
reference for IMbrave study
New results and additional 
follow-up data available
4.1.1.2 Intervention 
Period; 4.3 
Justification for 
Dose; 6 Study 
Intervention; and 
6.1 Study 
Intervention(s) 
Administered (Table 
6–1)
Modified the timing of regorafenib dose 
escalation, so it is allowed any time after the 
first cycle of regorafenib; removed the 
consultation with the sponsor in case of a 
decision not to escalate the dose
To allow more flexibility in the 
timing of dose escalation and 
to align with the regorafenib 
clinical oncology development 
program.
5.1 Inclusion 
Criteria
Updated Criterion #4 for duration of prior 
PD-1/PD-L1 treatment
To exclude hyper-progressors 
from the study 
Re-worded Criterion #4 to be more precise
Clarification of eligibility after 
disease progression
Specified a time window for Criteria #7 
and #8
Alignment with the SoA
5.2 Exclusion 
Criteria; 
6.5 Concomitant
Therapy; and 6.5.3 
Prohibited Prior and 
Concomitant 
Therapies 
Modified the vaccination criteria to exclude 
patients receiving recent live attenuated 
replication competent vaccines and to allow 
vaccines in a pandemic-related context
Clarification of vaccination 
criteria
6.6.1 Dose 
Modification and 
Management of 
Lower Gastro-
intestinal Toxicity 
(Table 6–4)
Updated dose modification guidance for 
Grade 2 diarrhea 
Align with wording of 
pembrolizumab SmPC
6.6.2.1 Hepatic 
Events of Clinical 
Interest
Updated ALT criteria for hepatic events of 
clinical interest
Align with available regulatory 
guidance
8.1 Efficacy 
Assessments
Updated the timing of tumor assessments 
after participants discontinue study 
treatment without confirmed radiological 
disease progression
Consistency throughout the 
protocol
Updated the review of centrally collected 
imaging data
Alignment of language with 
the central analysis plan


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Section Number
and Name
Description of Change
Brief Rationale
8.2.6 Baseline 
Characteristics
Specified that TMB, MSI, and PD-L1 
expression are to be collected only if results 
are available
Clarification of data collection
Corrected the time window of collection of 
medications taken prior to study intervention
Consistency throughout the 
protocol
8.8 Biomarkers
Modified sentence on biomarker reporting
Clarification of meaning
9.2. Sample size 
determination
Updated the number of responders required 
to rule out an ORR of ≤ 20% in scenario 2:
34 responders are sufficient to rule out an 
ORR ≤20% using an exact binomial test
Correction of error 
9.4.2 Safety 
Analyses
Specified that in the pilot phase, safety 
analyses will be done by first line treatment 
only and not overall
The analyses are planned to
identify the respective safety 
profile of the drug combination 
in each of the two populations
Updated details regarding analysis of 
laboratory abnormalities
In clinical trials using 
CTCAE v.5.0, values of 
laboratory parameters are no 
longer graded
10.5.2 mRECIST 
for HCC
Described that non-enhancing atypical liver 
lesions can be selected as target lesions if 
needed but typical liver lesions should be 
prioritized; updated the criteria for complete 
response related to porta hepatis lymph 
nodes
Clarification of measurable 
disease within the liver 
parenchyma
10.5.3 iRECIST 
(Table 10–11)
Removed tumor imaging timing details, 
instead refer to the SoA
Consistency throughout the 
protocol
Throughout
Made several minor editorial and document 
formatting revisions, which are not 
summarized
Consistency, readability
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............................................................... 2
Table of Contents ..................................................................................................................... 6
Table of Tables ......................................................................................................................... 9
Table of Figures........................................................................................................................ 9
1.
Protocol Summary .......................................................................................................... 10
1.1
Synopsis......................................................................................................................... 10
1.2
Schema........................................................................................................................... 13
1.3
Schedule of Activities (SoA) ......................................................................................... 14
1.3.1
Schedule of Activities................................................................................................. 14
1.3.2
Biomarker Sampling................................................................................................... 24
1.3.3
Pharmacokinetic and Immunogenicity Sampling....................................................... 25
2.
Introduction..................................................................................................................... 26
2.1
Study Rationale.............................................................................................................. 26
2.2
Background.................................................................................................................... 27
2.2.1
Hepatocellular Carcinoma.......................................................................................... 27
2.2.2
Regorafenib ................................................................................................................ 29
2.2.3
Pembrolizumab........................................................................................................... 31
2.2.4
Combination of Regorafenib and Anti-PD-1 Antibody ............................................. 32
2.3
Benefit/Risk Assessment ............................................................................................... 33
2.3.1
Risk Assessment......................................................................................................... 33
2.3.2
Benefit Assessment .................................................................................................... 33
2.3.3
Overall Benefit / Risk Assessment............................................................................. 34
3.
Objectives and Endpoints............................................................................................... 34
4.
Study Design .................................................................................................................... 36
4.1
Overall Design ............................................................................................................... 36
4.1.1
Study Periods.............................................................................................................. 37
4.2
Scientific Rationale for Study Design ........................................................................... 38
4.3
Justification for Dose..................................................................................................... 39
4.4
End of Study Definition................................................................................................. 41
5.
Study Population............................................................................................................. 42
5.1
Inclusion Criteria ........................................................................................................... 42
5.2
Exclusion Criteria .......................................................................................................... 45
5.3
Lifestyle Considerations ................................................................................................ 48
5.4
Screen Failures............................................................................................................... 48
6.
Study Intervention .......................................................................................................... 49
6.1
Study Intervention(s) Administered............................................................................... 51
6.2
Preparation/Handling/Storage/Accountability............................................................... 51
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 52
6.4
Study Intervention Compliance ..................................................................................... 52
6.4.1
Pembrolizumab........................................................................................................... 52
6.4.2
Regorafenib ................................................................................................................ 52
6.5
Concomitant Therapy .................................................................................................... 53


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6.5.1
Drug-drug Interactions Relevant for Regorafenib...................................................... 54
6.5.2
Drug-drug Interactions Relevant for Pembrolizumab ................................................ 55
6.5.3
Prohibited Prior and Concomitant Therapies ............................................................. 55
6.5.4
Permitted Concomitant Therapies .............................................................................. 56
6.5.5
Post-study Therapy..................................................................................................... 58
6.6
Dose Modification ......................................................................................................... 58
6.6.1
Dose Modification and Management of Lower Gastrointestinal Toxicity................. 63
6.6.2
Dose Modification and Management of Liver Toxicity............................................. 64
6.6.3
Dose Modification and Toxicity Management for Immune-related AEs Associated 
with Pembrolizumab................................................................................................... 70
6.6.4
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab........................................................................................................... 72
6.6.5
Rescue Medication and Supportive Care.................................................................... 75
6.7
Intervention after the End of the Study.......................................................................... 75
7.
Discontinuation of Study Intervention and Participant Discontinuation / 
Withdrawal...................................................................................................................... 75
7.1
Discontinuation of Study Intervention........................................................................... 76
7.1.1
Withdrawal Criteria.................................................................................................... 76
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 78
7.3
Lost to Follow-up........................................................................................................... 79
8.
Study Assessments and Procedures............................................................................... 79
8.1
Efficacy Assessments .................................................................................................... 80
8.2
Safety Assessments........................................................................................................ 82
8.2.1
Physical Examinations................................................................................................ 83
8.2.2
Vital Signs .................................................................................................................. 83
8.2.3
Electrocardiograms..................................................................................................... 83
8.2.4
Clinical Safety Laboratory Assessments .................................................................... 84
8.2.5
ECOG Performance Status......................................................................................... 84
8.2.6
Baseline Characteristics.............................................................................................. 85
8.3
Adverse Events and Serious Adverse Events ................................................................ 86
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 86
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 87
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 87
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 87
8.3.5
Pregnancy ................................................................................................................... 88
8.3.6
Adverse Events of Special Interest............................................................................. 88
8.4
Treatment of Overdose .................................................................................................. 88
8.5
Pharmacokinetics........................................................................................................... 89
8.6
Pharmacodynamics ........................................................................................................ 90
8.7
Genetics ......................................................................................................................... 90
8.8
Biomarkers..................................................................................................................... 90
8.8.1
Pharmacodynamics Biomarkers ................................................................................. 91
8.8.2
Biomarkers that May Associate with Response ......................................................... 91
8.8.3
Other Biomarkers ....................................................................................................... 92
8.9
Immunogenicity Assessments........................................................................................ 92
8.10
Medical Resource Utilization and Health Economics ................................................... 92
9.
Statistical Considerations ............................................................................................... 92


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9.1
Statistical Hypotheses.................................................................................................... 93
9.2
Sample Size Determination ........................................................................................... 93
9.3
Populations for Analyses ............................................................................................... 94
9.4
Statistical Analyses........................................................................................................ 94
9.4.1
Efficacy Analyses....................................................................................................... 94
9.4.2
Safety Analyses .......................................................................................................... 95
9.4.3
Other Analyses ........................................................................................................... 95
9.5
Interim Analyses............................................................................................................ 95
9.6
Data Monitoring Committee (DMC) or other Review Board........................................ 96
10. Supporting Documentation and Operational Considerations .................................... 96
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 96
10.1.1
Regulatory and Ethical Considerations ...................................................................... 96
10.1.2
Financial Disclosure ................................................................................................... 97
10.1.3
Informed Consent Process.......................................................................................... 97
10.1.4
Data Protection ........................................................................................................... 97
10.1.5
Committees Structure ................................................................................................. 97
10.1.6
Dissemination of Clinical Study Data ........................................................................ 98
10.1.7
Data Quality Assurance.............................................................................................. 98
10.1.8
Source Documents...................................................................................................... 99
10.1.9
Study and Site Start and Closure................................................................................ 99
10.1.10 Publication Policy..................................................................................................... 100
10.2
Appendix 2: Clinical Laboratory Tests........................................................................ 101
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................ 105
10.3.1
Definition of AE....................................................................................................... 105
10.3.2
Definition of SAE..................................................................................................... 106
10.3.3
Recording and Follow-up of AE and/or SAE........................................................... 107
10.3.4
Reporting of SAEs.................................................................................................... 108
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information....... 110
10.4.1
Definitions ................................................................................................................ 110
10.4.2
Contraception ........................................................................................................... 110
10.4.3
Pregnancy ................................................................................................................. 112
10.5
Appendix 5: Tumor response criteria (RECIST 1.1, mRECIST for HCC, and 
iRECIST) ..................................................................................................................... 113
10.5.1
RECIST 1.1 .............................................................................................................. 113
10.5.2
mRECIST for HCC .................................................................................................. 117
10.5.3
iRECIST ................................................................................................................... 123
10.6
Appendix 6: CYP3A4 Inhibitors and Inducers............................................................ 129
10.7
Appendix 7: New York Heart Association Functional Classification......................... 130
10.8
Appendix 8: Barcelona Clinic Liver Cancer (BCLC) Classification........................... 130
10.9
Appendix 9: Child-Pugh Classification ....................................................................... 131
10.10 Appendix 10: Guideline for Diagnosing Esophageal Varices..................................... 131
10.11 Appendix 11: AASLD Practice Guideline (Diagnostic Algorithm for HCC)............. 132
10.12 Appendix 12: Abbreviations........................................................................................ 132
10.13 Appendix 13: Protocol Amendment History ............................................................... 137
11. References ...................................................................................................................... 137


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Table of Tables
Table 1–1: Schedule of Activities ............................................................................................ 14
Table 1–2: Schedule of Biomarker Blood Sampling ............................................................... 24
Table 1–3: Pharmacokinetic and Immunogenicity Sample Collection Plan............................ 25
Table 3–1: Objectives and Endpoints....................................................................................... 34
Table 5–1: Adequate Organ Function Laboratory Values ....................................................... 43
Table 6–1: Administration of Study Intervention .................................................................... 51
Table 6–2: Regorafenib Dose Reduction Scheme.................................................................... 59
Table 6–3: Dose Modification Guidance, Non-immune Toxicities......................................... 60
Table 6–4: Dose Modification Guidance, Lower Gastrointestinal Toxicity............................ 63
Table 6–5: Dose Modification Guidance; Specific Guidance for Liver Toxicity.................... 65
Table 6–6: Guidance on Assessment and Further Dosing Following Occurrence of Hepatic 
Events of Clinical Interest ..................................................................................... 67
Table 6–7: Dose Modification Guidance, Other Immune-related Adverse Events ................. 70
Table 6–8: Dose Modification Guidance, Pembrolizumab-associated Infusion Reactions..... 73
Table 8–1: Definitions for ECOG PS Grading......................................................................... 85
Table 9–1: Populations for Analyses ....................................................................................... 94
Table 10–1: Laboratory Testing Standard Schedule.............................................................. 101
Table 10–2: Protocol-Required Safety Laboratory Assessments per panel........................... 102
Table 10–3: Hepatitis Virus Panel ......................................................................................... 104
Table 10–4: Highly Effective Contraceptive Methods .......................................................... 111
Table 10–5: RECIST 1.1: Response for Participants with Target and Non-target Lesions... 116
Table 10–6: RECIST 1.1: Response for Participants with Non-target Lesions Only............ 116
Table 10–7: mRECIST: Response for Participants with Target and Non-target Lesions...... 120
Table 10–8: mRECIST: Response for Participants with Non-target Lesions Only............... 121
Table 10–9: Response for Participants with Target and Non-target Lesions......................... 123
Table 10–10: Response for Participants with Non-target Lesions Only................................ 123
Table 10–11: Imaging and Treatment after First Radiologic Evidence of PD....................... 127
Table 10–12: Overview of CYP3A4 Inducers and Strong CYP3A4 Inhibitors .................... 129
Table of Figures
Figure 1–1: Study Schema ....................................................................................................... 13
Figure 4–1: Study Design......................................................................................................... 36
Figure 4–2: Study Design and Planned Analyses .................................................................... 39
Figure 10–1: iRECIST: Process for Assessment of Disease Progression.............................. 128
Figure 10–2: BCLC Staging and Treatment Strategy............................................................ 130


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: An Open-Label Study of Regorafenib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Hepatocellular Carcinoma (HCC) after PD-1/PD-L1 
Immune Checkpoint Inhibitors 
Short Title: Pilot study of regorafenib plus pembrolizumab in advanced HCC patients who 
have been previously treated with PD-1/PD-L1 Immune Checkpoint Inhibitors
Rationale: Recent clinical data support immunotherapy with checkpoint inhibitors as 
treatment options in first line (1L) for patients with advanced HCC, including nivolumab and 
pembrolizumab in monotherapy regimens and the recently approved combinations of 
atezolizumab and bevacizumab, and nivolumab in association with ipilimumab. In addition, 
other combination treatments with PD-1/PD-L1 inhibitors, such as durvalumab in association 
with tremelimumab, atezolizumab in association with cabozantinib, and pembrolizumab in 
association with levantinib, among others, are being assessed in Phase 3 trials.
The approved regimens in 1L have demonstrated superior survival benefits in the HCC patient 
population when compared to the current standard of care with oral multi-kinase inhibitors, 
such as sorafenib. However, a high unmet clinical need remains for patients with advanced 
HCC who have progressed on 1L treatment options with immunotherapy agents.
The rationale for combining immunotherapy with anti-angiogenic treatments in second line
(2L) is supported by promising clinical activity observed in early phase trials for treatment-
refractory cancers, such as metastatic renal cell carcinoma (RCC), after progression with a 
PD-1/PD-L1 immune checkpoint inhibitor (Lee et al. 2020).
Regorafenib is an oral small molecule that potently blocks multiple protein kinases and is 
approved for the treatment of HCC in patients who progressed after 1L therapy with 
sorafenib. Pembrolizumab is a highly selective and potent humanized immunoglobulin G4 
(IgG4) monoclonal antibody that binds to the PD-1 receptor, blocking interaction with PD-
-L1 and PD-L2, thereby enhancing the functional activity of the target lymphocytes to 
facilitate tumor regression. Pembrolizumab has also demonstrated a survival benefit in 
patients who have progressed on initial treatment with sorafenib. Based on complementary 
modes of action between multi-kinase inhibitors (MKIs) and PD-1 inhibitors and their 
potentially synergistic effects on the cancer-immunity pathway, the combination of 
regorafenib and pembrolizumab might provide a greater clinical benefit in HCC patients.


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Objectives and Endpoints (Primary and Secondary):
Objectives
Endpoints
Primary
Pilot and Expansion phases 
To demonstrate the objective anti-tumor 
activity of regorafenib in combination 
with pembrolizumab as a 2L treatment 
for advanced HCC
Objective response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors, version 1.1
(RECIST 1.1) by central assessment
Secondary
Pilot and Expansion phases 
To evaluate other measures of anti-
tumor activity of regorafenib in 
combination with pembrolizumab as a 
2L treatment for advanced HCC

Duration of response (DOR) per RECIST 1.1 by 
central assessment 

Objective response rate (ORR) per RECIST 1.1 by 
investigator assessment

Duration of response (DOR) per RECIST 1.1 by 
investigator assessment
To evaluate safety and tolerability of 
regorafenib in combination with 
pembrolizumab

Number of participants with adverse events (AEs)

Number of participants with serious adverse events 
(SAEs)

Number of participants with safety-relevant changes 
in clinical parameters 

Number of participants with dose modification (dose 
interruption, dose reduction, dose discontinuation)
2L = second line; AE = adverse event; DOR = duration of response; HCC = hepatocellular 
carcinoma; ORR= objective response rate; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors 1.1; SAE = serious adverse event 
Overall Design: This is a multicenter, open-label, single arm, Phase 2 trial of regorafenib in 
combination with pembrolizumab.
Patients with advanced or metastatic HCC who have received only one line of systemic 
therapy with PD-1/PD-L1 immune checkpoint inhibitors will be enrolled. All participants will 
be assigned to receive a starting dose of regorafenib of 90 mg every day (QD) for 3 weeks of 
every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg QD is well tolerated 
after the first 4-week cycle of regorafenib, the dose should be escalated to the established 
MTD for regorafenib for this treatment combination (120 mg, QD) on the 3 weeks on/ 1 week 
off schedule. Participants will be treated with 400 mg pembrolizumab intravenously (IV) 
every 6 weeks (Q6W). 
The study is divided into an initial pilot phase and an expansion phase. Results from the pilot 
phase will inform the selection of the appropriate population for further study in the 
expansion phase.


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a) Pilot phase: Approximately 52 participants will be enrolled to receive regorafenib in 
combination with pembrolizumab
o
Cohort 1: 26 participants after one systemic line of therapy consisting of 
atezolizumab plus bevacizumab treatment combination only
o
Cohort 2: 26 participants after one systemic line of therapy consisting of any IO 
containing first line treatment (excluding atezolizumab with or without 
bevacizumab) in monotherapy or combination regimens
b) Expansion phase: If the target ORR is achieved in the pilot phase (i.e. at least 
8 responders out of 26 treated in cohort 1 or at least 8 responders in each cohort), the 
study can enroll approximately 67 new additional participants. These additional 
participants can be from cohort 1 (i.e. patients progressing on atezolizumab plus 
bevacizumab combination) or the combined population from cohort 1 plus cohort 2 
(i.e., patients progressing on any immune checkpoint inhibitor), depending on which 
cohorts meet the response rate criteria for expansion.
Disclosure Statement: This is an open-label sequential treatment study with a single arm, 
consisting of a pilot phase and an expansion phase.
Number of Participants: Approximately 170 participants will be screened to achieve a target 
of approximately 119 treated participants in total, including the pilot and expansion phases.
Note: "Enrolled" means a participant's, or their legally acceptable representative’s (if 
acceptable by local law), agreement to participate in a clinical study following completion of 
the informed consent process. 
Intervention Groups and Duration: In the pilot phase, participants will be enrolled in two 
cohorts based on the treatment received in first line. The participant population for the 
expansion phase will be determined based on the pilot phase.
The start of the screening period is defined by signing of the informed consent form (ICF).
Participants will be screened for eligibility up to 28 days prior to Week 1 Day 1 (W1D1)
The start of the intervention period is defined by the first administration of the study 
intervention combination. Participants will be treated in 6-week cycles for pembrolizumab 
(400 mg IV, Q6W) and in 4-week cycles for regorafenib. Regorafenib will be administered 
orally (90 mg, QD starting dose) on a 3 weeks on / 1 week off schedule. If the starting dose of 
90 mg QD is well tolerated after the first 4-week cycle of regorafenib, the dose should be 
escalated to the established MTD for regorafenib for this treatment combination (120 mg, 
QD) on the 3 weeks on/ 1 week off schedule. Participants will receive study intervention until 
disease progression (as defined by RECIST 1.1), unacceptable toxicity, consent withdrawal, 
withdrawal from the study at the discretion of the investigator or his/her designated 
associate(s), or until any other withdrawal criteria are met. Treatment beyond radiological 
progression is possible if the participant is still benefiting from treatment.
Participants who complete 18 infusions of pembrolizumab (after approximately 2 years of 
treatment) need to discontinue treatment with pembrolizumab. Regorafenib treatment can be 
continued beyond 2 years until withdrawal criteria are met.
After permanent discontinuation from study intervention, the active follow-up period begins,
including safety and efficacy follow-up visits. An end of treatment (EoT) visit will be 


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performed first, within 14 days (window of +7 days) after the last dose of study intervention 
or decision to discontinue intervention. A safety follow-up visit will take place 30 days 
(window of +7 days) after the last administration of study intervention, and additionally, 
90 days (window of +7 days) after the last administration of pembrolizumab. Efficacy follow-
up visits will take place for participants who discontinued study intervention for reasons other 
than radiologically confirmed progressive disease (PD), death, withdrawal of consent, or lost 
to follow-up. These visits include tumor assessments, study intervention-related toxicity/AEs, 
and information about subsequent anti-cancer therapy. Active follow-up will be terminated by 
radiological PD, the start of a new anti-cancer treatment, death, withdrawal of consent for 
further participation, or lost to follow-up.
After completion of the active follow-up period, participants will enter the long-term follow-
up period. Participants will be followed for survival status and subsequent anti-cancer therapy 
by a telephone call at 3-month intervals (± 14 days) until the end of the study, withdrawal of 
consent, lost to follow-up, or death, whichever comes first.
Data Monitoring Committee: Not applicable
1.2
Schema
An overview of the study schema is presented in Figure 1–1.
Figure 1–1: Study Schema
EoT = End of treatment; FU = follow-up; W1D1 = Week 1 Day 1
The overall study design (see Figure 4–1) is described in Section 4.1. 


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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities
Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Informed 
consent
X
IxRSa
X
-----------------------------------------------------------------------------
Contact the IxRS 
as described in a
General
Demography
X
See Section 8.2.6
Medical history 
(including 
substance 
usage: drugs, 
alcohol, 
tobacco, and 
caffeine)
X
Prior disease 
histology, 
diagnosis, disease 
classification, 
treatments, co-
existing diseases, 
prior surgery, and 
allergy history
Inclusion and 
exclusion 
criteria
X
X
X
Re-check status 
before 1st dose of 
study medication


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
BCLC staging 
X
See Appendix 8, 
Section 10.8
AFP 
X
X
Child-Pugh 
score
X
See Appendix 9, 
Section 10.9
History of prior 
anti-cancer 
treatment 
X
Systemic therapy, 
surgery, loco-
regional therapy 
and radiotherapy


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Blood or urine 
pregnancy test 
if applicable 
(women of 
childbearing 
potential only)b
Xf
Monthly 
X
X
Monthly testing 
should be 
conducted as per 
local regulations 
where applicable, 
up to and 
including 
whichever is 
latest: the safety 
FU visit or 
4 months after the 
last 
pembrolizumab 
infusion
Hepatitis B and 
C screening, 
Hepatitis virus 
panel
X
If clinically indicated 
See Table 10–3
Safety 
See Section 8.2


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
12-lead ECG
X
X
X
See Section 8.2.3; 
must be preceded 
by 5 minutes of 
rest
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.2; 
must be preceded 
by 5 minutes of 
rest
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.5
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
After EoT: Up to 
30 (+7) days after 
last regorafenib or 
pembrolizumab 
dose; up to 90
(+7) days for SAE 
related to 
pembrolizumab 
unless a new 
anticancer therapy 
has been initiated
See Section 8.3


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Concomitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
After EoT: Up to 
30 (+7) days after 
last regorafenib or 
pembrolizumab 
dose; up to 90 
(+7) days for
concomitant 
medication for
SAE related to 
pembrolizumab 
unless a new 
anticancer therapy 
has been initiated
Full physical 
examination 
X
X
X
See Section 8.2.1
Directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.1
Laboratory assessments 
See Section 8.2.4
Panel A
X
Xj
X
X
X
X
X
See Section 10.2
Panel B 
X
X
X
X
X
X
X
X
X
X
See Section 10.2


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Treatment intervention 
Pembrolizumab 
infusion
X
X
X
X
X
Every 6 weeks 
until a maximum 
of 18 infusions are 
completed
Regorafenib 
and diary 
dispensing
X
X
X
X
X
X
Regorafenib 
administrationc
X
X
X
X
X
X
X*
X*
X*
X*
X*
X*
The regorafenib 
break must not be 
shorter than
7 days and should 
not be longer than 
10 days.
* 3 weeks on, 
1 week off, QD.


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Drug 
accountability, 
collect unused 
study 
intervention and 
check 
participant diary
X
X
X
X
X
X
Efficacy






Tumor 
assessment
X
Every 6 weeks (±7days) until PD during the first 54 weeks of treatment; Every 9 weeks (±7days) until 
PD afterwards
Schedule for 
tumor 
assessments to 
be followed 
regardless of 
potential dose 
delays for either 
drug.
See Section 8.1
for details 
Survival status
X


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Review of 
subsequent 
anti-cancer 
therapy
X
X
Research sample collection
Regorafenib PK 
sampling
X
X
X
X
X
See Table 1–3 for 
details, and see 
Section 8.5
Pembro PK 
sampling
See Table 1–3 for sampling time points
IM sampling
See Table 1–3 for sampling time points
Biomarker 
blood sampling
See Table 1–2 for sampling time points
Biomarker 
baseline tumor 
tissuesd
X
See Section 8.8


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
Biomarker on-
treatment / EoT
tumor tissuee
X*
X**
*Mandatory if 
medically feasible 
on W6D1 (+/- 3 
days)
**Optional biopsy
at EoT (+7 days)
for BM collection 
after progression
See Section 8.8
admin. = administration; AE = adverse event; AFP = alpha-fetoprotein; BCLC = Barcelona Clinic Liver Cancer staging; BM = biomarker; D = day; DC = discontinuation of study intervention;
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance status; eCRF = electronic case report form; EoT = end of treatment; FU = follow-up; hCG = human 
chorionic gonadotropin; IM = immunogenicity; IxRS = Interactive Voice/Web Response System; PD = progressive disease; pembro = pembrolizumab; PI/ICF = patient information/Informed 
consent form; PK = pharmacokinetic(s); Q4W = every 4 weeks; Q6W = every 6 weeks; QD = once daily; rego = regorafenib; SAE = serious adverse event; subseq = subsequent; W = week(s)
a. Contact the IxRS to record the following: 1. To register the participant who has signed the PI/ICF (a unique participant identifier will be assigned), 2. In case the participant is a screening failure, 
3. On the week of every pembrolizumab infusion so that the specific participant drug vial(s) can be provided for dispensing purposes, 4. On every 4th week so that the specific participant drug 
bottle(s) of regorafenib can be provided for dispensing purposes, 5. In case the participant has discontinued study intervention (EoT) for any reason.
b. Highly sensitive (serum or urine) hCG pregnancy test (as needed for women of childbearing potential). Postmenopausal women who have not had periods for more than 1 year or surgically 
sterilized women will not be required to undergo a pregnancy test (this information should be recorded under medical history on the eCRF). 
c. Site personnel are asked to call participants for at least the first 3 cycles to remind them of omitting regorafenib during the 4th week of a cycle.
d. Provision of recent tumor tissue (i.e. tumor tissue obtained within 180 days of enrollment and after the last dose of most recent anti-cancer therapy OR a new biopsy) is mandatory for all 
participants at screening. Exceptions will be accepted for participants with no recent baseline tumor tissues after documented discussion and approval by the sponsor. Archival tumor tissue is 
mandatory if available.
e. On treatment: W6D1 (± 3 days), mandatory if medically feasible. At progression: EoT (+7 days), optional. The lesion accessible for biopsy may not be the only target lesion and should not be 
located in a previously irradiated field. Ideally, the same lesion should be biopsied before treatment and on treatment whenever possible.
f. Pregnancy testing should be done within 24 hours before the first dose for urine and within 72 hours before the first dose for serum.


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Table 1–1: Schedule of Activities
Procedure
Screening
Intervention Period (weeks)
End of 
treatment 
(DC)
Active follow-up
Long-
term 
follow-
up visits 
after DC 
Notes
Safety follow-up 
visits
Efficacy
follow-
up visits 
until PD
Within 
28 
days 
prior to 
the 
first 
dose
Within 
7 days 
prior to 
the 
first 
dose
W
1
D1
W
2
D1
W
3
D1
W
4
D1
W
5
D1
W
6
D1
W
7
D1
W
8
D1
W
9
D1
W 
13
D1
W 
17
D1
W 
19
D1
Subseq
pembro 
infusion 
visit
Q6W
Subseq 
rego 
admin. 
visit 
Q4W
Within 14 
days after 
last dose
or DC 
decision
(both rego 
and 
pembro)
30 days 
after 
last 
study 
dose
90 days 
after last 
pembro 
infusiong
Every 6 
weeks / 
Every 9 
weeksh
Every 3 
months
Visit window
± 3 days
+7 days
+7 days
+7 days
±7days
±14 days
g. If pembrolizumab is permanently discontinued first and the day 90 safety follow-up visit after the last dose of pembrolizumab falls into the regorafenib treatment period or regorafenib day 30 
safety follow-up period, no separate pembrolizumab day 90 safety follow-up visit is necessary as the information gathering and examinations will occur with regorafenib treatment cycle visit, 
EoT visit, or day 30 safety follow-up visit (required for either regorafenib, pembrolizumab, or combination). All pregnancies and exposure during breastfeeding should be collected from the 
start of study intervention through 120 days following discontinuation of study intervention, or 30 days following discontinuation of study intervention if the participant initiates new anti-cancer 
therapy.
h. Every 6 weeks (±7 days) until PD during the first 54 weeks of treatment; every 9 weeks (±7days) until PD afterwards
i. Study intervention-related AEs only
j. Optional; however, Panel A is required on W1D1 if screening tests were not completed within 7 days of first study intervention.


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1.3.2
Biomarker Sampling
Table 1–2: Schedule of Biomarker Blood Sampling
Procedure
Screening
Intervention Period (weeks)a
End of 
treatment 
(DC)
Within 
28 days 
prior to 
the first 
dose
Within   
7 days 
prior to 
the first 
dose
W1
D1
W2
D1
W3
D1
W4
D1
W5
D1
W6
D1
W7
D1
W8
D1
W9
D1
W13
D1
W19
D1
W25
D1
Within 14 
days after 
last dose or 
DC decision 
(DC of both 
rego and 
pembro)
± 3 days
+ 7 days
Whole blood for 
pharmacogenetics
X
Biomarker blood for 
flow cytometry 1b
X
X
X
X
X
X
X
X
X
X
Biomarker blood for 
flow cytometry 2b
X
X
X
X
X
X
X
X
X
X
Biomarker serum
X
X
X
X
X
X
X
X
X
X
Biomarker plasma 
X
X
X
X
X
X
X
X
X
X
Biomarker plasma 
for ctDNA 
X
X
X
X
X
X
X
X
ctDNA = circulating tumor deoxyribonucleic acid; D = day; DC = discontinuation of study intervention; pembro = 
pembrolizumab; W = week(s)
a: All samples are to be collected pre-dose.
b. Blood will be collected for flow cytometry from participants enrolled in the expansion phase only, and may only be 
collected in a subset of participants.


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1.3.3
Pharmacokinetic and Immunogenicity Sampling
Table 1–3: Pharmacokinetic and Immunogenicity Sample Collection Plan
Sampling time
Regorafenib,
M-2 and M-5 PK
Pembrolizumab 
PKb,c
Pembrolizumab 
immunogenicityc
Exploratory 
immunogenicityd
W1 D1
pre-dose and at 
0.5 ha and 3-4 ha after 
oral intake 
pre-infusion
pre-infusion
pre-infusion
W2 D1
pre-dose
W3 D1
pre-dose and 2-4 ha
after oral intake
W5 D1
pre-dose and at 
0.5 ha and 3-4 ha after 
oral intake 
W7 D1
pre-dose and 2-4 ha
after oral intake
pre-infusion 
pre-infusion
pre-infusion
W13 D1
pre-infusion
pre-infusion
W19 D1
pre-infusion
pre-infusion
W25 D1
pre-infusion
pre-infusion
W37 D1
pre-infusion
pre-infusion
W49 D1
pre-infusion
pre-infusion
W73 D1
pre-infusion
pre-infusion
W97 D1
pre-infusion
pre-infusion
ADA = anti-drug antibodies; D = day; h = hour(s); M-2 / M-5 = metabolites of regorafenib; PK = 
pharmacokinetics; W = week
Note: Also refer to Section 8.5.
a.
If regorafenib is not administered on the day of PK sampling, the pre-dose samples will be collected and 
the post-dose samples will not be collected.
b.
Pembrolizumab pre-dose samples should be taken just prior to start of infusion (within 24 hours before 
infusion of pembrolizumab). If the infusion is delayed and a pre-dose sample is already collected, there 
is no need to collect an additional pre-dose sample. If pembrolizumab is not administered on the 
scheduled day, PK pre-dose samples should still be collected. Otherwise PK sampling should always be 
linked to the pembrolizumab administration.
c.
Pembrolizumab PK and ADA samples will be collected while the participant is receiving pembrolizumab 
treatment. Samples will be collected during the pilot phase of the study and may be collected during the 
expansion phase based on emerging data.
d.
Additional exploratory ADA samples will be collected during the pilot phase of the study and may be 
collected during the expansion phase based on emerging data. 


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2.
Introduction
2.1
Study Rationale
This clinical study aims to evaluate the efficacy and safety of regorafenib in combination with 
pembrolizumab for the treatment of advanced hepatocellular carcinoma (HCC) in adult 
participants who have been previously treated with PD-1/PD-L1 immune checkpoint inhibitor
in monotherapy or combinations regimens.
The rationale for evaluating regorafenib in combination with pembrolizumab in patients with 
unresectable advanced HCC is as follows:

Treatment of advanced HCC remains an area of high unmet need in 2L. Patients 
with tumors in the advanced stage (Barcelona Clinic Liver Cancer [BCLC] stage C) 
have a dismal prognosis if untreated, with a median overall survival (OS) of 8 months
(Llovet et al. 2008). 
Until 2020, only two oral MKIs, sorafenib and levantinib, were the approved first line 
systemic treatments for advanced HCC. However, the landscape is rapidly changing
for patients with unresectable HCC. Recently, the Food and Drug Administration 
(FDA) approved the combination of atezolizumab, a PD-L1 checkpoint inhibitor, and 
bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor 
(VEGF), as first line treatment. In 2020, the FDA approved the combination of 
nivolumab, a PD-L1 checkpoint inhibitor, and ipilimumab, an anti-CTLA-4 antibody
in patients with HCC previously treated with sorafenib. There are additional ongoing 
Phase 2 and 3 clinical trials with immune checkpoint inhibitors in monotherapy and 
combination regimens also targeting the first line setting. 
The best regimen in second line is not well established and all the current options were 
approved for the patients who were previously treated with MKI. Therefore, an 
ongoing high unmet medical need remains for patients with unresectable HCC who 
progressed or did not tolerate these novel immunotherapy agents.

Regorafenib has established clinical activity as a single agent in advanced HCC.
Regorafenib is an MKI and is the first systemic treatment shown to provide a survival 
benefit in HCC patients progressing on sorafenib treatment (Bruix et al. 2017). 
Regorafenib is approved for second line HCC treatment, and has shown a comparable 
level of clinical benefit in the second line setting as observed with sorafenib as first
line therapy. Pembrolizumab, an anti-PD-1 antibody, is approved for the treatment of 
patients with HCC previously treated with sorafenib (Zhu et al. 2018).

Preliminary results from the ongoing Phase 1b study of regorafenib in 
combination with pembrolizumab in patients with advanced HCC with no prior 
systemic therapy have shown promising efficacy and an acceptable safety profile. 
Regorafenib is approved for the treatment of patients with HCC who progressed after 
first line therapy with sorafenib. Pembrolizumab is a highly selective and potent 
humanized IgG4 monoclonal antibody that binds to the PD-1 receptor, blocking 
interaction with PD-L1 and PD-L2, thereby enhancing the functional activity of the 
target lymphocytes to facilitate tumor regression. Of the 35 participants treated with 
120 mg regorafenib QD (3 weeks on, 1 week off), 31 were evaluable for efficacy and 
9 (29%) achieved a partial response (PR) per RECIST 1.1, with a disease control rate 
(DCR) of 94%. At the MTD of regorafenib (120 mg/day), approximately three-


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quarters of the participants had a regorafenib dose reduction or interruption. An 
additional exploratory cohort was established to evaluate regorafenib 80 mg QD
(3 weeks on, 1 week off).  As of NOV 2020, 22 participants had been treated with 
regorafenib at the 80 mg/day dose level. Of the 21 participants who were evaluable for 
efficacy, 3 (14%) had a PR with a DCR of 86%. The efficacy data were immature at 
the NOV 2020 cut-off, as treatment was ongoing in 13 of 22 participants (59%). The 
80 mg regorafenib dose level demonstrated a more favorable safety profile, with 50% 
of the participants requiring a regorafenib dose modification (dose reduction or 
interruption).  

Targeting both the anti-angiogenic and immune checkpoint pathways may 
provide synergistic anti-tumor activity. The rationale for combining immunotherapy 
with anti-angiogenic treatments has been outlined by Khan and Kerbel (Khan and 
Kerbel 2018) and is supported by both preclinical and clinical results in various 
indications including HCC (Ikeda et al. 2018, Kato et al. 2019). Immune checkpoint 
inhibitors appear to affect the tumor vasculature as well, which may synergize with the 
inhibition of VEGF signaling by regorafenib. Therefore, therapies combining 
regorafenib with a PD-1 antibody, such as pembrolizumab, present an opportunity to 
improve the effectiveness of second line therapy in patients with unresectable 
advanced or metastatic HCC.

Combination of MKI and ICI may provide mechanisms to overcome resistance to 
immunotherapy. Despite promising efficacy in different tumor indications, some 
patients fail to respond to immune checkpoint inhibitors (ICI), and others who 
demonstrate encouraging results can acquire resistance during treatment. Resistance to 
ICIs has been linked to local immunosuppression effects (O'Donnell et al. 2017). 
MKIs are associated with modifications in the tumor microenvironment, including the 
alteration of immune cell infiltration, which can lead to a decreased function of 
immune suppressor cells (Kwilas et al. 2015). Based on the current approved 
treatments in 1L for HCC, fewer than one-third of patients respond to immunotherapy, 
therefore, there is also an opportunity to explore whether a different combination of 
treatment including a MKI can overcome ICI resistance and improve response among 
HCC patients.
2.2
Background
2.2.1
Hepatocellular Carcinoma
HCC is an aggressive tumor that frequently occurs in the setting of chronic liver disease and 
cirrhosis and accounts for up to 85% of all primary liver cancers worldwide (Bray et al. 
2018). Liver cancer was reported to be the fourth most common cause of cancer death in the 
world and to be responsible for nearly 782,000 deaths in 2018 (accounting for 8.2% of total 
cancer deaths) (Bray et al. 2018). Although there are a number of treatment options available 
for HCC, mortality is still high. 
For 1L, sorafenib and lenvatinib (oral multi-kinase inhibitors) are indicated based on proven 
benefit in Phase 3 studies. In the SHARP trial, sorafenib was shown to improve OS from 
7.9 to 10.7 months compared to placebo in patients with advanced HCC (Llovet et al. 2008).
Lenvatinib has been shown to be non-inferior to sorafenib as first line treatment in terms of 
OS in the REFLECT trial in patients with unresectable HCC (Kudo et al. 2018). 


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There are recent data supporting immunotherapy with checkpoint inhibitors, in monotherapy 
or combination regimens, as treatment options in 1L. 
Recently, the combination of atezolizumab, a PD-L1 checkpoint inhibitor, and bevacizumab, 
a monoclonal antibody that inhibits VEGF, and also the combination of nivolumab, a PD-L1 
checkpoint inhibitor, and ipilimumab, an anti-CTLA-4 antibody, were approved as front line 
treatments for treatment for patients with advanced HCC previously treated with sorafenib. 
The regulatory approval of the atezolizumab and bevacizumab combination was based on 
results of the Phase 3 IMbrave 150 trial, which demonstrated a significant improvement in 
median OS and progression-free survival (PFS) in the atezolizumab plus bevacizumab 
treatment arm when compared to patients under sorafenib treatment. The results based on 
additional follow-up data showed a hazard ratio (HR) of 0.66 (95% CI [0.52; 0.85], 
p ≤0.0009) for OS after a median follow-up of 15.6 months (Finn et al. 2021).
The efficacy of the nivolumab and ipilimumab for patients with advanced HCC was 
determined in the Phase I/II CheckMate040 trial, a multicenter, multiple cohort, open-label 
trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. After 
a follow-up of 28 months, 33% (95% CI [20; 48]) of the patients responded to this treatment 
combination, with 8% achieving complete response (CR) and 24% PR. The DOR ranged from 
4.6 to 30.5 months (Yau et al. 2019a).
Multiple studies to assess combination treatments for 1L are ongoing and the landscape for 1L 
therapy in patients with advanced HCC is rapidly changing.
Although the primary endpoint of OS did not achieve statistical significance, preliminary 
results of the Phase 3 CheckMate 459 trial showed clinically meaningful improvement in OS 
(median 16.4 versus 14.7 months) of nivolumab when compared to sorafenib in patients with 
advanced HCC (Yau et al. 2019b). The interim results of the Phase 1b KEYNOTE-524 study 
also showed promising anti-tumor activity (ORR of 44.8% per mRECIST evaluation) for the 
combination of lenvatinib and pembrolizumab in patients with advanced HCC not eligible for 
loco-regional treatment (Llovet et al. 2019).
In addition combinations such as durvalumab, an anti-PD-L1, with tremelimumab, an 
anti-CTLA-4 antibody, cabozantinib, a multi-receptor tyrosine kinase inhibitor, plus 
atezolizumab, among others, are being assessed in 1L in large Phase 3 trials for patients 
with advanced HCC. 
For 2L, regorafenib, ramucirumab and cabozantinib have been approved based on Phase 3
studies that showed survival benefits compared to placebo in patients treated with sorafenib. 
Clinical data also support pembrolizumab and nivolumab in monotherapy as treatment 
options for patients previously treated with sorafenib.
Cabozantinib is a potent inhibitor of several receptor tyrosine kinases, which demonstrated 
superior efficacy in OS (10.2 versus 8 months), in the patient population after second or third 
line therapy (Abou-Alfa et al. 2018).
Ramucirumab is a recombinant human IgG1 monoclonal antibody that binds to VEGF 
receptor 2 (VEGFR2), which also demonstrated superior OS (8.5 versus 7.3 months; 95% CI
[0.53; 0.95]) over placebo in Child-Pugh A HCC patients with alpha-fetoprotein (AFP) ≥400 
who had progressed after first line sorafenib treatment (Zhu et al. 2019).
Results from the Phase 2 KEYNOTE-224 study support the benefits of pembrolizumab (anti-
PD-1 monoclonal antibody) as an alternative PD-1 inhibitor for the patients previously treated 
with sorafenib. The median duration of treatment was of 4.2 months, with an ORR of 17% 


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and with 44% stable disease (SD). These results were confirmed in the Phase 3 KEYNOTE-
240 trial of best supportive care (BSC) plus either pembrolizumab or placebo for second line 
therapy of advanced HCC, which also demonstrated survival benefit in second line HCC. 
After a median follow-up of 13.8 months, both PFS (3 versus 2.8 months) and OS
(13.9 versus 10.6 months, HR 0.78, 95% CI [0.61; 0.998]) were improved. The ORR was 
higher for pembrolizumab (18.3% versus 4.4%), there were more complete responders with 
pembrolizumab (6 versus none), and responses were durable (median DOR 13.8 months, 
range 1.5 to 23.6+ months) (Finn et al. 2020). 
Nivolumab monotherapy also showed superior efficacy in patients with HCC and Child-
Pugh A cirrhosis who have progressed on or were intolerant to sorafenib based on the results 
of the multicohort Phase 1/2 CheckMate 040 trial. The ORR by RECIST 1.1, was 15% 
(95% CI [6; 28]) in the dose escalation phase, with 3 CR and 4 PR. The median DOR was 
17 months (95% CI [6; 24]) and the 6-month and 9-month OS rates were both 66% 
(95% CI [51; 78]) (El-Khoueiry et al. 2017). 
Regorafenib is approved for the treatment of patients with HCC who progressed during 
sorafenib treatment based on the RESORCE study, a randomized, double-blind, placebo-
controlled, Phase 3 study (Bruix et al. 2017). There, the addition of regorafenib to BSC 
resulted in significantly better OS compared to placebo plus BSC, with a HR of 0.63 (95% CI
[0.50; 0.79]; one-sided p<0.0001) and a median OS of 10.6 months vs. 7.8 months; this 
represents a 37% reduced risk of death in the regorafenib group compared to the placebo 
group. In addition, the study showed similar clinical benefit for regorafenib in the second line 
setting as observed with sorafenib in the first line.
Although these drugs are available for patients previously treated with tyrosine kinase 
inhibitors, a high unmet clinical need remains in this patient population for the patients who 
have progressed on first line treatment options with immunotherapy agents.
2.2.2
Regorafenib 
Regorafenib (BAY 73-4506) is an oral small molecule tyrosine kinase inhibitor that potently 
blocks multiple protein kinases, including kinases involved in tumor angiogenesis 
(VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis 
(VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R). In preclinical studies, regorafenib 
has demonstrated potent anti-tumor activity as a single agent in a broad spectrum of tumor 
models including hepatocellular tumor models, which is likely mediated by its 
anti-angiogenic and anti-proliferative effects. 
2.2.2.1
Pharmaceutical and Therapeutic Background
The recommended dose of regorafenib as monotherapy is 160 mg (4 tablets, each containing 
40 mg regorafenib), taken orally once daily for 3 weeks on therapy followed by 1 week off 
therapy to comprise a cycle of 4 weeks.
Based on the dose escalation study (study 11650), the 160 mg QD dose given for 3 weeks
followed by 1 week off treatment in repeated 4 weeks cycles was selected for future Phase 2 
and 3 studies in adults. Three large randomized Phase 3 company-sponsored studies in
metastatic colorectal cancer (mCRC), gastrointestinal stromal tumor (GIST), and HCC have 
reported positive outcomes with this dosing regimen.
Regorafenib undergoes extensive and complex metabolism, including oxidation and
glucuronidation leading to metabolites that can be reduced and / or cleaved in the intestinal
milieu, resulting in enterohepatic cycling in vivo. Regorafenib is metabolized primarily in the


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liver by oxidative metabolism mediated by cytochrome P450 3A4 (CYP3A4), as well as by 
glucuronidation mediated by UGT1A9. The main circulating metabolites of regorafenib in 
human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are 
pharmacologically active. Whereas plasma concentrations of M-2 and M-5 after a single dose 
of regorafenib are lower than those of the parent compound, steady state plasma 
concentrations of M-2 and M-5 are comparable to those of regorafenib. 
Metabolites may be reduced or hydrolyzed in the gastrointestinal tract by microbial flora,
allowing reabsorption of the unconjugated drug and metabolites (enterohepatic circulation).
Co-administration of a single dose of regorafenib after pre-treatment with neomycin (a poorly
absorbed antimicrobial agent that eradicates the gastrointestinal microflora) had no significant
effect on the exposure of regorafenib. There was a decrease in the exposure of M-2 and M-5
by 76% and 86%, respectively.
The concentrations of regorafenib and its major pharmacologically active metabolites M-2 
and M-5 were highest when given after a low fat (light) breakfast as compared to either a high
fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when 
administered with high fat breakfast, and 36% when administered with a low fat breakfast, 
compared to fasting. 
Plasma concentration-time profiles for regorafenib as well as for the major circulating
metabolites showed multiple peaks across the 24 hour dosing interval, which are attributed to
enterohepatic circulation. Protein binding of regorafenib to human plasma proteins in vitro is
high (99.5%). Following oral administration, mean elimination half-life for regorafenib and
its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies. The mean
elimination half-life for the metabolite M-5 is approximately 60 hours (range from 40 to
100 hours).
Accumulation of regorafenib at steady state results in about a 2-fold increase in plasma
concentrations, which is consistent with the elimination half-life and dosing frequency. At
steady state, regorafenib reaches mean maximum observed plasma concentrations of about
3.9 mg/L (8.1 micromolar) after oral administration of 160 mg regorafenib, with a peak to
trough ratio of mean plasma concentrations of less than 2.
The pharmacokinetics of regorafenib in Child-Pugh A and B (mild to moderate) hepatic 
impaired patients were similar to the pharmacokinetics in patients with normal hepatic 
function. There are no data for patients with Child-Pugh C (severe) hepatic impairment, since
regorafenib is mainly eliminated via the liver, and exposure might be increased in this patient 
population. 
Age did not affect the regorafenib pharmacokinetics over the studied age range (29-85 years).
The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is
within the same range as seen in Caucasians.
2.2.2.2
Pre-clinical and Clinical Trials
In pre-clinical studies regorafenib has demonstrated potent anti-tumor activity in a broad 
spectrum of tumor models including colorectal, breast, pancreatic, non-small cell lung cancer, 
gastrointestinal stromal tumor, gastric cancer, head and neck squamous cell 
carcinoma/esophageal squamous cell carcinoma, liver cancer, glioma, and pediatric 
medulloblastoma, which is likely mediated by its anti-angiogenic and anti-proliferative effects 
(Abou-Elkacem et al. 2013, Schmieder et al. 2014, Takigawa et al. 2016, Wilhelm et al. 2011, 
Zopf et al. 2011); see the Investigator’s Brochure (IB) for more information.


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In addition, regorafenib has shown anti-metastatic effects in vivo. Major human metabolites 
(M-2 and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo
models.
As of 26 SEP 2018, more than 8,300 subjects with advanced solid-organ malignancies have 
been treated with regorafenib cumulatively in clinical studies and access programs, and 
approximately 141,722 patients have been exposed to regorafenib (post-marketing patients). 
Currently, regorafenib is approved in more than 90 countries (including the United States of 
America [USA], the European Union [EU], and Japan). Approved indications include 
pretreated advanced colorectal cancer (CRC), pre-treated advanced gastrointestinal stromal 
tumor (GIST) and pre-treated advanced HCC.
2.2.3
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity 
of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based 
on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an IV immunotherapy for advanced malignancies. Pembrolizumab is 
indicated for the treatment of patients across a number of indications. For more details on 
specific indications and background information refer to the current IB / approved labeling.
2.2.3.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis 
in various malignancies. In particular, the presence of CD8+ T cells and the ratio of CD8+ 
effector T cells/FoxP3+ regulatory T cells (T-regs) correlates with improved prognosis and 
long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma (Dudley et al. 2005, Hunder et al. 2008).
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
(Greenwald et al. 2005, Okazaki et al. 2001).
The structure of murine PD-1 has been resolved (Zhang et al. 2004). PD-1 and its family
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 


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involved in the CD3 T cell signaling cascade (Chemnitz et al. 2004, Okazaki et al. 2001, 
Riley 2009, Sheppard et al. 2004). The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins (Francisco et al. 2010, Parry et al. 2005). As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in
patients with HCC.
2.2.3.2
Pre-clinical Data
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities (Blank et al. 2004, Curran et al. 2010, Hirano et al. 2005, Pilon-Thomas et al. 
2010, Spranger et al. 2014, Strome et al. 2003, Weber 2010). Anti-mouse PD-1 or anti-
mouse PD-L1 antibodies have demonstrated anti-tumor responses in models of squamous 
cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal 
carcinoma (Curran et al. 2010, Nomi et al. 2007, Pilon-Thomas et al. 2010, Strome et al. 
2003, Zhang et al. 2004). In such studies, tumor infiltration by CD8+ T cells and increased 
IFN-γ, granzyme B and perforin expression were observed, indicating that the mechanism 
underlying the anti-tumor activity of PD-1 checkpoint inhibition involved local infiltration 
and activation of effector T cell function in vivo (Curran et al. 2010). Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see the IB).
2.2.4
Combination of Regorafenib and Anti-PD-1 Antibody 
The rationale for combining immunotherapy with anti-angiogenic treatments has been 
outlined by Khan and Kerbel (Khan and Kerbel 2018) and is supported by both pre-clinical 
and clinical results in various indications including HCC (Ikeda et al. 2018, Kato et al. 2019). 
Pre-clinically, the combination of regorafenib with anti-PD-1 demonstrated beneficial anti-
tumor activity versus single agents in mouse models of colorectal cancer (CRC) (Hoff et al. 
2017), melanoma (Wu et al. 2019), and HCC (data on file). 
Mechanistically, this effect may be mediated by 
1. a reduction/reprogramming of tumor associated macrophages by the inhibition of the 
CSF1R by regorafenib (Hoff et al. 2017).
2. suppression of interferon gamma induced PD-L1 and indolamine-2,3-dioxygenase 
(IDO1) expression, with minor effects on major histocompatibility complex 1 
(MHC1) expression due to inhibition of RET and RAF (Wu et al. 2019).
3. increased infiltration of cytotoxic T cells in HCC tumors, mediated by elevated 
expression of CXCL10 (the ligand for CXCR3), which occurs on T cells (data on file).
Furthermore, VEGF signaling is known to suppress immune activity either directly on 
immune cells or indirectly by affecting the tumor vasculature (Khan and Kerbel 2018). 
Regorafenib as a potent VEGFR kinase inhibitor may thereby attenuate the 
immunosuppressive effects of VEGF. Inhibition of VEGFR and its signaling pathway may 
normalize tumor blood vessels and improve cytotoxic T cell infiltration (Zopf et al. 2016). 
Immune checkpoint inhibitors appear to affect the tumor vasculature as well, which may 
synergize with the inhibition of VEGF signaling by regorafenib (Tian et al. 2017).


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Additional clinical evidence of the potential synergistic effects of combining immune 
checkpoint inhibitors with VEGF inhibitors is also derived from REGONIVO, an open-label, 
dose-finding, and dose-expansion Phase 1b study of regorafenib and nivolumab in patients 
with advanced microsatellite-stable CRC and gastric cancer (Fukuoka et al. 2019). The 
combination was tolerable and an encouraging 38% ORR was observed across tumor types.
A multicenter, non-randomized, open-label dose escalation Phase 1b study of regorafenib in 
combination with pembrolizumab in patients with advanced HCC with no prior systemic 
therapy (study 19497) is currently being conducted to determine the safety and tolerability of 
regorafenib in combination with pembrolizumab. Preliminary data from this trial (NOV 2020)
did not result in any new safety signals considering the safety profile of either drug alone, and 
also showed promising anti-tumor activity (ORR 29%, DCR 94%, for patients treated at the 
120mg MTD).
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
Both regorafenib and pembrolizumab have manageable and well-understood safety profiles, 
and no new safety signals have been seen with the combination to date in HCC.
Pembrolizumab is generally well-tolerated but can induce immune-related adverse events 
(irAEs). Study participants will be closely monitored for development of irAEs and will 
receive treatment such as administration of corticosteroids, anti-inflammatory therapies, and 
other appropriate supportive care measures. Overlapping side effects such as liver toxicity, 
diarrhea, and skin reactions are possible. More detailed information about the known and 
expected benefits and risks, and expected AEs of regorafenib and pembrolizumab can be 
found in the most recent IB of each drug.
Additional considerations on safety monitoring: every effort will be made to minimize AEs of 
this drug combination during the study, through participant selection (e.g., only Child-Pugh A 
patients will be enrolled) and extensive safety monitoring. Special importance will be given to 
liver toxicity, as fatal cases of liver failure following toxic hepatitis have been reported in 
adult patients on regorafenib, and as there is a potential overlapping toxicity with 
pembrolizumab. Liver function tests will be closely monitored in all participants (weekly for 
the first 8 weeks and then monthly with mandatory assessments before each regorafenib 
treatment cycle).
No drug-drug interaction between regorafenib and pembrolizumab is expected because 
pembrolizumab is a therapeutic monoclonal antibody that is not metabolized and is also not a 
cytokine modulator. This is supported by preliminary pharmacokinetics (PK) data from the 
ongoing Phase 1b study 19497 indicating that regorafenib exposure, when administered in 
combination with pembrolizumab, is similar to regorafenib monotherapy. Since 
pembrolizumab is cleared by nonspecific proteases, similar to endogenous proteins, no effect 
of regorafenib on pembrolizumab PK is expected.
2.3.2
Benefit Assessment
Regorafenib is a potent MKI with an extensive kinase-inhibition profile, exhibiting robust 
efficacy data in pre-treated HCC patients. The RESORCE study showed similar clinical 
benefit for regorafenib for the second line setting as observed with sorafenib in the first line. 
This observed level of clinical benefit in a pre-treated population suggests that regorafenib 


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has the potential to offer benefit in a patient population previously treated with other 1L 
systemic therapy, justifying studying it in the 2L setting.
Recently published data support the combination of an MKI with an anti-PD-L1 as an option 
for treatment-refractory cancer such as metastatic RCC after progression with a PD-1/PD-L1 
immune checkpoint inhibitor. In the Phase 2 trial of lenvatinib in combination with 
pembrolizumab for disease progression after PD-1/PD-L1 immune checkpoint inhibitor in 
metastatic RCC, 65% of patients had prior PD-1/VEGF combination therapy and 37% had 
prior ipilimumab/nivolumab during a median prior duration of immunotherapy of 7 months. 
The objective response of the study treatment combination was of 51%, with a median PFS of 
11.7 months and median DOR of 9.9 months (Lee et al. 2020).
Immune checkpoint inhibitors have shown promising clinical activity and durable responses
in patients with HCC. Based on complementary modes of action between MKIs and PD-1 
inhibitors and their potentially synergistic effects on the cancer-immunity pathway, the 
combination of regorafenib and pembrolizumab might provide a greater clinical benefit in 
HCC patients. 
Preliminary data from the Phase 1b study 19497 of regorafenib in combination with 
pembrolizumab in patients with advanced HCC with no prior systemic therapy have 
demonstrated a potential efficacy signal in 1L and a tolerable safety profile. As of NOV 2020, 
9 out of the 31 participants who started 120 mg regorafenib QD (3 weeks on / 1 week off) and 
pembrolizumab 200mg Q3W and were evaluable for efficacy achieved PR per RECIST 1.1, 
with a DCR of 94%. Of the 21 patients who started 80 mg regorafenib QD (3 weeks on / 
1 week off) and pembrolizumab 200mg Q3W and were evaluable for efficacy, 3 achieved PR
per RECIST 1.1, with a DCR of 86%. Efficacy data for the 80 mg cohort were immature as of 
the cut-off date for this analysis.
2.3.3
Overall Benefit / Risk Assessment 
In preclinical and clinical studies, regorafenib has demonstrated potent anti-tumor activity as 
a single agent in a broad spectrum of tumor models including hepatocellular tumor models, 
which is likely mediated by its anti-angiogenic and anti- proliferative effects. A positive 
benefit to risk profile is expected and combining regorafenib with an anti-PD-1 such as 
pembrolizumab is a potential and promising second line therapeutic option in advanced liver 
cancer.
Based on the data available to date, the conduct of the clinical trial is regarded as justified.
3.
Objectives and Endpoints
The purpose of this study is to evaluate the efficacy and safety of regorafenib in combination 
with pembrolizumab for the treatment of advanced HCC in adult participants who have been 
previously treated with a PD-1/PD-L1 immune checkpoint inhibitor. The objectives and 
endpoints for the study are summarized in Table 3–1.
Table 3–1: Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate the objective anti-tumor activity of
regorafenib in combination with pembrolizumab as 
2L treatment for advanced HCC

ORR per RECIST 1.1a by central 
assessment


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Table 3–1: Objectives and Endpoints
Objectives
Endpoints
Secondary
To evaluate other measures of anti-tumor activity 
of regorafenib in combination with pembrolizumab 
as 2L treatment for advanced HCC

DOR per RECIST 1.1 by central 
assessment

ORR per RECIST 1.1 by investigator 
assessment 

DOR per RECIST 1.1 by investigator 
assessment 
To evaluate safety and tolerability of regorafenib in 
combination with pembrolizumab

Number of participants with AEs 

Number of participants with SAEs 

Number of participants with safety-
relevant changes in clinical parameters

Number of participants with dose 
modification (dose interruption, dose 
reduction, dose discontinuation)
Tertiary/Exploratory
To establish further exploratory indicators of 
efficacy of regorafenib in combination with 
pembrolizumab
DCR per RECIST 1.1 by central 
assessment and investigator assessment
PFS as per RECIST 1.1 by central 
assessment and investigator assessment
Overall survival (OS)
ORR per HCC mRECIST and iRECIST by 
investigator assessment
DOR per HCC mRECIST and iRECIST by 
investigator assessment
To evaluate the PK of regorafenib when 
concomitantly administered with pembrolizumab
To evaluate PK and immunogenicity of 
pembrolizumab when concomitantly administered 
with regorafenib
Exposure of regorafenib and 
pembrolizumab, and incidence of anti-
drug antibody (ADA) for pembrolizumab
To identify biomarkers in baseline tumor 
materials and/or blood that may associate with 
response
To explore pharmacodynamic effects of 
regorafenib and pembrolizumab combination
To evaluate the PK/pharmacodynamic
relationship for correlative biomarkers in blood 
such as peripheral lymphocytes, circulating 
proteins or nucleic acids (DNA or RNA), and/or 
tissues as well as measures of safety and/or 
efficacy 
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
Correlation of biomarkers before 
treatment with other study endpoints 
Change from baseline in levels of 
biomarkers in blood or tumor 
Retrospective exploratory analysis of the 
relationship between regorafenib 
exposure and biomarker, safety and/or 
efficacy measures
Various biomarkers (e.g., diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)
2L = second line; ADA = anti-drug antibodies; AE = adverse event; DCR = disease control rate; DNA = 
deoxyribonucleic acid; DOR = duration of response; HCC = hepatocellular carcinoma; ORR = objective 
response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event
a. See Appendix 5 (Section 10.5) for tumor response criteria RECIST 1.1, HCC mRECIST, and iRECIST


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4.
Study Design
4.1
Overall Design
This is an open-label, Phase 2 trial to evaluate efficacy and safety of regorafenib in 
combination with pembrolizumab in patients with advanced HCC post PD-1/PD-L1 immune 
checkpoint inhibitors, in monotherapy or combination regimens.
This study will investigate if the combination of regorafenib with PD-1 inhibitor 
pembrolizumab can improve the clinical outcome for patients with advanced HCC in the 
second line setting and follows a two phase design, consisting of an initial pilot phase and an 
expansion phase (see Figure 4–1): 
a)  Pilot phase: Approximately 52 participants will be enrolled to receive regorafenib in 
combination with pembrolizumab
o
Cohort 1: 26 participants after one systemic line of therapy consisting of 
atezolizumab plus bevacizumab treatment combination only 
o
Cohort 2: 26 participants after one systemic line of therapy consisting of any IO 
containing first line treatment (excluding atezolizumab with or without 
bevacizumab) in monotherapy or combination regimens
b)  Expansion phase: If the target ORR is achieved in the pilot phase (i.e. at least 
8 responders out of 26 treated in cohort 1 or at least 8 responders in each cohort), the 
study can enroll approximately 67 new additional participants. These additional 
participants can be from cohort 1 (i.e. patients progressing on atezolizumab plus 
bevacizumab combination) or the combined population from cohort 1 plus cohort 2 (i.e., 
patients progressing on any immune checkpoint inhibitor), depending on which cohorts 
meet the response rate criteria for expansion (see Section 9.2).
Results from the pilot phase will inform the selection of the appropriate population for further 
study in the expansion phase.
Figure 4–1: Study Design
ECOG = Eastern Cooperative Oncology Group performance status; HCC = hepatocellular carcinoma; IV = 
intravenous; IO = immune oncology; ORR = objective response rate; PD-1 = Programmed cell death 1; PD-
L1 = Programmed death-ligand 1; Q6W = every 6 weeks; W = week
Patients with 
advanced HCC 
progressed on 1L 
anti-PD-1/PD-L1 
therapy
ECOG 0/1
Child-Pugh A
Regorafenib 90 mg 
starting dose (120 mg
dose escalation)         
3W on/1W off
+
Pembrolizumab 
400 mg IV Q6W
Pilot phase
approximately 52 patients
Cohort 1: 26 patients after 
atezolizumab plus bevacizumab 
treatment combination 
Cohort 2: 26 patients after any IO 
containing first line treatment
If target ORR achieved in
Cohort 1, or in both Cohorts 
Expansion phase
Additional 67 patients 


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4.1.1
Study Periods
4.1.1.1
Screening Period
The start of the screening phase is defined by signing of the ICF. Participants will be screened 
for eligibility up to 28 days immediately prior to W1D1.
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 assignment to treatment of each participant into 
the study to ensure that all inclusion and exclusion criteria have been satisfied. See the 
schedule of activities (SoA) in Section 1.3.1 for the procedures during the screening period.
4.1.1.2
Intervention Period
The start of the intervention period is defined by the first administration of the combination 
study intervention. 
Participants will be treated with 400 mg pembrolizumab IV Q6W. 
Regorafenib will be given orally (p.o.) at a starting dose of 90 mg QD for 3 weeks of every 
4 weeks (i.e., 3 weeks on, 1 week 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 daily any time after the 
first cycle of regorafenib, starting with W5D1. Dose modification guidelines for dose 
reduction in case of toxicity are detailed in Section 6.6.
To support participants in establishing the drug intake rhythm (i.e. 6-week cycle for 
pembrolizumab, 4-week cycle for regorafenib), the site personnel are asked to call 
participants regularly for at least the first 3 regorafenib treatment cycles to remind them of 
omitting regorafenib during the 4th week of a cycle.
Participants will continue to receive study intervention until disease progression as defined by 
RECIST 1.1, unacceptable toxicity, consent withdrawal, withdrawal from the study at the 
discretion of the investigator or his/her designated associate(s), or until any other withdrawal 
criteria are met. Treatment beyond radiological progression is possible if the participant is still 
benefiting from treatment (see Section 6).
Participants who complete 18 infusions of pembrolizumab need to discontinue treatment with 
pembrolizumab. Regorafenib treatment can be continued beyond 2 years until withdrawal
criteria are met. Treatment with individual drugs (regorafenib or pembrolizumab) may 
continue on schedule even if the other drug is interrupted or permanently discontinued due to 
toxicity. 
During the study, participants will undergo evaluations for safety, efficacy, PK, and tissue and 
blood/plasma for biomarker will be collected. See the SoA in Section 1.3 for the assessments 
during the intervention period.
4.1.1.3
Active Follow-up
A mandatory safety follow-up visit will take place 30 days (window of +7 days) after the last 
administration of the last study intervention (regorafenib and/or pembrolizumab).
If applicable, an additional safety follow-up must occur 90 days (window of +7 days) after the 
last pembrolizumab administration. Longer safety follow-up for pembrolizumab is required 
due to the long half-life of the antibody. Note: If pembrolizumab is permanently discontinued 
first and the day 30 or the day 90 safety follow-up visit after the last infusion of 


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pembrolizumab falls into the regorafenib treatment period or regorafenib day 30 safety 
follow-up visit, no separate pembrolizumab day 30 or day 90 safety follow-up visit is 
necessary as the information gathering and examinations will occur with regorafenib 
treatment cycle visit, EoT visit, or day 30 safety follow-up visit. If regorafenib is discontinued 
first and the day 30 safety follow-up visit falls into pembrolizumab treatment or 
pembrolizumab day 30 follow-up visit, no separate regorafenib safety follow-up visit is 
necessary. 
All pregnancies and exposure during breastfeeding should be collected from the start of study 
intervention through 120 days following discontinuation of study intervention, or 30 days 
following discontinuation of study intervention if the participant initiates new anti-cancer 
therapy.
Participants who discontinue study intervention due to radiologically confirmed PD will 
complete the mandatory safety follow-up visits.
Participants who discontinue from the study for any reason other than PD (or death, 
withdrawal of consent, or lost to follow-up) will be followed for progression during the active 
follow-up period. During the active follow-up period, computed tomography (CT) / magnetic 
resonance imaging (MRI) evaluations will be performed at efficacy follow-up visits (see the 
SoA in Section 1.3.1). In addition, study intervention-related toxicity/AE, information about 
survival status, and subsequent anti-cancer therapy will be followed up until completion of the 
active follow-up. 
Active follow-up will be terminated by radiological PD, or the start of a new anti-cancer 
treatment, or death, or withdrawal of consent for further participation, or lost to follow-up.
4.1.1.4
Long-term Follow-up
All surviving participants will enter the long-term follow-up period after discontinuing from 
the active follow-up period except for participants who explicitly withdraw consent or are lost 
to follow-up. 
Participants will be followed for OS and subsequent anti-cancer therapy at 3-month intervals 
(± 14 days) until the end of the study, withdrawal of consent, lost to follow-up, or death, 
whichever comes first (telephone contact is sufficient). Participants may be contacted at 
additional times throughout the course of the study in order to collect survival data to ensure 
that long-term follow-up data is current.
4.2
Scientific Rationale for Study Design
Recent clinical data support immunotherapy with checkpoint inhibitors as treatment options 
in first line for patients with advanced HCC. Although these drugs are available, a high unmet 
clinical need remains for the patients with advanced HCC who have progressed in first line 
treatment options with immunotherapy agents.
Regorafenib has established activity as a single agent and has been shown to provide survival 
benefit in HCC patients progressing on sorafenib treatment (Bruix et al. 2017). 
Pembrolizumab has been granted accelerated FDA approval for the treatment of HCC patients 
who have been previously treated with sorafenib (Zhu et al. 2018).
This study follows a two-phase design, consisting of an initial pilot phase and an expansion 
phase (Figure 4–2). 


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An interim analysis is planned when the last participant enrolled in each of the cohorts is 
assessed for ORR (as defined by RECIST 1.1) during at least two post-baseline scans, or has 
been followed for approximately 14 weeks from the first dose, unless they have discontinued 
before due to progression or any other reason. Both cohorts will be analyzed separately and 
no pause of recruitment is expected between the study phases until the results of the interim 
analysis become available.
Figure 4–2: Study Design and Planned Analyses
Participants recruited in the pilot phase to one or both cohorts that achieve the response rate 
criterion for expansion will also be analyzed as part of the expansion phase.
The expansion phase will continue until the achievement of the study primary completion 
parameters outlined in Section 4.4.
4.3
Justification for Dose
Regorafenib dose
Regorafenib PK has been well characterized in patients with various solid tumors including 
HCC patients. In the dose-finding study 11650, regorafenib PK was investigated for dose 
levels of 10 mg, 30 mg, 60 mg, 120 mg, 160 mg up to 220 mg QD with a schedule of 3 weeks 
on / 1 week off. The regorafenib dose of 160 mg QD for the first 3 weeks of each 4-week 
cycle was declared as the MTD/RP2D based on exposure and a positive benefit-risk profile. 
This dosing regimen was further evaluated in several pivotal Phase 3 studies and approved 
worldwide, as monotherapy, in several indications including 2L HCC. 
Recently, clinical evidence has been generated suggesting an increased benefit with the 
combination of regorafenib and anti-PD-1 agents such as pembrolizumab or nivolumab. The 
REGONIVO study is an open-label, dose-finding, and dose-expansion Phase 1b trial of 
regorafenib and nivolumab in patients with advanced microsatellite-stable CRC and gastric 
cancer (Fukuoka et al. 2019). In this study, the combination was shown to be tolerable and an 
encouraging 40% objective response rate was observed as compared to the historical response 
rate of regorafenib monotherapy in this population of 1-2% (Grothey et al. 2013). The MTD
for regorafenib in this combination, based on pre-defined dose-limiting toxicity (DLT)
criteria, was deemed to be 120 mg. However, in the first 18 participants treated at the 120 mg 
dose of regorafenib in the dose expansion cohort, all but one required dose reduction to 80 mg 
for AEs mostly related to Grade 3 skin toxicities. All remaining participants (N=18) were 
treated with a regorafenib starting dose of 80 mg and tolerated treatment well. Regorafenib 
exposure is similar across tumor types (CRC vs. HCC) and has shown comparable 
tolerability, so the results from the Phase 1 study mentioned above were considered for dose 
selection of the planned Phase 3 study in HCC.


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The ongoing Phase 1b study, 19497, designed to investigate regorafenib in combination with 
pembrolizumab as 1L treatment in patients with HCC, has declared regorafenib 120 mg QD at 
a schedule of 3 weeks on / 1 week off as the MTD. Out of 18 evaluable participants for DLT, 
four had DLT events including Grade 3 HFSR, Grade 3 liver function test (LFT) increase 
accompanied with Grade 2 bilirubin increase (2 each). Based on the modified toxicity 
probability interval (mTPI) study design, regorafenib 120 mg daily 3 weeks on / 1 week off in 
combination with pembrolizumab was defined as the MTD for this combination however, the 
dose of 120 mg is associated with a relatively high incidence of dose reduction and 
discontinuation and a new expansion cohort has been opened for recruitment to evaluate 
80 mg QD (3 weeks on / 1 week off) in NOV 2019. The combination indicated a preliminary 
efficacy signal. As of NOV 2020, preliminary efficacy data show PR by RECIST 1.1 in 9 out 
of the 31 participants who started 120 mg regorafenib QD (3 weeks on / 1 week off) and were 
evaluable for efficacy. 
As a result of the high discontinuation rate associated with the 120 mg dose as well as the 
results from the REGONIVO study, the planned Phase 2 study will use a regorafenib starting 
dose level of 90 mg QD in cycle 1, if tolerated, escalating to 120 mg any time after the first 
cycle of regorafenib in a 3 weeks on / 1 week off schedule (for details on dose modification, 
see Section 6.6).
The rationale for changing from an 80 mg starting dose to a 90 mg starting dose is based on 
emerging data from ongoing clinical studies (Fukuoka et al. 2019) of regorafenib in 
combination with IO (e.g. nivolumab or pembrolizumab), where 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, the 
sponsor 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 3 weeks of each 
4-week 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.
Pembrolizumab dose
The planned dose of pembrolizumab for this study is 400 mg Q6W.
A 400 mg Q6W dosing regimen of pembrolizumab is approved by the US FDA for use in 
both monotherapy and combination therapy settings. This dosing regimen is expected to have 
a similar benefit-risk profile as 200 mg Q3W, in all indications in which 200 mg Q3W 
pembrolizumab is currently appropriate (Lala et al. 2018). Specifically, the dosing regimen of 
400 mg Q6W for pembrolizumab is considered adequate based on modeling and simulation 
(M&S) analyses, given the following rationale:

PK simulations demonstrating that in terms of pembrolizumab exposures –

Average concentration over the dosing interval (Cavg) (or area under the curve 
[AUC]) at 400 mg Q6W is similar to that at the approved 200 mg Q3W dose, 
thus bridging efficacy between dosing regimens.


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
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of 
those achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of 
patients.

Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the 
highest clinically tested dose of 10 mg/kg every 2 weeks (Q2W), supporting 
that the safety profile for 400 mg Q6W should be comparable to the 
established safety profile of pembrolizumab. 

Exposure-response (E-R) for pembrolizumab has been demonstrated to be flat 
across indications, and OS predictions in melanoma and non-small cell lung 
cancer (NSCLC) demonstrate that efficacy at 400 mg Q6W is expected to be 
similar to that observed at 200 mg Q3W.
4.4
End of Study Definition
The end of the study (EoS) as a whole will be reached when the last visit of the last patient
(LPLV) has been achieved in all participating centers.
LPLV of a participant is reached if he/she has completed the last scheduled procedure shown 
in the SoA (see Section 1.3; this also includes telephone contacts during long-term follow-up) 
unless the participant died or withdrew consent or is lost to follow-up. 
Furthermore, to reach EoS, either the following criteria or both need to be satisfied in this 
study: 

All participants have disease progression or are no longer on study intervention
(regorafenib and/or pembrolizumab).

The last included participant has been followed for at least 2 years since the first study
treatment administration or is deceased.
Decisions on trial termination, protocol amendment, or cessation of patient recruitment can be 
made by the sponsor at any point in the study, guided by the monitoring boundaries at the 
interim analysis of the pilot phase, cumulative safety review, or strategic expectations for the 
study compounds after primary completion has been reached.
If the study is stopped by the sponsor but benefits are observed for ongoing participants, 
further treatment options may be discussed and agreed between the investigator, sponsor, and 
the participant (for further information refer to Section 6.5.5). Therefore, the LPLV date may 
also be reached based on the last participant switching to a roll-over study, post-trial access 
program or being switched to commercial drug supply with no cost to the participant.
Primary completion
The primary completion date according to FDA Amendment Act is defined as date that the 
final participant was examined or received an intervention for the purposes of final collection 
of data for the primary outcome. In this trial, the primary completion is defined as when all
evaluable participants in the expansion phase have been assessed for objective response rate 
as defined by RECIST 1.1.
Participants are considered evaluable for efficacy once they have completed at least two post-
baseline scans or have been followed for approximately 14 weeks from the first study 
treatment dose, unless they have discontinued before due to progression or any other reason.


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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
Inclusion criteria must be met at the time of screening unless otherwise specified.
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. ≥18 years of age on the day of signing informed consent.
Type of Participant and Disease Characteristics
2. Histological or cytological confirmation of HCC or non-invasive diagnosis of 
HCC as per American Association for the Study of Liver Diseases (AASLD) 
criteria (see Appendix 11, Section 10.11) in cirrhotic participants.
3. Unresectable advanced HCC eligible for systemic therapy.
4. Participants must have progressed after only one prior line of systemic 
immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered either as 
monotherapy or in combination with other checkpoint inhibitors or other therapies
(for prior therapy in the cohorts in the pilot phase see Section 4.1). A wash out 
period of at least 28 days or 5 half-lives, whichever is shorter, must be completed 
for eligibility in this trial. PD-1/PD-L1 treatment progression is defined by 
meeting all of the following criteria:
a.
Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb or 
received PD-1/PD-L1 treatment for 8 weeks, whichever is longer. 
b. Has demonstrated disease progression after PD-1/PD-L1 treatment as defined 
by RECIST 1.1 (see Appendix 5, Section 10.5.1). In the absence of rapid 
clinical progression, the initial evidence of RECIST 1.1 disease progression is 
to be confirmed using iRECIST (see Appendix 5, Section 10.5.3) by a second 
assessment no less than four weeks from the date of the first documented 
progressive disease. 
i. This determination is made by the investigator. Once progressive disease is 
confirmed, the initial date of RECIST 1.1 progressive disease documentation 
will be considered that date of disease progression.
ii. In cases of unequivocal clinical or radiological progression, disease 
progression confirmation may not be required after documented discussion 
and approval by the sponsor.
c.
Progressive disease has been documented within 12 weeks from the last dose 
of anti-PD-1/PD-L1 mAb. 
5. Participants who receive anti-PD-1 therapy as adjuvant treatment following 
complete resection of liver cancer and have disease recurrence (unresectable loco-
regional disease or distant metastases) are eligible if they progressed while on 
active treatment or within 6 months of stopping anti-PD-1 therapy. This will be 
considered the first line of systemic therapy.


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For these participants, the following applies: 
1) a second assessment to confirm disease progression beyond recurrence is 
not required; and 
2) they must have received at least 2 prior doses of anti-PD-1/PD-L1 mAb.
6. Barcelona Clinic Liver Cancer (BCLC) stage B or C (see Appendix 8, 
Section 10.8).
7. Liver function status should be Child-Pugh (CP) Class A (see Appendix 9, 
Section 10.9) within 7 days prior to the first dose of study intervention. CP status 
should be calculated based on clinical findings and laboratory results during the 
screening period.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
within 7 days prior to prior to the first dose of study intervention.
9. At least one measurable lesion by CT scan or MRI according to RECIST 1.1. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, may be considered measurable if there has been 
demonstrated progression in the lesion.
10. Have adequate organ function as defined in the following table (Table 5–1). 
Specimens must be collected within 7 days prior to the start of study intervention.
Table 5–1: Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1000/mm3
Platelets
≥60 000/mm3
Hemoglobin
≥8.5 g/dLa
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic/Pancreatic
Total bilirubin
≤2 mg/dL. Mildly elevated total bilirubin (<6 mg/dL) is 
allowed if Gilbert’s syndrome is documented.
AST and ALT
≤5.0 × ULN 
Lipase 
≤ 3 x ULN without symptoms
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
PT-INR <2.3 and aPTT <1.5 x ULN unless receiving 
treatment with therapeutic anticoagulation


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Table 5–1: Adequate Organ Function Laboratory Values
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; INR = international normalized ratio; CrCl = creatinine clearance; GFR =
glomerular filtration rate; PT = prothrombin time; ULN = upper limit of normal.
a. Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. 
Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
b. Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration 
of specific chemotherapies.
11. Participants with controlled (treated) hepatitis B virus (HBV) infection will be 
allowed if they meet the following criteria:

Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral 
load must be less than 500 IU/mL prior to first dose of study intervention. 

Participants on active HBV therapy with viral loads under 500 IU/ml should 
stay on the same therapy throughout study treatment.

Participants who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, 
and have an HBV viral load under 500 IU/mL that do not require HBV 
antiviral prophylaxis.
12. Participants may have a past or ongoing hepatitis C virus (HCV) infection. 
Participants must have completed their treatment at least 1 month prior to W1D1 
or have received at least 1 month of direct acting antiviral (DAA) HCV therapy 
with no DAA related safety events and stable LFTs. For participants not on anti-
HCV therapy at the time of study enrollment, DAAs for treatment of HCV 
infection can be initiated per the investigator’s discretion, if LFTs are stable after 
3-6 months of study intervention upon sponsor consultation.
13. Provision of recent tumor tissue (as defined below) is mandatory at screening. 
Exceptions will be accepted for participants with no recent baseline tumor tissues 
after documented discussion and approval by the sponsor.

Tumor tissue obtained within 180 days of enrollment and after the last dose of 
most recent anti-cancer therapy.

Or a new biopsy.
Sex
14. Male and/or female who meet the requirements for contraception and 
breastfeeding as follows (additional contraception guidance is provided in 
Appendix 4, Section 10.4.2):

A male participant must agree to use highly effective contraception (see 
Appendix 4, Section 10.4.2) during the intervention period and for 120 
days after the last dose of regorafenib and refrain from donating sperm 
during this period. 

A female participant is eligible to participate if she is not pregnant (see 
Appendix 4, Section 10.4.3), not breastfeeding, and at least one of the 
following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 4, Section 10.4.1.


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b) A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4, Section 10.4.2 during the study intervention period and for 
at least 120 days after the last dose of pembrolizumab, and 210 days 
after the last dose of regorafenib. 
Informed Consent
15. Capable of giving signed informed consent as described in Appendix 1
(Section 10.1), which includes compliance with the requirements and restrictions 
listed in the ICF and in this protocol.
Participants must provide a signed informed consent before any screening 
procedures.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply at the time of 
screening:
Medical Conditions
1. Pregnant or breastfeeding patients or expecting to conceive or father children 
within the projected duration of the study, starting with the screening visit through 
at least 120 days after the last dose of pembrolizumab, and 210 days after the last 
dose of regorafenib.
Note: A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) 
prior to treatment. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
2. Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes. 
3. Patients unable to swallow and retain oral medications.
4. Patients with disease that is suitable for local therapy administered with curative 
intent.
5. Patients who experienced any CTCAE ≥ 3 or any other immune-related toxicities
that led to permanent discontinuation of treatment with immune checkpoint 
inhibitors in 1 L.
6. Persistent proteinuria of 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 hours.
7. Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid 
therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
interventions. The use of physiologic doses of corticosteroids may be approved 
after consultation with the sponsor.
8. Active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 


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replacement therapy for adrenal or pituitary insufficiency) is not considered a form 
of systemic treatment and is allowed.
9. History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
10. History of interstitial lung disease. 
11. Major surgical procedure or significant traumatic injury within 28 days before start 
of study medication.
Note: If the participant received major surgery, he/she must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting study treatment.
12. Non-healing wound, non-healing ulcer, or non-healing bone fracture.
13. Patients with evidence or history of any bleeding diathesis, irrespective of severity.
14. Any hemorrhage or bleeding event CTCAE Grade ≥ 3 within 28 days prior to the 
start of study medication.
15. Patients with large esophageal varices at risk of bleeding that are not being treated 
with conventional medical intervention: beta-blockers or endoscopic treatment. 
Assessment of esophageal varices (see Appendix 10, Section 10.10) should be 
performed by endoscopy within 6 months of the start of study intervention. For 
patients in whom conventional medical intervention for known esophageal varices 
is already in place, assessment should be performed by endoscopy as per local 
standard of care.
16. Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism within 6 months before the start of study medication (except for portal 
vein thrombosis and adequately treated catheter-related venous thrombosis 
occurring more than one month before the start of study medication).
17. History of organ allograft.
18. Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 
antibodies).
19. Ongoing infection CTCAE Grade > 2 requiring systemic therapy.
20. Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV 
infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
21. Uncontrolled hypertension (systolic blood pressure ≥ 140 millimeter of mercury 
[mmHg] or diastolic pressure ≥90 mmHg) on more than 2 separate measurements 
despite optimal medical management.
22. Congestive heart failure of New York Heart Association (NYHA) class ≥2 (see 
Appendix 7, Section 10.7). 
23. Unstable angina (angina symptoms at rest), new-onset angina (begun within the 
last 3 months).
24. Myocardial infarction less than 6 months before start of study intervention.
25. Uncontrolled cardiac arrhythmias despite optimal medical management.
26. Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥2 
dyspnea). Note: Participants treated with thoracentesis/paracentesis within 14 days 


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prior to signing informed consent are eligible if clinically stable and have 
recovered to dyspnea Grade ≤1 or baseline after the procedure.
27. Patients with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 3 years 
prior to study entry and no additional therapy is required or anticipated to be 
required during the study period.
28. Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate 
provided they are radiologically stable, i.e., without evidence of progression for at 
least 4 weeks by repeat imaging (note that the repeat imaging should be performed 
during study screening), clinically stable and without requirement of steroid 
treatment for at least 14 days prior to first dose of study treatment.
29. Seizure disorder requiring medication.
30. Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., 
Crohn’s disease, malabsorption, or CTCAE Grade ≥2 diarrhea of any etiology.
31. Current evidence or suspicion of gastrointestinal perforation or fistula.
32. Known hypersensitivity (Grade ≥3) to any of the study interventions, study 
intervention classes, or excipients in the formulation.
Prior/Concomitant Therapy
33. Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L.
34. Prior treatment with regorafenib, in combination regimens with immune 
checkpoint inhibitors.
35. Patients who received prior radiotherapy within 2 weeks of start of study 
treatment. Participants must have recovered from all radiation-related toxicities, 
not require corticosteroids, and not have had radiation pneumonitis. A 1-week 
washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-
CNS disease.
36. Patients who have received a live vaccine or live attenuated replication competent 
vaccine within 30 days prior to the first dose of study intervention. Seasonal 
injectable influenza vaccines and vaccines administered in a pandemic context are 
allowed.
37. Prior transplantation of human cells, tissues and organs (e.g. liver transplant) or 
candidates for any type of transplantation. 
38. Transfusion of blood products (including platelets or red blood cells) within 7 days 
prior to signing informed consent, or administration of colony stimulating factors 
(including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior 
to signing informed consent. 
39. Patients on concomitant use of CYP3A4 inducers, strong CYP3A4 inhibitors (see 
Appendix 6 in Section 10.6) and strong UGT1A9 inhibitors (e.g. mefenamic acid, 
diflunisal, and niflumic acid) within 2 weeks prior to start of study intervention. 
Prior/Concurrent Clinical Study Experience
40. Previous assignment to treatment during this study. Participants permanently 
withdrawn from study intervention will not be allowed to re-enter screening.


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41. Previous (at least a minimum of 28 days, or 5 half-lives of an investigational drug 
before the start of study treatment, whichever is shorter) or concomitant 
participation in another clinical study with investigational medicinal product(s).
42. Participants must have recovered from all AEs due to previous therapies to 
Grade ≤1 or baseline. Participants with treatment-related alopecia and Grade ≤2 
neuropathy may be eligible.
Other Exclusions
43. History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation 
for the full duration of the trial, or is not in the best interest of the patient to 
participate, in the opinion of the treating investigator. 
44. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
5.3
Lifestyle Considerations
Meals and Dietary Restrictions
Regorafenib should be administered with a low fat meal. There is no dietary restriction for 
pembrolizumab administration, participants should maintain a normal diet unless 
modifications are required to manage an AE such as diarrhea, nausea, or vomiting.
For details, refer to Section 6.
5.4
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but do
not start administration of either study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. The following data are to be recorded for all 
screen failure patients: 

Confirmation of informed consent

Demographic information

The reason for premature discontinuation (if the participant leaves the study for any 
reason during the screening period)
For participants who experience an SAE, or an AE related to a study procedure:

AE CRF 

All information related to the SAE such as:

Concomitant medications

Medical history

Complementary SAE CRF and other relevant information (e.g. lab data, death (if 
applicable))
To assess any potential impact on participant eligibility with regards to safety, the investigator 
must refer to the current IBs for detailed information regarding warnings, precautions, 


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contraindications, AEs, and other significant data pertaining to the investigational product 
being used in this study. 
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once without the need of re-consent. Only the laboratory tests that are out of 
range need to be repeated. Re-testing must be performed within 14 days of the initial test and 
with approval from the sponsor. The investigator has to ensure that the re-testing procedures 
do not expose the participant to an unjustifiable health risk and that results are available 
within the 28-day screening period. Participants may not begin study intervention until the 
results of re-testing are available and documented to be within protocol required range. 
In the event that the laboratory test(s) cannot be performed within the 28-day screening period, 
or the re-test(s) do not meet the entrance criteria, or other eligibility criteria have changed and 
are not met anymore, the participant is considered a screen failure, and must be discontinued 
from the study.
Re-screening of patients who have failed screening may only be allowed once after discussion
with the sponsor’s designated medical representative and after approval by the sponsor.
Sponsor approval of re-screening for a patient who has failed screening must be documented.
The screen failure will be registered manually in the Interactive Voice/Web Response System 
(IxRS) to close the original patient identification number (PID), and re-screening will start 
again by the participant signing a new informed consent form and being assigned a new PID
via IxRS.
All required screening activities must be performed when the participant is re-screened for 
participation in the study. 
Note: The investigator must be informed as soon as possible about any medications taken 
from the time of screening until the participant is discharged from the study.
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
The following interventions are to be administered during the study:
Regorafenib
Refer to the Summary of Product Characteristics (SmPC) / most recent IB for regorafenib for 
more details regarding drug properties and formulation. 
Regorafenib will be given orally (p.o.) at a starting dose of 90 mg QD for 3 weeks of every 
4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily is well tolerated 
(absence of any grade rash/HFSR or other Grade 2 or higher clinically significant toxicity), 
the dose can be escalated to 120 mg any time after the first cycle of regorafenib, starting with 
W5D1. Dose modification guidelines for dose reduction in case of toxicity are detailed in 
Section 6.6. 
Regorafenib should be taken within 2 hours after a light meal with approximately 240 mL 
(8 fluid ounces) of water, preferably in the morning. If necessary, regorafenib may be taken at 
different times of the day, but there should be consistency with respect to dosing intervals (the 
recommendation is to have at least a 20-hour interval between doses).


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If a dose of regorafenib will be missed, the missed dose should be skipped (vomited tablets 
cannot be made up), and the next dose should be taken at the regular time. The subsequent 
dose of regorafenib should not be doubled. The investigator should be informed if the dose of
regorafenib taken has exceeded the scheduled dose.
Regorafenib may start up to 3 days after the scheduled day after a 7-day break due to 
administrative reasons. Participants who halt regorafenib therapy for more than 
28 consecutive days - including the 1-week drug holiday - should be withdrawn from 
regorafenib. 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.
On days when pre-dose PK blood samples will be collected, participants will take the 
morning dose of regorafenib at the clinic after all required samples are collected. On days 
when PK samples are not required, regorafenib can be taken at home or in the clinic. On days 
when biomarker blood samples will be collected, the biomarker blood samples shall be 
collected up to 1 hour before the morning dose if feasible.
Pembrolizumab
Refer to the SmPC / most recent IB for pembrolizumab for more details regarding drug 
properties and formulation. 
Pembrolizumab will be administered as a dose of 400 mg using a 30-minute IV infusion 
Q6W. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (i.e., infusion time is 
30 minutes, -5 min/+10 min). Pembrolizumab must be infused before regorafenib when study 
interventions are given on the same day. The Pharmacy Manual contains specific instructions 
for the preparation of the pembrolizumab infusion and administration of infusion solution.
Pembrolizumab may be administered up to 3 days before or after the scheduled day of dosing 
due to administrative reasons. Note: dosing interruptions are permitted in the case of medical / 
surgical events or logistical reasons (i.e. elective surgery, unrelated medical events, 
participant vacation, holidays) not related to pembrolizumab. Participants should be placed 
back on pembrolizumab therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the sponsor. The reason for interruption should be documented in 
the participant’s study record. See Section 6.6 for the maximum infusion delay time permitted 
due to treatment-related reasons. Pembrolizumab treatment should be stopped after a 
participant has received 18 infusions.
Participants will receive study intervention until tumor progression, unacceptable toxicity, 
withdrawal of consent, investigator’s decision to stop therapy for the participant, sponsor’s 
decision to terminate the study, or death. If in the opinion of the investigator, the participant 
may still derive clinical benefit despite disease progression, continuation of study intervention 
is permitted after discussion with the sponsor. 
At the investigator’s discretion, a participant may continue on study intervention beyond 
radiological progression as defined by RECIST 1.1 if the clinical condition of the participant 
is stable or the participant is improving symptomatically, and the investigator expects 
continued clinical benefit for the participant until subsequent progression determined by 
iRECIST criteria (see Section 7.1).


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6.1
Study Intervention(s) Administered
Table 6–1: Administration of Study Intervention
Intervention Name
Regorafenib
Pembrolizumab
Type 
Small molecule drug (MKI)
Monoclonal antibody, biologic
Dose Formulation
Tablet
Solution for infusion
Unit Dose Strength
30 mg / tablet
100 mg / 4 mL vial (25 mg/mL)
Dosage Level(s)
3 x 30 mg tablets every day for 
21 days (QD) of every 28 days cycle 
(i.e. 3 weeks on, 1 week off) as a 
starting dose of 90 mg. If the starting 
dose of 90 mg QD is well tolerated 
(absence of any grade rash/HFSR or 
other ≥ regorafenib related Grade 2 
toxicity, except asymptomatic lab 
abnormalities that resolve to Grade ≤1 
within 72 hours), the dose can be 
escalated to 120 mg orally QD
(4x30 mg tablets) any time starting 
with W5D1.
400 mg (4 x 100 mg / 4 mL vials) 
are to be administered as an IV 
infusion Q6W (see Pharmacy 
Manual for details)
Route of 
Administration
Oral
IV infusion
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Regorafenib will be provided centrally 
by the sponsor.
Pembrolizumab 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 of regorafenib 
30 mg. The bottles will be labeled as 
required per country requirement.
Pembrolizumab will be provided 
in glass injection vials. Each 
glass injection vial will be labeled 
as required per country 
requirement.
Current/Former 
Name(s) or Alias(es)
Stivarga / BAY 73-4506
Keytruda / MK-3475
D = day; HFSR = hand-foot skin reaction; IMP = investigational medicinal product; IV = intravenous; 
MKI = multi-kinase inhibitor; NIMP = non-investigational medicinal product; Q6W = every 6 
weeks; W = week
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.
Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.


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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 the site file.
Handling/Storage/Accountability at the participant’s home
Participants will follow the instructions provided by authorized site staff for storage and 
administration of study intervention at home, as well as for return of unused study 
intervention to the site.
6.3
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. Randomization is not applicable for the study. All participants 
will be centrally assigned to the study intervention using an IxRS and will be given a unique 
PID prior to the start of study intervention. 
6.4
Study Intervention Compliance
6.4.1
Pembrolizumab
Participants are dosed at the site, and they will receive pembrolizumab directly from the 
investigator or designee. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the electronic case report form (eCRF). The 
dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. 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.
6.4.2
Regorafenib
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Participants will be instructed to take study
intervention as scheduled, and to return all of the study intervention packaging including 
unused study intervention and empty packaging. Participants should fill in the paper-based 
patient drug diary after each intake of study intervention. To monitor compliance, drug 
accountability information will be documented for each participant. Compliance will be 
assessed by counting returned tablets during the site visits and documented in the source 
documents and eCRF. To support participants in establishing the drug intake rhythm (i.e. 6-
week cycle for pembrolizumab, 4-week cycle for regorafenib), the site personnel are asked to 
call participants regularly for at least the first 3 regorafenib treatment cycles to remind them 
of omitting regorafenib during the 4th week of a cycle. Deviation(s) from the prescribed 
dosage regimen should be recorded in the eCRF. A record of the number of tablets dispensed 
to and returned by each participant must be maintained and reconciled with intervention 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 intervention must be discussed with the participant at the time of the visit, and any 
explanation must be documented in the source records. An adequate record of receipt, 
distribution, and return/destruction of all study intervention must be kept.


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A record of the number of study intervention(s) tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
When participants are dosed at the site, they will receive regorafenib directly from the 
investigator or designee.
6.5
Concomitant Therapy
Medication other than the investigational products should not be taken during the study 
without consulting the investigator. 
Any medication that is considered necessary for the participant’s welfare, and which is not 
expected to interfere with the evaluation of the study medications, may be given at the 
discretion of the investigator. 
All concomitant medications that may affect efficacy or toxicity or are taken for any 
concurrent medical conditions at the time of enrollment or  during the study (including 
start/stop dates, dose frequency, route of administration and indication) must be recorded in 
the participant’s source documentation, as well as in the appropriate pages of the eCRF. 
In general, participants should be closely monitored for side effects of all concomitant 
medications regardless of elimination pathway, especially those with narrow therapeutic 
index, such as warfarin, quinidine and cyclosporine.
Administration of contrast media for protocol-specified radiological procedures does not need 
to be reported, unless there is an AE related to the contrast medium injection (e.g. allergic 
reaction). 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The investigator should discuss any questions regarding this with the sponsor. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the sponsor and the participant.
Listed below are specific prohibited medications for concomitant therapy or vaccination 
during the course of the study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than regorafenib and pembrolizumab

Radiation therapy 
Note: Palliative radiotherapy during the study for local pain control or to the brain 
may be allowed at the investigator’s discretion.

Live or live attenuated replication competent vaccines within 30 days prior to the first 
dose of study treatment and while participating in the study. Note: killed vaccines are 
allowed. 

Systemic glucocorticoids are permitted only for the following purposes:


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o
To modulate symptoms of an AE that are suspected to have an immunologic 
etiology
o
As needed for the prevention of emesis
o
Premedication for IV contrast allergies
o
Short-term oral or IV use in doses >10mg/day prednisone equivalent for chronic 
obstructive pulmonary disease (COPD) exacerbations
o
For chronic systemic replacement, not to exceed 10 mg/day prednisone 
equivalent
o
In addition, the following glucocorticoid use is allowed:

For topical use or ocular use

Intra-articular joint use

For inhalation in the management of asthma or COPD
Note: Inhaled steroids are allowed for management of asthma.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded for 
SAEs and events of clinical interest (ECIs) as defined in Section 8.3.6.
6.5.1
Drug-drug Interactions Relevant for Regorafenib
6.5.1.1
Inhibitors / Inducers of CYP3A4
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a 
single dose of regorafenib (160 mg on Day 5) resulted in an increase in mean exposure (AUC) 
of regorafenib of approximately 33%, and a decrease in mean exposure of the active 
metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is 
recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity as their 
influence on the steady-state exposure of regorafenib and its metabolites has not been studied.
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single 
dose of regorafenib (160 mg on Day 7) resulted in a reduction in AUC of regorafenib of 
approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, 
and no change in exposure of active metabolite M-2. Other CYP3A4 inducers may also 
increase metabolism of regorafenib. Inducers of CYP3A4 should be avoided, or selection of 
an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 
should be considered.
Appendix 6 (Section 10.6) provides an overview of the most commonly used strong CYP3A4 
inhibitors and CYP3A4 inducers that should be avoided during the study.
6.5.1.2
UGT1A1 and UGT1A9 Substrates 
In vitro data indicate that regorafenib as well as its active metabolites M-2 inhibit 
glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at 
concentrations which are achieved in vivo at steady state. 
Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted 
in an increase of approximately 44% in mean exposure (AUC) of SN-38, a substrate of 
UGT1A1 and an active metabolite of irinotecan. An increase in mean exposure (AUC) of 
irinotecan of approximately 28% was also observed. This indicates that co-administration of 


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regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. The 
clinical significance is unknown and is dependent on the substrate.
6.5.1.3
Breast Cancer Resistance Protein and P-glycoprotein Substrates
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of 
rosuvastatin (5 mg), a breast cancer resistance protein (BCRP) substrate, resulted in a 3.9-fold 
increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax. This 
indicates that co-administration of regorafenib may increase the plasma concentrations of 
other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it 
is recommended to monitor participants closely for signs and symptoms of increased exposure 
to BCRP substrates. 
6.5.1.4
CYP Isoform-selective Substrates
A cytochrome P450 enzyme probe substrate study in cancer patients was conducted to 
evaluate the effect of regorafenib on the pharmacokinetics of CYP2C9 substrate warfarin 
(10 mg), CYP2C19 substrate omeprazole (40 mg), CYP3A4 substrate midazolam (2 mg) and 
CYP2C8 substrate rosiglitazone (4 mg) and to provide information about potential changes in 
exposure of these substrates when administered with regorafenib.
Overall, 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
Drug-drug Interactions Relevant for Pembrolizumab 
No formal PK drug interaction studies have been conducted with pembrolizumab. Since
pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug
interactions are expected.
6.5.3
Prohibited Prior and Concomitant Therapies
Participants are prohibited from receiving the following therapies during the screening and 
intervention periods of this trial:

The use of systemic corticosteroids or immunosuppressants before starting 
pembrolizumab should be avoided because of their potential interference with the 


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pharmacodynamic activity and efficacy of pembrolizumab. Note: replacement therapy 
such as physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency (in dosing not exceeding 10 mg daily of prednisone equivalent) is not 
considered a form of systemic treatment, and inhaled steroids are allowed for 
management of asthma. Moreover, systemic corticosteroids or other 
immunosuppressants can be used after starting pembrolizumab to treat immune-
related adverse reactions.

Disease-specific anti-neoplastic therapies, including kinase inhibitors, 
immunotherapy, chemotherapy, or experimental therapies other than regorafenib and 
pembrolizumab.

Surgery for symptom management or tumor control.

Strong CYP3A4 inhibitors or CYP3A4 inducers (See Section 6.5.1.1, and 
Appendix 6 in Section 10.6).

Co-administration of strong UGT1A9 inhibitors (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.

Live vaccines or live attenuated replication competent vaccines within 30 days prior to 
the first dose of trial treatment and while participating in the trial. Seasonal injectable 
influenza vaccines and vaccines administered in a pandemic context are allowed.
The exclusion criteria describe other medications that are prohibited in this trial (Section 5.2). 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
6.5.4
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.

Treatment with non-conventional therapies (e.g. herbs or acupuncture) and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the investigator. However, St John’s Wort (herbal 
preparation based on the plant species hypericum) is not permitted.

Participants who are therapeutically treated with an agent such as warfarin or heparin 
or novel oral anticoagulants (NOACs) such as dabigatran or rivaroxaban will be 
allowed to participate provided that no prior evidence of underlying abnormality in 
coagulation parameters exists. Close monitoring of at least weekly evaluations for 
participants on warfarin will be performed until the INR is stable based on a 
measurement that is pre-dose as defined by the local standard of care.

P-glycoprotein substrates: clinical data indicate that regorafenib has no effect on 
digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein 
substrates, such as digoxin, without a clinically meaningful drug interaction (see 
Section 6.5.1.3).

Participants may receive palliative or supportive care for any underlying illness.

Palliative and supportive care for other disease-related symptoms and for toxicity 
associated with treatment will be offered to all participants on this trial. The use of 
anti-diarrheal or anti-emetics according to standard practice is strongly encouraged.


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
Bisphosphonates and/or RANKL (receptor activator of nuclear factor kappa-Β ligand)
inhibitor therapies (such as denosumab) for bone metastases may be continued if 
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.

Radiotherapy:
o
Palliative radiotherapy during the study is allowed for local pain control after 
individual benefit-risk assessment provided that:

In the opinion of the investigator, the participant does not have PD,

No more than 25% of the participant’s bone marrow is irradiated,

The radiation field does not encompass a target lesion, and

The radiation field does not encompass a lung field (to reduce the risk for 
interstitial lung disease [ILD] caused by irradiation pneumonitis). 
o
Regorafenib may only be continued during palliative radiotherapy after an 
individual benefit-risk assessment. The investigator should consult the sponsor.
o
Pembrolizumab must be held during radiation treatment and should be resumed no 
earlier than the next scheduled administration of study intervention. 
Note: administration of palliative radiation therapy to a symptomatic solitary lesion or 
to the brain will be considered clinical progression for the purposes of determining 
PFS.

Analgesics.

Nutritional support.

Major surgery for any reason different than symptom management or tumor control 
should only be performed during the study period if, in the opinion of the investigator 
and after careful individual benefit / risk assessment (taking into account the potential 
wound healing complications that have been described with all anti-VEGF drugs), the 
surgery will be beneficial for the participant. It is recommended to stop regorafenib 
treatment two weeks before surgery. The decision to resume regorafenib after surgery 
should be based on clinical judgment of adequate wound healing. Participants should 
be placed back on study therapy within 4 weeks of the scheduled interruption of 
regorafenib.
Note: if treatment interruption of regorafenib will be >28 consecutive days - including 
the 1 week drug holiday – the participant must be discontinued from regorafenib. 
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 the sponsor.
Participants who experience a delay of more than 12 weeks before the subsequent 
pembrolizumab infusion must be discontinued from pembrolizumab.

Participants may receive other medications that the investigator deems to be medically 
necessary.


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6.5.5
Post-study Therapy
There are no prohibited therapies during the post-intervention active and long-term follow-up 
periods. Further new anti-cancer treatment after the end of the study combination treatment 
will be at the discretion of the investigator. Information on at least the first new anti-cancer 
regimen must be recorded in the participant’s source documentation, as well as in the 
appropriate pages of the eCRF.
At the conclusion of the study, participants who demonstrate clinical benefit may be eligible 
to continue to receive study treatment. They may receive further treatment, assessments 
and/or be followed either via a post-trial access program, a roll-over study - subject to 
approval by the competent health authority and ethics committee - or through any other 
mechanism in accordance with local legal and compliance rules. This applies to participants
on study treatment and in follow-up.
Until the transition to other supportive programs, participants will continue to follow all the 
procedures and visits required in the current version of the protocol.
6.6
Dose Modification
Based on the known toxicity profiles of regorafenib and pembrolizumab, 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 
pembrolizumab; similarly, immune-related AEs are likely to be associated with 
pembrolizumab rather than regorafenib. However, some drug-related AEs such as rash, 
diarrhea, abnormal thyroid function, and fatigue are overlapping. Therefore, it is important to
evaluate each AE and consider time of onset, perform the appropriate work-up for 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 of regorafenib and pembrolizumab will be based on the highest grade of 
AE that occurred since the last contact. If a participant experiences multiple toxicities, dose 
modification will be based on the toxicity with the highest grade. In case of multiple toxicities 
of the same grade, the investigator may modify the dose based on the toxicity that appears 
most likely related to study interventions.
In case of dose delays, assessments should be performed on Day 1, according to the SoA (see 
Section 1.3).
Regorafenib dose modifications should be done according to Table 6–2.
The recommendations regarding dose adjustments and treatment interruptions from Table 6–3
to Table 6–8 can be used as support for the clinical decision and respective monitoring/
treatment guidance. A careful decision will be made by investigators based on all clinical 
information, e.g. relatedness to study medications. 
Once a dose reduction of regorafenib has been performed, there will be no intra-participant re-
escalation.
Where it is indicated to reduce regorafenib one dose level, Table 6–2 should be followed:


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Table 6–2: Regorafenib Dose Reduction Scheme
Dose Level
Daily Regorafenib 
(3 weeks on, 1 week off)
Daily Regorafenib 
(3 weeks on, 1 week off)
Current Dose
90 mg
120 mg
Dose Level -1
60 mg 
90 mg
Dose Level -2
Not applicable
60 mg 


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Table 6–3: Dose Modification Guidance, Non-immune Toxicities
Event
Regorafenib
Pembrolizumab
Hematologic toxicities
G3/4 Neutropenia
G3/4 Anemia
G3/4 Thrombocytopenia

Hold until recovery to ≤ G2 and reduce 1 dose levela

1st re-appearance: Hold until recovery to ≤ G2 and 
reduce 1 additional dose levela

2nd re-appearance: discontinue

G3 (excluding G3 neutropenia):
-
Hold and restart at same dose if resolution to 
≤G1 or baseline ≤ 12 weeks of last infusion
-
Hold and consider discontinuation if NO 
resolution ≤ 12 weeks of last infusion

G4: discontinueb
Non-hematologic toxicities
General guidance for G2 events

No modifications

Consider withholding for persistent symptoms

Restart at same dose if resolution to ≤ G1 or 
baseline ≤12 weeks of last infusion

Consider discontinuation if NO resolution 
≤12 weeks of last infusionb
General guidance for G3 events

Hold until recovery to ≤ G2 and restart at same dose 
level or reduce 1 dose levela (at the investigator’s 
discretion)

1st + 2nd re-appearance: Hold until recovery to ≤ G2 and 
reduce 1 dose levela (at the investigator’s discretion)

3rd re-appearance: Discontinue

Discontinuation is required for gastrointestinal 
perforation or fistula

Hold until recovery in case of cardiac ischemia and/or 
infarction. At the investigator’s discretion restart at 
same dose level or reduce 1 dose levela. Permanently 
discontinue if there is no resolution.

Hold and restart at same dose if resolution to 
≤G1 or baseline ≤ 12 weeks of last infusion

Hold and discontinue if NO resolution ≤ 12 weeks 
of last infusionb
General guidance for G4 events 

Hold until recovery to ≤ G2 and reduce 1 dose level

1st re-appearance: Hold until recovery to ≤ G2 and 
reduce 1 additional dose levela

2nd re-appearance: Discontinue

Discontinuation is required for gastrointestinal 
perforation or fistula

Hold until recovery in case of cardiac ischemia and/or 

Discontinueb


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Table 6–3: Dose Modification Guidance, Non-immune Toxicities
Event
Regorafenib
Pembrolizumab
infarction. At the investigator’s discretion restart at 
same dose level or reduce 1 dose levela. Permanently 
discontinue if there is no resolution.
Specific guidance for hand-foot skin reaction (HFSR)
G1

Maintain dose level and institute supportive measures 
immediately for symptomatic relief

No modification
G2

1st occurrence: Consider decrease by 1 dose level and 
institute supportive measures immediatelya. If no 
improvement, interrupt for ≥ 7 days, until toxicity 
resolves or improves to G1

No improvement ≤ 7 days or 2nd occurrence: Interrupt 
until toxicity resolves or improves to G1. When 
resuming treatment, treat at reduced dose levela.

3rd occurrence: Discontinue

No modification 
G3

1st occurrence: Institute supportive measures 
immediately. Interrupt therapy for ≥ 7 days until toxicity 
resolves or improves to G1. When resuming treatment, 
decrease by 1 dose levela.

2nd occurrence: Institute supportive measures 
immediately. Interrupt therapy for ≥ 7 days until toxicity 
resolves or improves to G1. When resuming treatment, 
decrease by 1 additional dose levela.

3rd occurrence: Discontinue

No modification 
Specific guidance for skin and subcutaneous disorders other than HFSR (includes rash, rash erythematous, rash follicular, rash generalized, 
rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, pruritus, eczema, dermatitis)
G2 

No modifications

Consider withholding for persistent symptoms

Restart at same dose if resolution to ≤ G1 or 
baseline ≤12 weeks of last infusion

Consider discontinuation if NO resolution 
≤12 weeks of last infusionb


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Table 6–3: Dose Modification Guidance, Non-immune Toxicities
Event
Regorafenib
Pembrolizumab
G3 

Hold until recovery to ≤ G2 and restart at same dose
level or reduce 1 dose levela (at the investigator’s 
discretion)

1st + 2nd re-appearance: Hold until recovery to ≤ G2 and 
reduce 1 dose levela (at the investigator’s discretion)

3rd re-appearance: Discontinue

Hold and restart at same dose if resolution to
≤G1 or baseline ≤ 12 weeks of last infusion

Hold and discontinue if NO resolution ≤ 12 weeks 
of last infusionb
G4 (when applicable)

Hold until recovery to ≤ G2 and reduce 1 dose levela

1st re-appearance: Hold until recovery to ≤ G2 and 
reduce 1 additional dose levela

2nd re-appearance: Discontinue

Discontinueb
Specific guidance for HYPERTENSION
G1

No change. Consider increased BP monitoring

No modification
G2

If symptomatic, hold until symptoms resolve AND 
diastolic BP ≤ 90 mmHg. At restart, continue at the 
same dose level

No modification
G3

Hold until diastolic BP ≤ 90 mm Hg, and if symptomatic, 
until symptoms resolve. 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 levela

If G3 hypertension recurs despite dose reduction and 
antihypertensive therapy, reduce another dose levela

No modification
G4

Discontinue

Discontinueb
BP = blood pressure; G1/2/3/4 = Grade 1/2/3/4; HFSR = hand-foot skin reaction; QD = every day
a: If reductions are required resulting in a dose of less than 60 mg QD of regorafenib, then regorafenib will be permanently discontinued. For Grade 3 
neutropenia, the participant could stay on regorafenib for the first appearance, or hold until resolved to Grade 2 or less, restart at the same dose level or 
lower after discussion between the investigator and the sponsor.
b: After consultation with the sponsor, if toxicity is considered at least possibly related to pembrolizumab. 


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6.6.1
Dose Modification and Management of Lower Gastrointestinal Toxicity 
Gastrointestinal (GI) toxicity in the form of diarrhea could be very common and a potentially serious event caused by regorafenib and 
pembrolizumab combination therapy, as both regorafenib and pembrolizumab may cause gastrointestinal adverse reactions. Diarrhea could be 
either the only presenting symptom of GI toxicity, potentially self-limiting, or part of immune checkpoint inhibitor-induced colitis that could 
require hospitalization and intensive treatment. Immune-related colitis (any grade) has been reported in 1.8% of patients receiving 
pembrolizumab. The median time to onset of immune-related colitis was 3.5 months whereas the median duration was 1.4 months, leading to 
discontinuation of pembrolizumab in 0.5% of patients. No predictive marker for the occurrence of gastrointestinal toxicity related to immune
checkpoint inhibitors has been validated yet. As such, it is important to distinguish among different types of diarrhea and exclude alternative 
etiology (e.g. disease progression, other medications, infections).
Table 6–4: Dose Modification Guidance, Lower Gastrointestinal Toxicity
General instructions for management of lower gastrointestinal toxicity:

Monitor all participants for signs and symptoms of enterocolitis (i.e. diarrhea, abdominal pain, blood or mucus in stool with or without fever) and 
bowel perforation (i.e. peritoneal signs and ileus)

For diarrhea G1 and G2:
o
Oral fluids, loperamide, avoid high fiber/lactose diet 

For diarrhea G2 (> 7 days) or higher, consider per local institutional guidelines: 
o
Blood tests (e.g. hematology and general chemistry including liver function tests (AST, ALT, Bilirubin))
o
Stool (e.g. culture, Clostridium difficile, cytomegalovirus (CMV) or other viral etiology, ova, and parasite)
o
GI consultation and imaging (e.g., CT scan of abdomen and pelvis and GI endoscopy with biopsy)
o
Administer corticosteroids (initial dose of 1-2 mg/kg prednisone or equivalent) followed by taper upon AE improving to ≤ G1 and continue 
to taper over at least 4 weeks

For severe and life-threatening diarrhea and/or immune-related colitis:
o
Consider hospitalization or outpatient facility for participants with dehydration or electrolyte imbalance 
o
Fluid and electrolytes should be administered via IV infusion
o
Urgent GI consultation and imaging (e.g., CT scan of abdomen and pelvis and GI endoscopy with biopsy)
o
IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids
Event
Regorafenib
Pembrolizumab
Diarrhea G1; <4 stools/day over baseline
No modifications
No modifications
Diarrhea G2; 4-6 stools/day over baseline
No modifications, BUT if diarrhea G2 persistent 
(not back to ≤ G1 in 7 days), hold regorafenib until 

G2: Withhold; restart at same dose if 
resolution to ≤ G1 or baseline ≤ 12 weeks of 


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Table 6–4: Dose Modification Guidance, Lower Gastrointestinal Toxicity
back to ≤ G1. Restart at same dose level or 
reduce 1 dose levela (at the investigator’s 
discretion).
last infusion and corticosteroid has been 
tapered
Diarrhea G3; ≥7 stools/day over baseline

G3: Hold regorafenib until back to ≤ G1. 
Restart at same dose level or reduce 1 dose 
levela (at the investigator’s discretion)

G3: Withhold; restart at same dose if 
resolution to ≤ G1 or baseline ≤ 12 weeks of 
last infusion and corticosteroid has been 
tapered

Recurrent G3: permanently discontinue
Diarrhea G4; Life-threatening consequences

G4: Interrupt until ≤ G1. Restart at one dose 
level belowa

G4: Permanently discontinue
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; CT = computed tomography; G1/2/3/4 = 
Grade 1/2/3/4; GI = gastrointestinal; IV = intravenous; irAE = immune-related adverse event; QD = every day
a: If reductions are required resulting in a dose of less than 60 mg QD of regorafenib, then regorafenib will be permanently discontinued.
6.6.2
Dose Modification and Management of Liver Toxicity
Elevation of liver enzymes could be a very common finding during the course of regorafenib and pembrolizumab combination therapy. In the
ongoing 19497 study of regorafenib and pembrolizumab in HCC patients in first line, as of 06 JAN 2020, 31% of the patients experienced 
Grade 3 treatment-emergent AE (TEAE) of AST or ALT increase and 6% of them experienced Grade 4 occurrences. 
A careful assessment should be done to define the proper etiology of any hepatic alteration found in the course of the study in order to exclude 
the underlying disease and an immune-mediated hepatic events as possible causes, before defining a liver toxicity as related to the study 
interventions. 
Participants with a history of HBV or HCV with elevated transaminases who meet the criteria below should be evaluated for viral 
exacerbation/reactivation and viral load and hepatitis serologies (as needed) should be performed for evaluation of viral 
exacerbation/reactivation:

Among participants with baseline AST/ALT ≤2×ULN: AST/ALT >5×ULN

Among participants with baseline AST/ALT >2×ULN: AST/ALT >3×the baseline level

AST/ALT >500 U/L regardless of baseline level


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Table 6–5: Dose Modification Guidance; Specific Guidance for Liver Toxicity
Event
Regorafenib
Pembrolizumab
General instructions:

If any of below outlined events will occur: Monitor liver function tests weekly or more frequently until recovery to baseline or stabilization

The recommendations regarding dose adjustments and treatment interruptions can be used as support for the clinical decision. A careful decision will be 
made by investigators based on all clinical information, e.g. relatedness to study medications

Follow the guidance provided in Table 6–6 with respect to Hepatitis B flare, Hepatitis C recurrence or flare and immune-related hepatitis

For any G3/4 increases in ALT/AST or bilirubin:
o
If the increases are primarily seen under ongoing regorafenib treatment (e.g. last pembrolizumab infusion was given one week before): 

Closely monitor for potential de-challenge, i.e. whether a decrease in ALT/AST and/or bilirubin values is seen within 3 days of regorafenib 
interruption 

In case no such decrease is seen and/or a further deterioration in liver function is seen: Administer corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) followed by taper
If immune-related hepatitis is suspected: Directly follow guidance provided in Table 6–6.
ALT/AST > 5 x ULN if ALT/AST ≤2 x ULN 
at baseline 
OR 
ALT/AST 3-fold increase from D1 level 
but not exceeding 8 x ULN if ALT/AST 
> 2 x ULN at baseline

Assess according to guidance given in Table 6–6

Hold until recovery to ≤ G1 or baseline, then reduce 
1 dose levela

At restart monitor liver function tests weekly for at least 
4 weeks

1st re-appearance: Discontinue 

Hold and assess + decide on potential restart 
according to guidance given in Table 6–6
ALT or AST > 5 x ULN accompanied by a 
t-hyperbilirubinemia ≥ 3 x ULN 

Assess according to guidance given in Table 6–6

At restart monitor liver function tests weekly for at least 
4 weeks

Hold until recovery to ≤ G1 or baseline, then reduce 
1 dose levela

A participant with Gilbert’s syndrome should be 
managed according to observed elevation of ALT 
and/or AST if the observed bilirubin increase is below 
actual increased baseline bilirubin value

Hold and assess + decide on potential restart 
according to guidance given in Table 6–6
Any t-bilirubin > 3.0 mg/dL irrespective of 
ALT/AST values

Assess according to guidance given in Table 6–6

Hold until recovery to ≤ G1 or baseline, then reduce 
1 dose levela

1st re-appearance: Discontinue 

For a participant with Gilbert’s syndrome a continuation 
of regorafenib might be considered at the discretion of 

Hold and assess + decide on potential restart
according to guidance given in Table 6–6


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Table 6–5: Dose Modification Guidance; Specific Guidance for Liver Toxicity
Event
Regorafenib
Pembrolizumab
the investigator if the observed bilirubin increase is 
below actual increased baseline bilirubin value
AST and / or ALT > 20 x ULN

Discontinue and assess according to guidance given in 
Table 6–6

Discontinue and assess according to 
guidance given in Table 6–6
Hepatic Encephalopathy

Discontinue unless hepatic encephalopathy is 
manageable and reversibleb and assess according to 
guidance given in Table 6–6

Discontinue unless hepatic encephalopathy 
is manageable and reversibleb and assess 
according to guidance given in Table 6–6
Child-Pugh score of > 9 points

Discontinue and assess according to guidance given in 
Table 6–6

Discontinue and assess according to 
guidance given in Table 6–6
New onset of clinically detectable ascites 
requiring intervention for >3 days

No modifications

Discontinue and assess according to 
guidance given in Table 6–6
Gastrointestinal bleeding suggestive of 
portal hypertension (e.g., esophageal or 
gastric varices)

Discontinue and assess according to guidance given in
Table 6–6

Hold and assess + decide on potential restart 
according to guidance given in Table 6–6
Recurrence of a severe or life-threatening 
event, or of any of the laboratory 
abnormalities listed above

Discontinue and assess according to guidance given in 
Table 6–6

Discontinue and assess according to 
guidance given in Table 6–6
If the participant is off study treatment 
therapy for infection, obstruction, or 
drug/alcohol-related toxicity for more than 
3 weeks, or if they have esophageal 
bleeding, or become CP C at any point

Discontinue and assess according to guidance given in 
Table 6–6

Discontinue and assess according to 
guidance given in Table 6–6
ALT = alanine aminotransferase; AST = aspartate aminotransferase; G1/2/3/4 = Grade 1/2/3/4; QD = every day; ULN = upper limit of normal
a: If reductions are required resulting in a dose of less than 60 mg QD of regorafenib, then regorafenib will be permanently discontinued. For Grade 3 
neutropenia, the participant could stay on regorafenib for the first appearance, or hold until resolved to Grade 2 or less, restart at the same dose level or 
lower after discussion between the investigator and the sponsor.
b: Hold until recovery to Grade ≤ 1 and restart at the same dose level or reduce 1 dose level a (at the investigator’s discretion) if hepatic encephalopathy is 
manageable and reversible, after discussion with the sponsor.


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6.6.2.1
Hepatic Events of Clinical Interest
The following events and laboratory abnormalities, if not associated with disease progression 
under study per investigator’s judgement, are considered as hepatic events of clinical interest 
(HECI) and must be reported as SAEs (within 24 hours of the investigator’s awareness): 

ALT:

ALT ≥5 × ULN if baseline ALT <2 x ULN

ALT >3 × baseline level if baseline ALT ≥2 x ULN

Any ALT >500U/L

Any t-bilirubin >3.0 mg/dL

Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:

New onset of clinically detectable ascites requiring intervention for >3 days

Hepatic encephalopathy
Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be made available. It may also be appropriate to conduct an additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including ALT and bilirubin that do not meet the criteria noted above. In these cases, the 
decision to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver blood 
tests that do not meet the criteria noted above are not ECIs for this trial.
Table 6–6: Guidance on Assessment and Further Dosing Following Occurrence of 
Hepatic Events of Clinical Interest
Assessment procedure to be applied

Notification of the sponsor within 24 hours via SAE report if applicable (see also Section 8.3). 
Refer to Section 8.3.6 for AEs of special safety interest that must be reported as SAEs

Consider a consultation with a hepatologist.

Consider a work-up for hepatitis if there is no underlying hepatitis, including hepatitis A, B, C, D, 
E, Epstein-Barr virus (EBV), cytomegalovirus (CMV).

Assess for ingestion of drugs/supplements with hepatotoxic potential.

Assess for alcohol ingestion.

Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal bleeding

Repeat ALT, AST, t-bilirubin, direct bilirubin, ALP, GGT, INR, and CBC (complete blood count) 
with differential.

Other laboratories or imaging studies as clinically indicated.

Consider liver biopsy if indicated by hepatologist.

Infection needs to be ruled out with cultures of blood, urine, and ascites (if possible), as well as 
chest X-ray and abdominal imaging if relevant. If an infection is found, antibiotics should be 
started.

If t-bilirubin is elevated above baseline, magnetic resonance cholangio-pancreatography or 
ultrasound with Doppler should be obtained to rule out vascular compromise, biliary obstruction, 
and/or tumor progression.

If biliary obstruction is present, consultation with a gastroenterologist and/or an interventional 
radiologist should be obtained to see if the obstruction may be relieved.

A careful review of drugs, including herbal and alternative medications, should be obtained, and 
alcohol use should be ruled out.

Hepatitis C-infected participants (including participants who previously achieved sustained 


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Table 6–6: Guidance on Assessment and Further Dosing Following Occurrence of 
Hepatic Events of Clinical Interest
virological response [SVR] for 12 consecutive weeks after the cessation of antiviral treatment 
[SVR 12]): Measure HCV RNA viral load.

Hepatitis B-infected participants: HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, 
and anti-HBs; participants should be questioned about compliance with the use of antiviral 
agents
Further information concerning Hepatitis B Flare
Hepatitis B flares are characterized by rapid elevations of ALT and AST to >5 × ULN and/or 
>3 × baseline. ALT elevation to ≥10 × ULN is common. In the absence of hepatic decompensation, 
ALT/AST elevations are typically isolated (i.e., limited/no elevations of bilirubin/ALP). Participants
who are compliant with antiviral therapy should have continued suppression of HBV DNA at the time 
of flare; thus, detection of HBV DNA should prompt questioning of participants for compliance. 
Laboratory abnormalities secondary to flare are typically observed for 3-5 weeks.
Among participants with HBV, a flare should be considered if this pattern is observed and there is 
no evidence of an alternative etiology. Guidelines for participants with a diagnosis of HBV flare are 
as follows:

Care should be instituted in consultation with a hepatologist.

For participants who have detectable HBV DNA, re-institute antiviral therapy.

If the participant is clinically stable, pembrolizumab dosing may be interrupted for up to 
12 weeks. Participants should undergo weekly laboratory tests including: AST, ALT, ALP, Tbil, 
Dbil, INR, HBsAg, HBV DNA (if detected at the onset of the flare). Obtain anti-HBe, anti-HBs, 
and HBV DNA levels (if not detected at the onset of the flare) every 2-3 weeks.

Restart pembrolizumab intervention only if ALT returns to normal or Grade 1 (if normal at 
baseline), or to baseline grade (if Grade 2 at baseline) within 12 weeks, and the participant is 
clinically stable, otherwise the participant should be permanently discontinued.
Further information concerning Hepatitis C Recurrence or Flare
Participants who achieved SVR 12 and participants with ongoing HCV infection are eligible for 
enrollment. In rare circumstances, HCV participants who achieve SVR 12 may relapse at later time 
points. Relapse is characterized by detection of HCV RNA, often accompanied by ALT elevations to 
>5 × ULN. In the absence of hepatic decompensation, ALT/AST elevations are typically isolated 
(i.e., limited/no elevations of bilirubin/ALP).
Among participants with uncontrolled hepatitis C, virologic flares are possible. Hepatitis C flares are 
characterized by rapid elevations of ALT and AST to >5 × ULN and/or >3 × baseline along with a 
rise in HCV RNA. ALT elevation to ≥10 × ULN and a 1 log elevation in HCV RNA level are common. 
In the absence of hepatic decompensation, ALT/AST elevations are typically isolated (i.e., limited/no 
elevations of bilirubin/ALP). Laboratory abnormalities secondary to flare or recurrence are typically 
observed for 3-5 weeks. 
Guidelines for participants with recurrent HCV infection or an HCV flare are described below:

Interrupt pembrolizumab intervention for up to 12 weeks

Restart pembrolizumab intervention only if ALT returns to normal or G1 (if normal at 
baseline), or to baseline grade (if G2 at baseline) within 12 weeks, and the participant is 
clinically stable, otherwise, the participant should be permanently discontinued
Recurrent HCV infection (relapse of HCV infection for participants successfully treated or 
with new HCV infection):
If the participant entered the study with an HCV RNA test of “Target not Detected” and has 
confirmed detectable HCV RNA (2 specimens, 1 week apart), then the participant has experienced 
a late HCV relapse or a recurrent infection. 

Question the participant about use of injection or inhalation drugs

At the time of first detection of HCV RNA, send a specimen for HCV genotyping or serotyping (if 
genotyping is not available) (local laboratory)

Measure AST, ALT, ALP, Tbil, Dbil, and INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV antiviral treatments should be strongly considered.
HCV Flare (hepatitis C exacerbation in participants with HCV RNA positive):

At the time of first detection of HCV RNA, send a specimen for HCV genotyping or serotyping (if 
genotyping is not available) (local laboratory)


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Table 6–6: Guidance on Assessment and Further Dosing Following Occurrence of 
Hepatic Events of Clinical Interest

Measure AST, ALT, ALP, Tbil, Dbil, INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV antiviral treatments should be strongly considered
Further information concerning Immune-related hepatitis
Description: Immune-related hepatitis due to study treatment should be suspected if any of the 
following is seen:

ALT baseline values are less than 2 × ULN, and AST or ALT laboratory values increase to 
≥5 × ULN

Among participants with baseline ALT ≥2 × ULN, levels increase to >3× the baseline level

ALT >500 U/L regardless of baseline level

Total bilirubin >3.0 mg/dL regardless of baseline level
Immune-related hepatitis is a diagnosis made after excluding other possible etiologies for the 
change. Viral flare (if applicable), biliary or vascular obstruction, infection, medications, and alcohol 
use must be ruled out (see below).
Management:

Interrupt pembrolizumab intervention for up to 12 weeks

Start IV corticosteroid (60 mg/day of prednisone or equivalent) followed by oral corticosteroid

Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, ALP, and INR

Restart pembrolizumab intervention only if: 
o
Abnormal laboratory values resolve to Grade ≤1 or baseline (if abnormal at 
baseline)
o
Taper steroid over 28 days
o
Steroid treatment is tapered to prednisone <10 mg/day or equivalent

Permanently Discontinue pembrolizumab intervention if:
o
Laboratory abnormalities do not resolve within 3 weeks
o
Steroids cannot be lowered to ≤10 mg/day (or prednisone equivalent) within 
12 weeks
o
Evidence of decompensation to CP C status
Further information concerning other causes: 

Rule out infection with blood, urine and ascites culture – antibiotics should be started if 
infection is found

If total bilirubin is elevated, imaging should be obtained to rule out vascular compromise, 
biliary obstruction, and/or tumor progression by imaging. If biliary obstruction is present,
consultation with a gastroenterologist and/or an interventional radiologist should be 
obtained to see if the obstruction may be relieved.

Ruled out alcohol use and hepatotoxic drugs including herbal and alternative medications

Interrupt pembrolizumab intervention for up to 12 weeks 

Restart pembrolizumab only if laboratory values have returned to Grade 1 or baseline (if 
normal or Grade 1 at start) or to baseline grade within 3 weeks
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-HBc = 
Hepatitis B core antibody; anti-HBe = hepatitis B e-antigen; anti-HBs = hepatitis B surface 
antibody; AST = aspartate aminotransferase; CP = Child-Pugh (score); Dbil = direct bilirubin; dL = 
deciliter; DNA = deoxyribonucleic acid; G1/2/3/4 = Grade 1/2/3/4; GGT = gamma-glutamyl 
transferase; HBeAg = Hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis 
B virus; HCV = hepatitis C virus; IV = intravenous; IgM = Immunoglobulin M; INR = international 
normalized ratio; mg = milligram; RNA = ribonucleic acid; SAE = serious adverse event; SVR = 
sustained viral response; Tbil = total bilirubin; ULN = upper limit of normal


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6.6.3
Dose Modification and Toxicity Management for Immune-related AEs Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These irAEs may occur shortly after the first dose or 
several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously. The irAEs may be 
fatal and may occur after discontinuation of pembrolizumab. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on 
the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids.
Table 6–7: Dose Modification Guidance, Other Immune-related Adverse Events
Event
Regorafenib
Pembrolizumab
Specific guidance for IMMUNE-RELATED ADVERSE EVENTS
General instructions concerning pembrolizumab:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2.
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
Pneumonitis

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment

G2 or higher: Interrupt until ≤ G1

Restart at same dose level for G2 and decrease by 
1 dose level for G3/4a

G2: Withhold

Recurrent G2, G3, or G4: Permanently discontinue 

Administer corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) followed by taper: add 
prophylactic antibiotics for opportunistic infections


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Table 6–7: Dose Modification Guidance, Other Immune-related Adverse Events
Event
Regorafenib
Pembrolizumab
Specific guidance for IMMUNE-RELATED ADVERSE EVENTS
New onset Type 1 Diabetes 
Mellitus (T1DM)
or 
G3 or G4 hyperglycemia 
associated with evidence of 
β-cell failure

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes

Interrupt until ≤ G1. Restart at same dose level.

Withholdb

Initiate insulin replacement therapy for participants 
with T1DM 

Administer anti-hyperglycemic in participants with 
hyperglycemia
Hypophysitis

Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency)

Interrupt until ≤ G1. Restart at same dose level.

G2: Withhold

G3/4: Withhold or discontinue (at the investigator’s 
discretion)b

Administer corticosteroids and initiate hormonal 
replacements as clinically indicated
Hyperthyroidism

Monitor for signs and 
symptoms of thyroid 
disorders

G2: No modifications

G3/4: Interrupt until ≤ G2. Restart at same dose level.

G2: Continue

G3/4: Withhold or discontinue (at the investigator’s 
discretion)b

Treat with non-selective beta-blockers (e.g. 
propranolol) or thionamides as appropriate
Hypothyroidism

Monitor for signs and 
symptoms of thyroid 
disorders

No modification

Initiate thyroid replacement hormones (e.g. levothyroxine 
or liothyronine) per standard of care

Continue

Initiate thyroid replacement hormones (e.g. 
levothyroxine or liothyronine) per standard of care
Nephritis and renal dysfunction

Monitor changes of renal 
function; grading according 
to increased creatinine or 
acute kidney injury

G2: Continue

G3/4: Interrupt until ≤ G2. Restart at same dose level.

G2: Withhold

G3/4: Permanently discontinue 

Administer corticosteroids (prednisone 1-2 mg/kg or 
equivalent) followed by taper
Neurological toxicities

G2 or higher: Interrupt until ≤ G1

Restart at same dose level for G2 and decrease by 1 
dose level for G3/4a

G2: Withhold

G3/4: Permanently discontinue

Based on severity of AE administer corticosteroids


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Table 6–7: Dose Modification Guidance, Other Immune-related Adverse Events
Event
Regorafenib
Pembrolizumab
Specific guidance for IMMUNE-RELATED ADVERSE EVENTS
Myocarditis

Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes

G2 or higher: Interrupt until ≤ G1 

Restart at same dose level for G2 and decrease by 1 
dose level for G3/4a

Grade 1: Withhold

Grade 2/3/4: Permanently discontinue

Based on severity of AE administer corticosteroids
Exfoliative dermatologic 
conditions

Suspected Steven-Johnson Syndrome (SJS), toxic 
epidermal necrolysis (TEN), or drug rash with 
eosinophilia and systemic symptoms (DRESS): Withhold

Confirmed SJS, TEN, or DRESS: Permanently 
discontinue

Based on severity of AE administer corticosteroids

Ensure adequate evaluation to confirm etiology or 
exclude other causes

Suspected SJS, TEN, or DRESS: Withhold

Confirmed SJS, TEN, or DRESS: Permanently 
discontinue

Based on severity of AE administer corticosteroids
All other immune-related AEs 
(e.g. immune-mediated arthritis, 
pancreatitis, uveitis, etc.)

Ensure adequate evaluation 
to confirm etiology or 
exclude other causes

G2 or higher: Interrupt until ≤ G1 

Restart at same dose level for G2 and decrease by 1 
dose level for G3/4a

Persistent G2: Withhold

G3: Withhold or discontinue based on the eventc

Recurrent G3 or G4: Permanently discontinue 

Based on severity of AE administer corticosteroids
AE = adverse event; DRESS = drug rash with eosinophilia and systemic symptoms; G1/2/3/4 = Grade 1/2/3/4; irAEs = immune-related adverse event; IV = 
intravenous; QD = every day; SJS = Steven-Johnson Syndrome; T1DM = type 1 diabetes mellitus; TEN = toxic epidermal necrolysis
a: If reductions are required resulting in a dose of less than 60 mg QD of regorafenib, then regorafenib will be permanently discontinued.
b: The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤Grade 2, pembrolizumab may be resumed.
c: Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis). 
6.6.4
Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction are provided in Table 6–8.


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Table 6–8: Dose Modification Guidance, Pembrolizumab-associated Infusion Reactions
Event
Regorafenib
Pembrolizumab
Premedication at Subsequent 
Dosing of Pembrolizumab
Specific guidance for PEMBROLIZUMAB-ASSOCIATED INFUSION REACTIONS

Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration

For further information, refer to CTCAE v 5.0
G1
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
No modification

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
None
G2
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for 
≤24 hours
No modification

Stop Infusion

Additional appropriate medical therapy may 
include but is not limited to: 
o
IV fluids 
o
Antihistamines 
o
NSAIDs 
o
Acetaminophen 
o
Narcotics

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.

If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 
100 mL/hour to 50 mL/hour). Otherwise dosing 
will be held until symptoms resolve and the 
participant should be premedicated for the 
next scheduled dose.

Participants who develop G2 toxicity despite 
adequate premedication, pembrolizumab 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with:
Diphenhydramine 50 mg p.o. (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg p.o. 
(or equivalent dose of analgesic).


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Table 6–8: Dose Modification Guidance, Pembrolizumab-associated Infusion Reactions
Event
Regorafenib
Pembrolizumab
Premedication at Subsequent 
Dosing of Pembrolizumab
Specific guidance for PEMBROLIZUMAB-ASSOCIATED INFUSION REACTIONS
should be permanently discontinued.
G3
Prolonged (i.e., not 
rapidly responsive 
to symptomatic 
medication and/or 
brief interruption of 
infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates)
G4
Life-threatening; 
pressor or ventilator 
support indicated
No modification

Stop Infusion

Additional appropriate medical therapy may 
include but is not limited to:
o
Epinephrine (In cases of anaphylaxis, 
epinephrine should be used 
immediately)
o
IV fluids
o
Antihistamines
o
NSAIDs
o
Acetaminophen
o
Narcotics
o
Oxygen
o
Pressors
o
Corticosteroids

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.

Hospitalization may be indicated.

Pembrolizumab should be permanently 
discontinued.
**In cases of anaphylaxis, epinephrine should be 
used immediately. Participant is permanently 
discontinued from further study drug treatment
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. For 
further information, refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov
CTCAE = Common Terminology Criteria for Adverse Events; G1/2/3/4 = Grade 1/2/3/4; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; p.o. = 
per os (oral)


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6.6.5
Rescue Medication and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.3 (Table 6–7). Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab. 
Note: If after the evaluation of the event it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Section 6.6 for
guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.7
Intervention after the End of the Study
Continued Access: Participants who are still on study intervention at the time of study 
completion/termination may continue to receive study intervention if they are experiencing 
clinical benefit. Continued access to study intervention will end when a criterion for 
discontinuation is met or 18 administrations of pembrolizumab had been administered. 
However, continuation of treatment with regorafenib can be individually discussed with the
investigator for participants who do not experience disease progression after 2 years based on 
clinical benefit.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation / Withdrawal
All participants who enter the study should complete all applicable study periods, including 
the EoT visit. Participants can be withdrawn from any study period at any time. 
Discontinuation from the intervention period alone does not constitute withdrawal from the 
study.
Participants who withdraw from the intervention period for any reason should come to the site 
for the safety follow-up visits and are to be encouraged to remain on the study for follow-up 
of primary, secondary and other objectives (i.e. continue in the active follow-up and long-
term follow-up periods). Participants are expected to participate in follow-up unless they 
explicitly object. Withdrawal of consent to the intervention period should be documented in 
the participant's medical record. If the participant does not wish to be followed up further, this 
additional consent withdrawal for follow-up must also be documented.
For a full list of withdrawal criteria, refer to Section 7.2.
In all cases, the reason for withdrawal must be recorded in the participant's medical records 
and in the eCRF. For participants who withdraw consent, no further study-related procedures 
will be allowed. The participant will not suffer any disadvantage as a result. 


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All participants who discontinue due to AEs should be followed up until they recover or 
stabilize, and the subsequent outcome recorded. If any participant dies during treatment, or 
within 30 days after the last dose of regorafenib if a participant was on regorafenib 
monotherapy, or within 90 days after the last dose of regorafenib/pembrolizumab treatment or 
pembrolizumab monotherapy administration, the investigator or his/her designated 
associate(s) will inform the sponsor and the cause of death should be recorded in detail within 
24 hours of awareness on a SAE form and transmitted to the sponsor.
7.1
Discontinuation of Study Intervention
In some circumstances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
discontinued, the participant will remain in the study to be evaluated for disease progression 
and/or OS. See the SoA (Section 1.3.1) for data to be collected at the time of withdrawal of 
study intervention, in follow-up, and for any further evaluations that need to be completed.
The study interventions may be interrupted for situations other than treatment-related AEs 
such as medical / surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the sponsor. The reason for interruption should be documented in 
the participant’s study record
7.1.1
Withdrawal Criteria
7.1.1.1
Withdrawal from Study Intervention Period
Participants MUST be withdrawn from the study intervention if any of the following occurs:

At their own request or at the request of their legally acceptable representative (if 
acceptable by local law). 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.

If, in the investigator's opinion, continuation of the study intervention would be 
harmful to the participant's well-being.

Progressive disease as per RECIST 1.1; however, treatment beyond radiological 
progression per iRECIST is possible if the participant is still benefiting from 
treatment.

Clinical progression (every effort should be made to obtain radiological confirmation 
of disease progression [PD] during active follow-up). 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 a new anti-cancer therapy.


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
Use of illicit drugs or other substances that may, in the opinion of the investigator or 
their designated associate(s), have a reasonable chance of contributing to toxicity or 
otherwise confound the results.

Pregnancy.

Participant lost to follow-up.

Death.
Participants MAY be withdrawn from the study intervention for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Participants should be taken off study intervention for disease progression. However, 
if a participant has radiographic progression but is achieving a clinically meaningful 
benefit, an exception to continue study intervention may be considered following 
consultation with the sponsor. 
o
If the investigator considers radiographic changes secondary to drug-induced 
inflammation and not to tumor progression (i.e. in case of suspected pseudo-
progression), the investigator may postpone a diagnosis of progressive disease 
until the next radiographic evaluation in the study, as per the criteria outlined 
in Appendix 10.5 in Section 10.5.3.

Withdrawal of study intervention for abnormal liver function should be considered by 
the investigator when a participant meets one of the conditions outlined in Table 6–3
or if the investigator believes that it is in best interest of the participant.

If a clinically significant electrocardiogram (ECG) finding is identified (including, but 
not limited to changes from baseline in QT interval corrected using Fridericia’s 
formula [QTcF]) after enrollment, the investigator or qualified designee will determine 
if the participant can continue in the study and if any change in participant 
management is needed. This 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 (Section 1.3.1) for data to be collected at the time of intervention permanent
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.1.2
Withdrawal of Regorafenib only
Participants must be withdrawn from regorafenib for the following reasons:

Participants 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 participant may continue to benefit from the regorafenib 
treatment, and after consultation with sponsor.

Unacceptable toxicity, i.e. an event requiring permanent discontinuation of 
regorafenib according to dose modification guidance in Section 6.6.
7.1.1.3
Withdrawal of Pembrolizumab only
Participants MAY be withdrawn from pembrolizumab for the following reasons:

Participants who experience a delay of more than 12 weeks to receive the subsequent 
pembrolizumab infusion due to treatment-related toxicity or corticosteroids cannot be 


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reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, according to 
dose modification guidance in Section 6.6.

Unacceptable toxicity, i.e. event requiring permanent discontinuation of 
pembrolizumab according to dose modification guidance in Section 6.6.

Discontinuation of pembrolizumab may be considered for participants who have 
attained a confirmed CR that have been received at least 8 infusions (24 weeks) of 
pembrolizumab and had at least 2 infusions with pembrolizumab beyond the date 
when the initial CR was declared.
7.2
Participant Discontinuation/Withdrawal from the Study
A participant must be withdrawn from the study at any time at his/her own request or at the 
request of their legally acceptable representative (if acceptable by local law).
A participant may be withdrawn from the study at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is expected to 
be uncommon.
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, and additionally requests destruction of her/his 
samples taken but not yet tested, the investigator must document this (either destruction by 
site or request to central lab, as applicable) in the site study records.
Withdrawal from active follow-up
Participants MUST be withdrawn from active follow-up if any of the following occurs:

At their own request or at the request of their legally acceptable representative (if 
acceptable by local law). At any time during the study and without giving reasons, a 
participant may decline to participate further. The participant will not suffer any 
disadvantage as a result. 

Radiologically confirmed PD is observed and/or clinical progression (for participants 
who discontinued study intervention before PD due to any other reason).

Start of subsequent systemic anti-cancer treatment.

Development of a second primary malignancy that requires a different treatment.

Substantial non-compliance with the requirements of the study.

If, in the investigator's opinion, continuation of the active visits would be harmful to 
the participant’s well-being.

Participants lost to follow-up.

Death.
Participants MAY be withdrawn from active follow-up if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance).
Withdrawal from long-term follow-up
Participants MUST be withdrawn from long-term follow-up if any of the following occurs:

Withdrawal of consent to long-term follow-up.


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
Participants lost to follow-up.

Death.
Participants MAY be withdrawn from long-term follow-up if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance).
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1
(Section 10.1.9).
8.
Study Assessments and Procedures
Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in 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.
Changes in study visit schedules, missed visits, or participant discontinuations may lead to 
missing information (e.g. for protocol-specified procedures). The specific information (e.g. 


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explanation of the basis of the missing data) will be captured in the CRF and the information 
will be summarized in the clinical study report. In all cases, existing regulatory requirements 
for maintaining investigational product accountability remain and should be addressed and 
documented.
8.1
Efficacy Assessments
Tumor Response Assessments
Assessment of disease
Tumor response evaluated using RECIST 1.1 (Eisenhauer et al. 2009) (see Appendix 5, 
Section 10.5.1) will be applied to determine the anti-tumor activity and efficacy variables of 
this study (see Section 9.4.1).
mRECIST guidelines (Lencioni and Llovet 2010) (see Appendix 5, Section 10.5.2) were
developed in order to evaluate the treatment response accounted for the induction of 
intra-tumoral necrotic areas in estimating the decrease in tumor load, and not just a reduction 
in overall tumor size.
iRECIST (Seymour et al. 2017) (see Appendix 5, Section 10.5.3) is based on RECIST 1.1, but 
adapted to account for the unique tumor response seen with immunotherapeutic drugs.
iRECIST may be used by the investigator to assess tumor response and progression and 
support treatment-related decisions in this study.
Both mRECIST and iRECIST will be used in exploratory analyses.
Imaging modalities:
The preferred and recommended imaging modality for tumor response assessment is multi-
detector CT with both oral and IV contrast. Anatomic coverage should be chest, abdomen and 
pelvis at all timepoints along with any other anatomic areas of known or suspected disease 
(e.g., neck, limbs). CT scans of the abdomen should be done in three phases (arterial, portal 
venous and late venous) for proper liver lesion detection followed by CT of the pelvis and 
chest in the late venous/delayed phase. The slice thickness for CT and MRI (see below) is 
strongly recommended to be ≤ 5mm.
MRI with IV gadolinium chelate-based contrast may be performed in lieu of contrast-
enhanced CT for the abdomen and pelvis when institutional policy does not recommend the 
use of CT or there is a contraindication to IV iodinated CT contrast. The chest should be 
evaluated by CT without contrast in case of allergy. Following a pre-contrast T1-weighted 
acquisition, contrast-enhanced MRI of the abdomen including the liver should be performed 
during the late arterial, the portal venous, and the delayed phases, followed by pelvic MRI 
during the delayed phase. The scan parameters for postcontrast imaging should be the same as 
those of the pre-contrast T1-weighted acquisition. If a participant develops a contraindication 
to CT contrast media during the course of the study after the baseline imaging, contrast-
enhanced MRI is recommended over non-contrast CT for the abdomen and pelvis. Even if IV 
contrast cannot be administered (for example, in the situation of allergy to contrast), a non-
contrast CT of the chest is still preferred over MRI or chest X-ray.
Ultrasound is not an acceptable modality to assess tumor response in this study. 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 was not 
present on the most recent prior CT chest assessment, this chest X-ray is acceptable as 
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For participants with known or suspected brain metastases and/or carcinomatous meningitis, 
brain MRI (with gadolinium-based contrast agent; preferred) or CT with iodinated contrast 
should be performed at screening. Participants with previously treated brain metastases may 
be included in the study provided they are radiologically stable, i.e., without evidence of 
progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be 
performed during study screening), clinically stable and without requirement of steroid 
treatment for at least 14 days prior to first dose of study treatment. Participants diagnosed 
with active CNS metastases and/or carcinomatous meningitis at baseline will not be allowed 
to enter the study. The MRI/CT scans should be repeated when clinically indicated.
If bone metastases are known or suspected, a whole-body bone scan with both anterior and 
posterior projection using a technetium-99m-labeled phosphonate tracer (methylene 
diphosphonate (MDP), hydroxymethylene diphosphonate (HMDP), hydroxyethylene 
diphosphonate (HDP), or 2,3-dicarboxypropane-1,1-diphosphonate (DPD)) should be 
performed at screening. 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. A newly-detected bone lesion on bone scan should be 
confirmed by radiologic assessment (X-ray, CT, MRI if not already evident on the CT/MRI 
tumor assessment scans).
For consistency, the same imaging modality and equivalent technique (e.g. contrast agent, 
slice thickness, field of view, protocol, sequence, phosphonate tracer) should be used for all 
scans and tumor assessments across all time points performed on an individual participant, 
including screening/baseline scans.
Initial tumor imaging:
The time points for CT/MRI scans are described in the SoA (Section 1.3.1). A baseline 
radiological tumor assessment will be conducted within 28 days before the start of study 
treatment. Scans performed as standard of care that were obtained prior to the participant
signing the informed consent may be used for the baseline tumor assessment, provided that 
they were performed within 42 days of starting study intervention and meet this protocol’s 
imaging requirements. The investigator must review screening images to confirm the 
participant has measurable disease per RECIST 1.1 and to determine this participant’s 
eligibility.
Tumor imaging on study:
Following treatment initiation, regardless of potential dose delays for either drug, subsequent 
tumor assessments will occur every 6 weeks with a maximum window of ± 7 days during the 
first 54 weeks and every 9 weeks ± 7 days thereafter. 


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For participants who discontinue study treatment without confirmed radiological disease 
progression, the investigator should perform a complete physical, laboratory, and radiological 
assessment as soon as possible. Every effort should then be made to continue to perform 
tumor assessments every 6 weeks ± 7 days during the first 54 weeks and every 9 weeks 
± 7 days thereafter. Imaging assessments will continue to be performed until whichever of the 
following occurs first: 

Investigator-assessed disease progression is confirmed 

The start of new anti-cancer treatment

Withdrawal of consent

Death

The end of the study
Response assessment:
RECIST 1.1 (see Appendix 5, Section 10.5.1) and mRECIST criteria for HCC (see 
Appendix 5, Section 10.5.2) will be used for radiological tumor evaluation in this study. 
iRECIST (see Appendix 5, Section 10.5.3, Table 10–11 and Figure 10–1) can be used by the 
investigator to assess tumor response and progression and support treatment-related decisions 
in this study.
By inclusion criteria, participants must have at least one evaluable and measurable lesion per 
RECIST 1.1 on the baseline scan. Tumor measurements and assessments are to be performed 
at the local sites and are to be entered in the eCRF. All scans should be interpreted by the 
same radiologist/investigator during the study, where at all possible. Any lesion that has been 
previously treated with radiotherapy should be considered as a non-target lesion. However, if 
a lesion previously treated with radiotherapy has clearly progressed on the baseline/screening 
scan, it can be considered as a measurable lesion.
The minimum time interval required between two tumor assessments for determination of SD 
is 6 weeks. Objective response should be confirmed by a repeat imaging assessment. CT/MRI 
scans for confirmation of response should be performed no sooner than 4 weeks after the 
initial scan demonstrating PR or CR. Participants will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor imaging 
if it is less than 4 weeks later. For these participants, tumor imaging may resume at the 
subsequent scheduled imaging time point.
Imaging data:
All image files (coded with study participant number and in Digital Imaging and 
Communications in Medicine (DICOM) format for CT/MRIs and bone scans) as well as 
imaging-related adjunctive data (e.g. dose of contrast agent) must be stored locally. In this 
study, image files and imaging-related adjunctive data will also be collected centrally by an 
imaging core laboratory designated by Bayer starting at the beginning of the study for a 
centralized independent imaging review of tumor response9. Further guidance on the 
acquisition of CT/MRIs and bone scans as well as information on how to transmit image files 
to the imaging core laboratory will be provided in the Imaging Guidance for this study. 
8.2
Safety Assessments
Standard safety monitoring and grading will be performed using CTCAE v. 5.0.


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Investigators should refer to the Safety Information sections of the current IBs of regorafenib 
and pembrolizumab for the expected side effects including unexpected AEs and 
hypersensitivity reactions. The IB will be updated if any new relevant safety data are 
obtained. 
Safety will be assessed by monitoring and recording all AEs and SAEs, cardiac, hematologic 
and blood chemistry parameters, vital signs, ECG, ECOG PS, and any abnormal findings 
observed during the performance of physical examinations.
Planned time points for all safety assessments are provided in the SoA (Section 1.3.1).
Therapeutic monitoring should be performed following dose modification of study 
intervention 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 follow-up activities outside of this protocol.
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 8.3). Additional assessments may be indicated at any time during the course of the 
study at the discretion of the investigator. In addition, lab tests may be repeated at the 
discretion of the investigator, if clinically indicated.
8.2.1
Physical Examinations
A full physical examination will be performed by the investigator or qualified designee as 
outlined in the SoA (Section 1.3.1). Full physical examination includes, at a minimum, 
assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems, and 
of skin status. Height and weight will also be measured and recorded. Height will be 
measured at screening only. 
The investigator or qualified designee will perform a symptom-directed physical exam as 
clinically indicated, according to the SoA (Section 1.3.1). New clinically significant abnormal 
findings should be recorded as AEs. Investigators should pay special attention to clinical signs 
related to previous serious illnesses.
8.2.2
Vital Signs
Body temperature, heart rate, oxygen saturation, and blood pressure will be assessed.
ECG, blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., television, cell phones).
When blood pressure measurement and PK sample collection are scheduled at the same time 
point, the participant’s blood pressure must be measured before collection of the PK sample.
8.2.3
Electrocardiograms
A 12-lead ECG will be locally obtained as outlined in the SoA (Section 1.3.1) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
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12-lead ECGs will be evaluated by a physician. He / She will document the diagnosis(-ses) 
including an overall assessment of the findings and their clinical relevance. The overall 
interpretation of the ECG (normal/abnormal, clinical relevance) and the ECG diagnosis will 
be documented in the source documents and on the eCRF.
8.2.4
Clinical Safety Laboratory Assessments
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to 
the SoA (Section 1.3.1) for the timing and frequency.
The 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 CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
All clinically significant abnormal laboratory tests during participation in the study or within 
30 days after the last dose of study intervention (and within 90 days after the last dose of 
pembrolizumab for the laboratory values assessed as/related to SAEs) should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator, unless a new anti-cancer therapy has been initiated.

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 Appendix 2 (Section 10.2), 
must be conducted in accordance with the SoA (Section 1.3.1).
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 CRF.
8.2.5
ECOG Performance Status
A participant’s ability to manage activities of daily living will be appraised using ECOG PS.
Grading definitions for ECOG PS are given in Table 8–1. The participant’s ECOG PS will be 
estimated according to the SoA (Section 1.3.1). Change of ECOG PS will be measured for 
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Table 8–1: Definitions for ECOG PS Grading
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light housework, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
ECOG PS = Eastern Cooperative Oncology Group performance status
8.2.6
Baseline Characteristics
Demographic
Baseline participant data pertaining to demographic information should be documented 
accordingly in the appropriate eCRFs include the following:

Date of birth (year, age) if allowed according to local law

Gender

Race, if legally allowed

Ethnicity, if legally allowed

Weight

Height

Childbearing status (if applicable)
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent

Considered relevant for the participant’s study eligibility
Other baseline characteristics
Other baseline characteristics will be collected, including but not limited to:

Baseline cancer characteristics, including cancer type, location of the primary tumor, 
histology, tumor stage at study entry, date of diagnosis of first metastasis, presence of 
metastases (e.g. liver, lung, brain or bone), date of most recent progression, prior 
cancer therapies and procedures. In addition, if results are available: tumor mutational 
burden (TMB), microsatellite instability (MSI) status, and PD-L1 expression.

All medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the participant within 28 days 
prior to the study intervention


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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.
The intensity of AEs should be documented using the CTCAE v. 5.0.
The study intervention action should be recorded separately for each study intervention as 
detailed in the eCRF.

Drug withdrawn

Drug interrupted

Drug delayed

Dose reduced

Dose not changed

Dose increased

Not applicable

Unknown
The definitions of an AE or SAE can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative (if acceptable by local law) 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 intervention (see Section 7). AEs
of Special Interest (AESI) have to be followed up regardless of causality or relationship to 
study intervention.
Investigators should refer to the Safety Information section of the current IB of regorafenib 
and the current IB of pembrolizumab for the expected side effects. As with any agent, there is 
always the potential for unexpected AEs, including hypersensitivity reactions. The IB will be 
updated if any new relevant safety data are obtained. 
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until 30 days after last dose 
of study intervention as specified in the SoA (Section 1.3.1). In addition, SAEs will be 
collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy 
has been initiated. See Section 8.3.5 for reporting of pregnancy and exposure during 
breastfeeding. 
An AE (irrespective of causal relationship) not completely resolved at the end of the pre-
defined collection period must be followed up until resolution or until the investigator 
considers the event will not improve further.
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 


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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 hours, as indicated in Appendix 3, Section 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided Appendix 3, 
Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AESI (as defined in Section 8.3.6), 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is provided in Appendix 3, Section 10.3.
8.3.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.


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8.3.5
Pregnancy
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4, 
Section 10.4.
If a participant inadvertently becomes pregnant while on study intervention, the participant 
will be immediately discontinued from study treatment. The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the sponsor. 
It is unknown whether pembrolizumab or regorafenib is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, participants who are breastfeeding are not eligible for enrollment.
All pregnancies and exposure during breastfeeding must be reported by the investigator, from 
the start of study intervention through 120 days following withdrawal of study intervention, or 
30 days following withdrawal of study intervention if the participant initiates new anti-cancer 
therapy. 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.
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, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
8.3.6
Adverse Events of Special Interest
Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECI) and 
must be reported to the sponsor.
ECI for this trial include: 
1. Pembrolizumab overdose, as defined in Section 8.4, that is not associated with clinical 
symptoms or abnormal laboratory results
2. HECIs as defined in Section 6.6.2.1
8.4
Treatment of Overdose
Overdose of regorafenib
For this study, any dose of regorafenib greater than 160 mg within one day will be considered 
an overdose.
In the event of an overdose, the investigator/treating physician should:

Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically.


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
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).

Any overdose or incorrect administration of study intervention should be noted on the 
Study Drug Administration eCRF.

AEs associated with an overdose or incorrect administration of study intervention 
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, refer to the most current version of the IB for 
regorafenib. 
There is no specific treatment for regorafenib overdose. The highest dose of regorafenib 
studied clinically is 220 mg QD. The AEs observed at this dose were primarily 
dermatological events, hoarseness, diarrhea, mucositis, and nausea. In the event of suspected 
overdose, regorafenib should be immediately withheld and supportive care instituted under 
the supervision of a qualified health care professional.
Overdose of pembrolizumab
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥2.5 times the study dose).
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.5
Pharmacokinetics
For all participants enrolled, sparse pharmacokinetic samples will be collected for 
determination of regorafenib and its metabolites M-2 and M-5 (in plasma) and 
pembrolizumab (in serum) as specified in Table 1–3.
Sampling times outside the suggested sampling time intervals will not be considered as 
protocol deviations. However, omission of samples specified in the PK sampling (Table 1–3) 
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 pembrolizumab 
infusion will be recorded in the eCRF as PK estimates will be based on the sampling times 
relative to dosing times. If regorafenib is not administered on the day of PK sampling, the pre-
dose samples will be collected and the post-dose samples will not be collected.
Samples may be collected irrespective of any dose modifications during the treatment cycle. 
No detailed dosing history is required before the pre-dose sample, but 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. In addition, the time of meal intake prior to regorafenib 
administration on PK sampling days needs to be reported in the patient diary and together 
with the dosing time is recorded in the eCRF.
Regorafenib data from this study may be pooled with data from other clinical studies for 
pharmacometric analysis. 
Model-determined exposures of regorafenib 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.


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The PK analyses will be performed using validated analytical methods. Exploratory 
measurements of other moieties may be performed, if needed.
PK samples for pembrolizumab will be held until the end of the study by the central lab. At 
that time, the determination will be made if analysis will be done on the samples, however, 
samples may be analyzed prior to the end of the study if safety or efficacy concerns arise.
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
Pharmacodynamics biomarkers are described in Section 8.8.1.
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), except for whole genome 
sequencing.
Timing: See the SoA (Table 1–1) and the schedule of biomarker blood sampling (Table 1–2) 
for planned time points of sample collection.
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.
For details regarding tumor tissue collection, refer to the below specification:
Tumor tissue requirement: Formalin-fixed paraffin-embedded block (preferred) or minimum 
of 20 slides, obtained from core biopsy or surgical specimen.
At screening:

Archival tumor tissue sample is mandatory if available.

Recent tumor tissue as defined below is mandatory for all participants. Exceptions will 
be accepted for participants with no recent baseline tumor tissues after documented 
discussion and approval by the sponsor.
o
an archival biopsy no older than 6 months and after the last anti-tumor 
treatment 
o
or a new biopsy.
On treatment / at EoT

New tumor biopsies at W6D1 (+/-3 days) is mandatory if medically feasible, in 
consultation with the sponsor.

Collection of a new biopsy at EoT (+ 7 days) is optional.


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Sample handling and storage: 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: Results of biomarker investigations may be reported separately (e.g., in a 
biomarker evaluation report).
8.8.1
Pharmacodynamics Biomarkers
Pharmacodynamics biomarkers will be evaluated in biomarker samples collected before and 
during treatment to investigate the impact of regorafenib and pembrolizumab on these 
biomarkers, and may be correlated with safety and/or efficacy. Tissue-based 
pharmacodynamics biomarker evaluations will be conducted in available paired tumor tissues 
(recent tumor tissues and on-treatment/EoT tumor biopsy).
Candidate pharmacodynamics biomarkers may include (but are not limited to):

Intra-tumor pharmacodynamics biomarkers such as immune cell infiltrations (e.g. 
Teff, Treg, macrophages), expression of immune genes/signatures (e.g. myeloid 
expression signature, Treg signature), and/or parameters in the regorafenib targeted 
pathways (e.g. VEGFR2) in paired tumor biopsies (pre- and on-treatment)

Quantification and characterization of immune cell populations in blood (e.g. Teff, 
Treg, macrophages, 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., sVEGFR2, angiopoietin 1 [Ang1]) 

Circulating miRNA 
8.8.2
Biomarkers that May Associate with Response
Baseline candidate biomarkers from tumor and blood samples will be evaluated for 
correlation with response to treatment (to identify possible “predictive biomarkers”). Samples 
from tumor materials and blood 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., myeloid expression signature, Treg signature, PD-L1 
expression) at baseline

Expression of parameters of interest for regorafenib (e.g. VEGFR2) in baseline tumor 
materials

Baseline TMB/tumor mutations (e.g. mutations in Wnt pathway) 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 


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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 pembrolizumab 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 pembrolizumab 
for analysis of anti-drug antibodies (ADAs) as specified in Table 1–3. Additional 
exploratory ADA samples will be collected as specified in Table 1–3, which may be used
for exploratory analyses including assessing the potential impact of ADAs formed against 
previous PD-1/PD-L1 treatment.
A decision to analyze the immunogenicity samples described above will be made during the 
course of the study. Until that time, samples will be stored at a central laboratory.
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).
8.10
Medical Resource Utilization and Health Economics
Not applicable.
9.
Statistical Considerations
This is a single arm, Phase 2 study with ORR per RECIST1.1 by central review as the 
primary endpoint. 
In the pilot phase of the study, the participant population for the expansion phase is 
determined. Participants from the pilot phase who match the population of the expansion
phase (atezolizumab plus bevacizumab vs. atezolizumab plus bevacizumab and other first line 
treatments) will be included in the analysis of the expansion phase.
Historical (background) response rate is assumed to be 20% (per RECIST 1.1, an ORR of 7% 
was observed in the regorafenib arm of the HCC trial RESORCE (Bruix et al. 2017), and an 
ORR of 18% was observed in the pembrolizumab arm of the HCC trial KEYNOTE-240 (Finn 
et al. 2020); as the sum of the ORR was about 25%, in order to show a synergistic effect this 
study is designed to rule out an ORR of 20%). Target response rate (i.e. true underlying 
response rate for which there is 95% power conditional on a positive pilot phase) will be 35%.
In addition to the number of responders, totality of data including tumor dynamics response 
(depth, durability) and overall safety data will be considered to make a determination to move
forward to the expansion phase.
A one-sided exact binomial test with a type-I error of 2.5% will be conducted at the end of the 
expansion phase to test the hypothesis. 


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9.1
Statistical Hypotheses
There will be no statistical hypothesis testing done in the pilot phase of the study.
The primary hypotheses to be tested in the expansion phase of the study is
H0: ORRCombination≤20% vs. H1: ORRCombination>20%
The primary hypothesis will be tested by an exact binomial test. The significance level will be 
a 1-sided alpha of 2.5%.
9.2
Sample Size Determination
It is expected that approximately 170 participants will be screened to achieve the 
119 evaluable participants for both study phases combined.
Pilot phase: A total of approximately 52 participants will be enrolled to receive regorafenib 
in combination with pembrolizumab divided in two cohorts: 26 of them after atezolizumab 
plus bevacizumab treatment combination (cohort 1); and 26 after any IO containing first line 
treatment (cohort 2), excluding atezolimab plus bevacizumab treatment combination.
Expansion phase: 2 scenarios should be considered depending on the pilot phase results.

Scenario 1: if in the pilot phase at least 8 responders out of the 26 treated in cohort 1
are observed

Scenario 2: if in the pilot phase at least 8 responders in each cohort are observed
In scenario 1, the study can continue to accrue 67 new additional participants after 
atezolizumab in combination with bevacizumab (i.e. a total of 93 participants after prior 
treatment with atezolizumab in combination with bevacizumab will be enrolled, representing 
the patient population of cohort 1). If 27 or more participants respond out of 93 evaluable 
participants (i.e. ORR 29%), the study will have ruled out an ORR ≤ 20% (with 1-sided alpha 
of 0.025), using an exact binomial test.
In scenario 2, the study can continue to accrue 67 new additional participants after any 
immune checkpoint inhibitor as defined in the pilot phase (i.e. a total of 119 participants will 
be enrolled, representing the patient population of cohort 1 and cohort 2). If 34 or more 
participants respond out of 119 evaluable participants (i.e. ORR 29%), the study will have 
ruled out an ORR ≤ 20% (with 1-sided alpha of 0.025), using an exact binomial test.
In case cohort 2 meets the response rate criterion and cohort 1 does not, the future direction 
for further evaluation in the expansion phase will be decided based on the totality of data and 
treatment landscape at the time.
If the true underlying response rate is 35%, given that at least 8 responders are observed in 
stage 1, the conditional power for the final analysis is at least 95%, under both scenarios 
above.


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9.3
Populations for Analyses
The populations for analyses are defined in Table 9–1.
Table 9–1: Populations for Analyses
Population
Description
Enrolled 
All participants who sign the ICF
Full Analysis Set
All participants who take at least 1 dose of study intervention will 
be included in the efficacy and safety evaluation
ICF = Informed consent form
All analyses will be performed on the Full Analysis Set. 
9.4
Statistical Analyses
Analyses 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).
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. The SAP will be finalized prior to first patient 
first visit (FPFV) and it will include a more technical and detailed description of the statistical 
analyses described in this section. 
9.4.1
Efficacy Analyses
9.4.1.1
General Considerations
All analyses will be conducted at one-sided type-I error level of 2.5% or two-sided type-I 
error level of 5% respectively. A one-sided exact binomial test will be conducted in the 
expansion phase to analyze the primary endpoint. Confidence intervals will be presented for 
selected variables.
9.4.1.2
Primary Efficacy Endpoint
The primary endpoint of the study is ORR based on RECIST 1.1 assessed by central review. 
ORR is defined as the proportion of participants with best overall response of confirmed CR 
or PR. 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.
In both study phases, the primary efficacy variable will be analyzed after all participants are 
available for efficacy. The analysis will be done on the Full Analysis Set. In the pilot phase, 
the analysis will be done by cohort. In the expansion phase, the analysis will be done on the 
participants who received the first line treatment determined in the pilot phase of the study. 
Methods used will include frequency tables (with the ORR table also including all “Best 
overall response” categories) as well as 95% two-sided Clopper-Pearson confidence intervals 
and the results of an exact binomial test.
9.4.1.3
Secondary Efficacy Endpoints
The secondary efficacy endpoints in this study are DOR as per RECIST 1.1 by investigator 
assessment and central review and ORR as per RECIST 1.1 by investigator assessment. 
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 disease progression or death (if death 


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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.
The analysis will be done on the Full Analysis Set. In the pilot phase, the analysis will be 
done by cohort. In the expansion phase, the analysis will be done on participants who received 
the first line treatment determined in the pilot phase of the study.
For analyses of the secondary endpoints, proportion-based efficacy variables will be using 
frequency tables as well as 95% two-sided Clopper-Pearson confidence intervals. With regard 
to time to event data, these will be summarized descriptively using Kaplan Meier 
methodology and plots, as well as median estimates based on Greenwood’s formula, 
including 95% two-sided confidence interval.
9.4.1.4
Tertiary/Exploratory Endpoints
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.
9.4.2
Safety Analyses
All safety analyses will be done on the Full Analysis Set. In the pilot phase, the analysis will 
be done by first line treatment (atezolizumab plus bevacizumab vs. other first line treatments).
In the expansion phase, the analyses will be done on participants who received the first line 
treatment determined in the pilot phase of the study.
The incidence of TEAEs (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 intervention withdrawal and/or 
modifications will be summarized. 
Laboratory abnormalities will be summarized by severity. Frequency and incidence rates will 
be provided. Frequency tables will also be provided for changes in severity from baseline to 
worst value post-baseline. The following summaries will be generated separately for 
hematology and biochemistry:

Worst change from baseline of abnormal hematological and biochemical laboratory 
values during treatment period

Incidence of abnormal hematological and biochemical laboratory values during the 
treatment period
9.4.3
Other Analyses 
PK and biomarker exploratory analyses will be performed and described in separate reports.
9.5
Interim Analyses 
An interim analysis will be performed to determine the participant population (participants 
after treatment with atezolizumab in combination with bevacizumab, or after any first line 
treatment) for the expansion phase of the study. 


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Both cohorts from the pilot phase will continue to be expanded until a sample size of
26 evaluable participants per cohort is reached. Participants are considered evaluable for 
efficacy when:

they have completed at least two post-baseline scans; or 

they have been followed for approximately 14 weeks from the first study intervention
dose; or

they have discontinued due to progression or any other reason before 14 weeks from 
the first study intervention dose. 
The interim analysis is planned when the last participant enrolled in each of the cohorts from 
the pilot phase has reached the evaluation criteria outlined above. The interim analysis will be 
conducted on the Full Analysis Set. Both cohorts will be analyzed separately.
For this futility analysis, no formal adjustment of the type-I error will be performed.
9.6
Data Monitoring Committee (DMC) or other Review Board
Not applicable.
A Steering Committee may considered by the sponsor for the expansion phase.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.


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


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10.1.6
Dissemination of Clinical Study Data
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 US and EU on or after 01 JAN 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 electronic CRF 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 CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. The investigator must permit study-related monitoring, audits, 
IRB/IEC review, and regulatory agency inspections and provide direct access to source data 
documents.
Monitoring details describing strategy (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 non-compliance 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 CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator 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.
Data collection tool


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The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Participant data necessary for analysis and reporting will be transmitted into a 
validated database or data system (LSH).
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet-based electronic data capture (EDC) software system RAVE, 
which Bayer has licensed from Medidata Solutions Worldwide. RAVE has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively 
applies the logic to ensure data are complete and reflect the clinical data requirements of the 
study. Data queries resulting from the application of the software logic are resolved by the site 
personnel. The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via a 
secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
The RAVE system contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer.
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. The site 
must implement processes to ensure availability of all required source documentation. 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 CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
The definition of what constitutes source data can be found in the source data location list 
(SDLL) (part of the monitoring plan, not part of the protocol) archived at site, and the monitor 
will work with the site to complete this checklist.
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 sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.


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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
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 
participants and should assure appropriate therapy and/or follow-up.
Reasons for premature study termination or suspension may include but are not limited to:

If the risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g. SAEs) 

Results of parallel clinical Bayer studies or emerging data from literature

Results of parallel animal studies (on e.g. toxicity, teratogenicity, 
carcinogenicity or reproduction toxicity)

If the study conduct (e.g. recruitment rate; dropout rate; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame

Strategic reasons (e.g. the clinical development of the drug is stopped)
The site is entitled to end its participation in the study if necessary due to medical or ethical 
reasons.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. The final 
decision on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.
In the event of study closure, participants on treatment and those in post-study follow-up must 
be taken care of in an ethical manner.
10.1.10
Publication Policy
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.


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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
All laboratory analyses detailed in the SoA (Section 1.3.1) and in Table 10–2 and Table 10–3
will be performed locally. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local regulations.
AFP will be assessed as described in the SoA (Section 1.3.1).
Serum or urine pregnancy tests are performed as outlined in the SoA (Section 1.3.1). The 
frequency of pregnancy tests may be higher if required by local regulations. Refer to 
Section 5.1 for screening pregnancy criteria. Details on Contraceptive Guidance and 
Collection of Pregnancy Information can be found in Section 10.4. 
The schedule for testing and the laboratory tests included in Panel A and B are described in 
Table 10–1 and Table 10–2, respectively. The schedule and criteria for hepatitis virus testing 
is outlined in Table 10–3.
Investigators must document their review of each laboratory safety report.
Table 10–1: Laboratory Testing Standard Schedule
Visit
Panel A
(see Table 10–2)
Panel B
(see Table 10–2)
Screening (within 7 days of first study intervention)
X a
Before each pembrolizumab infusion
X b
Before each regorafenib dose after 7 days break
X c
Regorafenib D1 for in-between weeks within the first 
8 weeks (first 2 cycles)
X
EoT visit
X
Safety follow-up visit
X
D1 = Day 1; EoT = end of treatment; W1D1 = Week 1 Day 1
a: If for any reason tests were performed more than 7 days prior to the first dose of study 
intervention, they should be repeated on W1D1.
b: If there is a pembrolizumab dosing delay or pembrolizumab withdrawal, Panel A is required at
least every 4 weeks on Day 1 before each regorafenib administration 
c: Not required if sampling for Panel A has been done within the previous 5 days.


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Table 10–2: Protocol-Required Safety Laboratory Assessments per panel
Panel A
Panel B
Hematology
Hb
X
X
Hct
X
Platelet count
X
X
WBC
X
ANC
X
X
ALC
X
AMC
X
ABC
X
AEC
X
Biochemistry
Sodium
X
Potassium
X
AST
X
X
ALT
X
X
GGT
X
Total bilirubin
X
X
Direct bilirubin
(X) if t-bilirubin 
elevated
ALP
X
Uric acid
X
Total protein
(X) if deemed 
clinically indicated
Albumin
X
Total calcium
X
Lipase
X
Amylase
X
Magnesium
X
Triglycerides
X
Phosphate
X
LDH
Xb
Xb
Glucose (non-fasting)
X
Creatinine/CG c
X
Urea/BUN
X


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Table 10–2: Protocol-Required Safety Laboratory Assessments per panel
Panel A
Panel B
Coagulation
INR
X
aPTT
X
Thyroid
FT3
X
FT4
X
TSH
X
Urinalysis a
Analytes: Urinalysis dipstick: blood, glucose, ketones, 
bilirubin, protein, leukocytes, urobilinogen, nitrite, 
specific gravity, and pH
Microscopic urinalysis: RBC microscopic, WBC 
microscopic, epithelial cells, casts, and crystals
X
ABC = absolute basophil count; AEC = absolute eosinophil count; ALC = absolute lymphocyte 
count; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMC = absolute 
monocyte count; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin 
time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CG = Cockcroft-Gault 
(equation); EoT = end of treatment; FT3 = free triiodothyronine; FT4 = free thyroxine; GFR 
= glomerular filtration rate; GGT = gamma-glutamyl transferase; Hb = hemoglobin; Hct = 
hematocrit; INR = prothrombin time-international normalized ratio; LDH = lactate 
dehydrogenase; RBC = red blood cell count; TSH = thyroid stimulating hormone; WBC = 
white blood cell count.
a: If protein dipstick result is 3+ or abnormal (based on type of urine test strip used), a 
laboratory urine analysis should be done for the quantification of proteinuria by urinary 
protein/creatinine ratio on a random urine sample preferably taken at mid-morning.
b: At screening and EoT visit
c: Cockcroft-Gault formula for GFR: 


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Table 10–3: Hepatitis Virus Panel
Screening:

Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B 
core antibody (HBcAb) (total and IgM) and HBV-DNA viral load to be performed at 
baseline unless pre-study results are available within 3 months before informed consent 
and participants are clinically stable
If analysis results are:
o
(1) HBsAg+ or
o
(2) anti-HBc+ and anti-HBs-, HBsAg- and HBV-DNA viral load <100 IU/mL,
o
the following analyses are required: anti-HDV, anti-HBe and HBeAg

Anti-HCV antibody (anti-HCV) to be performed at baseline unless pre-study results are 
available within 3 months before informed consent and participants are clinically stable
o
If the participant is found to be anti-HCV Ab positive, the following analyses are 
required: (HCV)-RNA viral load and HCV genotyping or serotyping (if genotyping 
is not available)
Intervention period + up to safety follow-up visit, if clinically indicated

HCV recurrence/flare: 
o
Measure HCV-RNA viral load (At the time of first detection of HCV RNA, send a 
specimen for HCV genotyping or serotyping (if genotyping is not available) (local 
laboratory))
o
Measure AST, ALT, ALP, Tbil, Dbil, and INR weekly
o
Measure HCV RNA levels every 2 weeks
o
Therapy with HCV antiviral treatments should be strongly considered

HBV flare: 
o
Measure HBV-DNA viral load. 
o
Participants should undergo weekly laboratory tests including: AST, ALT, ALP, 
Tbil, Dbil, INR, HBsAg, HBV DNA (if detected at the onset of the flare). 
o
Obtain anti-HBe, anti-HBs, and HBV-DNA levels (if not detected at the onset of 
the flare) every 2-3 weeks
See Table 6–6
Anti-HBc+ = hepatitis B core antibody positive; anti-HBe = hepatitis B e-antigen; anti-HBs- = 
hepatitis B surface antibody negative; anti-HCV = anti-hepatitis C virus antibody; 
anti-HDV = hepatitis D antibody; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; Dbil = direct bilirubin; DNA = 
deoxyribonucleic acid; HBcAb = hepatitis B core antibody; HBeAg = hepatitis B e-antigen; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B 
virus; IgM = immunoglobulin M; INR = prothrombin time-international normalized ratio;
RNA = ribonucleic acid; Tbil = total bilirubin


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a participant 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.
Treatment-emergent adverse event (TEAE) definition:

A TEAE is defined as any AE arising or worsening after the start of first study 
intervention administration until 30 days after the last administration of any study 
intervention.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” 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.


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Events NOT meeting the AE definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (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.


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e. Is a congenital anomaly/birth defect
f. Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3
Recording and Follow-up of AE and/or SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the 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.

There may be instances when copies of medical records for certain cases are 
requested by the contract research organization (CRO) and/or 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 investigator will make an assessment of intensity for each AE and SAE reported during 
the study based on NCI-CTCAE v. 5.0.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of causality

The investigator is obligated to assess the relationship between study intervention 
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.


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Assessment of causality

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 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 for 
regorafenib and pembrolizumab.

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 follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

Immune-related AEs (also called immune-mediated AEs) 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. 
irAEs can include events with an alternate etiology which were exacerbated by the 
induction of autoimmunity.

Every AE must be assessed by the investigator with regard to whether it is 
considered immune-mediated.

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 follow-
up period, the investigator should provide access to any post mortem findings 
including histopathology

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor 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.


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SAE reporting to the sponsor via an 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 offline 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 offline, 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 Investigator Site File.
SAE reporting to the sponsor via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator Site File.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
10.4.1
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.
10.4.2
Contraception
Regorafenib and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it 
is not known if pembrolizumab has transient adverse effects on the composition of sperm.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, male participants must agree to use highly effective contraception during the 
treatment period and for 120 days after the last dose of regorafenib. Female participants of 
childbearing potential must adhere to the contraception requirement (from the day of study 
intervention initiation, or 14 days prior to the initiation of study intervention for oral 
contraception) throughout the study period and for 120 days after the last dose of 
pembrolizumab, and 210 days after the last dose of regorafenib, whichever occurs last. If 
there is any question that a participant of childbearing potential will not reliably comply with 
the requirements for contraception, that participant should not be enrolled in the study. 


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Contraception guidance: 
The investigator or a designated associate is requested to advise the participants 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 sexual intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent.

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 10–4 when having sexual intercourse with a 
WOCBP who is not currently pregnant.

Men with a pregnant or breastfeeding partner must agree to remain abstinent or use 
barrier contraception during each episode of sexual intercourse during the protocol-
defined time in Section 5.1.

Refrain from donating sperm during the protocol-defined time frame 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 10–4 and during the protocol-defined time frame in Section 5.1:
Table 10–4: 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 ovulationb

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 ovulationb

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.


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Table 10–4: Highly Effective Contraceptive Methods
WOCBP = woman of childbearing potential
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. 
b. Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. In this case, two highly effective methods of 
contraception should be utilized during the protocol-defined time frame in Section 5.1.
10.4.3
Pregnancy
10.4.3.1
Pregnancy testing
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test.
Additional pregnancy testing should be performed as outlined in the SoA (Section 1.3.1). The 
frequency of pregnancy tests may be higher if required by local regulations.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected.
10.4.3.2
Collection of Pregnancy Information
Female participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents of the neonate, unless local 
law or specific circumstances of the respective case allow otherwise, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any post-study pregnancy related SAE considered reasonably related to the study 
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 be 
immediately discontinued from study treatment.


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Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from both the study participant 
and the pregnant female partner, the investigator will record pregnancy information on 
the appropriate form and submit it to 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. 
10.5
Appendix 5: Tumor response criteria (RECIST 1.1, mRECIST for HCC, 
and iRECIST)
Response and progression will be evaluated in this study using RECIST 1.1 (Section 10.5.1). 
Modified RECIST for HCC (Section 10.5.2) and iRECIST (Section 10.5.3) will be used as 
exploratory analyses. 
10.5.1
RECIST 1.1
The RECIST 1.1 criteria, based on the measurement of the longest diameter of tumor lesions, 
were designed and validated to assess treatment response in solid tumors (Eisenhauer et al. 
2009). 
Measurable Disease: 
Non-nodal tumor lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI. If scans 
with slice thicknesses greater than 5mm are used, the minimum size should be twice 
the slice thickness.

20 mm by chest X-ray

10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable)
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 (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability. 
Tumor lesions situated in a previously irradiated area are not considered measurable unless 
there has been demonstrated progression in the lesion.
Baseline assessment


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Non-Measurable Disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to < 15mm short axis) are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitic involvement of skin or lung, inflammatory breast disease, abdominal 
masses/ abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques and blastic bone lesions are all non-measurable.
Target Lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs should be identified as target lesions and be 
recorded and measured at baseline. These 5 lesions should be selected on the basis of their 
size (lesion with the longest diameter), be representative of all involved organs and should be 
suitable for reproducible repeated measurements. 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 tumor regression of the measurable 
dimension of the disease. If there are >5 measurable lesions, those not selected as target 
lesions will be considered together with non-measurable disease as non-target lesions.
Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above the 5 listed as target lesions, including pathological lymph nodes (with 
short axis ≥10 mm and < 15 mm) should be identified as non-target lesions and should also be
recorded at baseline. Measurements are not required but these lesions should be noted at 
baseline and should be followed as “present”, “absent” or in rare cases “unequivocal 
progression”. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the eCRF (e.g.; ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
Best Response
The best overall response is the best response recorded from the start of the study intervention 
until the end of intervention. The participant’s best overall response assignment will depend 
on the findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. While some non- target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
All participants will have their best response on study classified as outlined below: 
Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor 
(both target and non-target). Any pathological lymph nodes (whether target or non-target) 
must have a reduction in short axis to < 10mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions.
Stable Disease (SD): Steady state of disease. Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions.
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 


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an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions 
or the appearance of one or more new lesions will also constitute progressive disease. (Note: 
the appearance of one or more new lesions is also considered progression). Ascites or pleural 
effusion will be recorded as disease progression only if proven malignant.
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response 
criteria are met, since a normal lymph node is defined as having a short axis of <10mm.
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 withdrawal of study intervention. 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.
Response duration
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study).
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
Stable disease duration
Stable disease is measured from treatment allocation 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).
The following text descriptions of the visit response are logically equivalent to the tables 
below.


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Table 10–5: RECIST 1.1: Response for Participants with Target and Non-target 
Lesions
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
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
CR = complete response; NE = non-evaluable; PD = progressive disease; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; 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.
Table 10–6: RECIST 1.1: Response for Participants with Non-target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/non-PD*
Not evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response; NE = non-evaluable; PD = progressive disease; RECIST = Response 
Evaluation Criteria in Solid Tumors
* Non-CR/non-PD is preferred over “stable disease” for non-target disease.
Methods of Measurement
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. All measurements must be 
recorded in millimeters (or decimal fractions of centimeters), if applicable.
Clinical Lesions – Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes) and ≥ 10mm diameter as assessed using 
calipers. For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is recommended.
Chest X-ray – Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, chest CT is preferable.
CT / MRI – CT is the best currently available and reproducible methods to measure target 
lesions selected for response assessment. CT scans should be performed with cuts of 5 mm or 
less in slice thickness. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. This 


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applies to the chest, abdomen and pelvis. Head & neck and extremities usually require 
specific protocols.
Ultrasound – Ultrasound is not useful in assessment of lesion size and should not be used as 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. 
Endoscopy / Laparoscopy – The utilization of these techniques for objective tumor 
evaluation is not advised. 
Cytology / Histology – These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to 
be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
10.5.2
mRECIST for HCC
The modified version of RECIST for HCC combines a quantitative assessment of a set of 
lesions using unidimensional measurements with a qualitative assessment of all other lesions.
The modifications introduced for the assessment of intrahepatic lesions are based on the 
modified RECIST criteria published in 2010 for the assessment of HCC (Lencioni and Llovet 
2010).
Results from a number of previous clinical studies in HCC have demonstrated that RECIST 
does not adequately capture the extent of tumor necrosis induced by interventional therapies 
or new molecular targeting drugs. Only viable tumor, assessed by properly designed CT or 
MRI studies, should be included in the tumor burden, and viable tumor should be defined as 
uptake of contrast agent in the arterial phase of dynamic imaging studies. Consequently, a 
modification of RECIST was first proposed by a panel of experts, and further expanded. This 
proposal is based on the fact that the diameter of the target lesions with viable tumor tissue 
should be the basis of measurements for intrahepatic lesions. The measurement of the longest 
viable tumor diameter for the assessment of response according to mRECIST can be only 
applied in case of typical lesions. Conversely, for non-enhancing atypical lesions, as well as 
for any extrahepatic neoplastic niches, the measurements of the longest overall tumor 
diameter as per conventional RECIST should prevail. In addition, there are specific 
modifications of the original criteria regarding the assessment of vascular invasion, lymph 
nodes, ascites, pleural effusion, and new lesions (European Association for the Study of the 
Liver [EASL]- European Organisation for Research and Treatment of Cancer [EORTC]
clinical practice guidelines) (EASL-EORTC 2012).
The expert panel has adopted the concept of viable tumor endorsed by EASL and proposed 
amendments to RECIST in the determination of tumor response for HCC, which have been 
incorporated into the criteria in this trial as described herein.
Definitions
Intrahepatic lesions: Malignant findings within the liver parenchyma, the portal vein, and the 
porta hepatis region. The rules for the assessment of intrahepatic lesions (including when a 
new lesion is considered to have appeared) incorporate the referenced modifications for HCC.


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Extrahepatic lesions: All malignant lesions, other than those defined as intrahepatic as above. 
These lesions will be assessed using the standard RECIST 1.1 approach.
Measurable lesions: Lesions that, at baseline, meet the requirements for being reproducibly 
quantifiable. The requirements are different for intrahepatic and extrahepatic lesions, and are 
described below. Lesions that meet the requirements are considered eligible for quantitative 
assessment during the study.
Non-measurable lesions: Lesions that, at baseline, do not meet the below-described 
requirements, cannot be chosen for quantitative assessment, and must be assessed 
qualitatively.
Target lesions: Lesions that are chosen at baseline (from the set of measurable lesions) for 
quantitative assessment throughout the trial, using rules outlined below. A lesion that has 
been selected as a target lesion remains a target lesion for the rest of the trial.
Non-target lesions: Lesions that are not chosen at baseline for quantitative assessment, and 
must be assessed qualitatively throughout the trial. A lesion that has been selected as a non-
target lesion remains a non-target lesion for the rest of the trial.
Typical HCC enhancement: A lesion is considered to have typical HCC enhancement if it 
shows enhancement during the arterial phase of contrast administration, with washout in the 
portal venous or late venous phase.
Baseline Assessment
Measurable disease:
Non-nodal tumor lesions: Measurable lesions are those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI. If scans 
with slice thickness greater than 5mm are used, the minimum size should be twice the 
slice thickness.

20 mm by chest X-ray

10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable)

For typical lesions within the liver parenchyma, only the portion of the lesion that 
shows typical HCC enhancement should be included in the measurement. For atypical 
lesions, the longest overall diameter should be measured.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT or MRI scan 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability.
Tumor lesions situated in a previously irradiated area are not considered measurable unless 
there has been demonstrated progression in the lesion.
Non-measurable disease:
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with short axis 10-14 mm) are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitic involvement of 


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skin or lung, inflammatory breast disease, abdominal masses/ abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques 
and blastic bone lesions are all non-measurable.
Intrahepatic lesions: For lesions in the liver parenchyma, those that show typical HCC 
enhancement with longest diameter <10 mm, as well as those that show typical enhancement 
in a complex pattern that does not lend itself to reproducible measurement are considered 
non-measurable. 
Porta hepatis lymph nodes: Lymph nodes detected at the porta hepatis can be considered 
malignant, but not measurable, if the lymph node short axis is at least 2 cm. Nodes in the 
porta hepatis are never considered measurable.
Portal vein thrombosis: Malignant portal vein thrombosis should be considered a non-
measurable lesion.
Selection of target and non-target lesions: 
At baseline, lesions are divided into those that will be followed quantitatively (target lesions) 
and those that will be followed qualitatively (non-target lesions).
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and be recorded 
and measured at baseline. These 5 lesions should be selected on the basis of their size (lesion 
with the longest diameter), be representative of all involved organs and should be suitable for 
reproducible repeated measurements. For the purposes of this selection, paired organs (such 
as the lungs) should be regarded as a single organ, and all lymph nodes should be regarded as 
a single organ.
If measurable lesions are present in the liver parenchyma, they should always be selected as 
target lesions before any other lesions are chosen. Up to 2 liver lesions can be selected, just as 
with any other organ. Typical liver lesions should be prioritized over atypical lesions when 
selecting target lesions.
The sum of the diameters (longest typically-enhancing diameter for typical liver lesions, 
longest diameter for atypical liver lesions and extrahepatic non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum of 
diameters. The baseline sum of diameters will be used as the reference measurement when 
looking for evidence of objective response at later visits.
If there are more than five measurable lesions, those not selected as target lesions will be 
considered together with non-measurable disease as non-target lesions.
Non-target lesions include all non-measurable lesions, plus any measurable lesions over and 
above the 5 listed as target lesions. It is possible to record multiple non-target lesions 
involving the same organ as a single item on the eCRF (e.g.; ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
Post-baseline assessment
At every planned follow-up scan visit as described in the protocol after baseline, the 
investigator will assess the target lesions selected at baseline quantitatively (as described 
below), assess the non-target lesions selected at baseline qualitatively, and search for new 
lesions. The lesion assessments are then combined into an assessment of the entire participant 
at that visit (called the visit response or the overall response).


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Target lesion assessment
The investigator will measure each target lesion in the same manner as at baseline. 
Extrahepatic non-nodal lesions and atypical liver lesions will be measured using their longest 
diameter. Malignant lymph nodes (excluding those in the porta hepatis, which can never be 
target lesions) will be measured in short axis diameter. Intrahepatic typical lesions will be 
measured in the longest diameter that shows typical HCC enhancement (excluding areas of 
necrosis).
If a lesion decreases in size to the point where it is still present, but cannot be measured 
accurately, a default value of 5 mm should be recorded for its diameter. If a lesion has 
disappeared, a value of 0 mm should be recorded for its diameter. If a lesion has split into 
distinct fragments, the longest diameter of each fragment should be measured, and the 
diameters added together. If two lesions have merged, the longest diameter of the entire 
resulting lesion should be measured.
The sum of diameters will be calculated by adding all target lesion diameters. The sum of 
diameters is always compared to two reference points: the baseline sum of diameters, and the 
smallest sum of diameters seen during the trial (also called the nadir). The baseline may 
actually be the nadir, if there has been no reduction in the sum of diameters during the trial. 
The target lesion response is then classified as follows:
Table 10–7: mRECIST: Response for Participants with Target and Non-target Lesions
Complete response (CR)
Complete disappearance of target lesions outside the liver
Complete disappearance of typical HCC enhancement from all target 
liver lesions
All target lymph nodes <10 mm
Partial response (PR)
At least a 30% decrease in the sum of diameters from baseline
Progressive disease (PD)
At least a 20% increase in the sum of diameters from the smallest 
value seen during the trial (including baseline), with at least a 5 mm 
absolute increase in the sum
Stable disease (SD)
Neither enough shrinkage to qualify as PR, nor enough growth to 
qualify as PD
Non-evaluable (NE)
One or more target lesions not evaluated because of imaging issues, 
coverage, or change in imaging technique
CR = complete response; HCC = hepatocellular carcinoma; PD = progressive disease; PR = partial 
response; mRECIST = modified RECIST
Note that when lymph nodes are included as target lesions, a CR may occur even when the sum of 
diameters is not zero, since a normal lymph node will have a diameter greater than zero but
less than 10 mm.
Non-target lesion assessment
Non-target lesions are assessed as a whole. After examining each non-target lesion, the 
investigator will classify the non-target lesion response as follows: 


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Table 10–8: mRECIST: Response for Participants with Non-target Lesions Only
Complete response (CR)
Complete disappearance of non-target lesions outside the liver
Complete disappearance of typical HCC enhancement from all non-
target liver lesions
All non-target lymph nodes <10 mm (<20 mm for porta hepatis lymph 
nodes)
Resolution of malignant portal vein thrombosis (if present)
Progressive disease (PD)
Unequivocal progression of non-target lesions as a whole
Non-CR/Non-PD
Non-target lesions still present, without unequivocal progression
Not all evaluated
One or more non-target lesions not evaluated because of imaging 
issues, coverage, or change in imaging technique
CR = complete response; HCC = hepatocellular carcinoma; PD = progressive disease; mRECIST = 
modified RECIST
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 withdrawal of study intervention. A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal.
Cytopathologic confirmation of the neoplastic nature of any effusion that appears or worsens 
during treatment is required to declare PD.
New lesions
Outside the liver, any new lesion that is considered unequivocally malignant is evidence of 
progression, with no minimum size requirement. 
For lesions within the liver, a new lesion can be classified as HCC (and therefore evidence of 
progression) if its longest diameter is at least 1 cm and it shows typical HCC enhancement. A 
new lesion that is at least 1 cm without typical HCC enhancement can be diagnosed as HCC if 
it shows at least 1 cm growth in subsequent scans. A lesion that is smaller than 1cm in longest 
diameter is not considered a new lesion according to the rules of this protocol.
An individual radiological event will be adjudicated in retrospect as progression at the time it 
was first detected by imaging techniques, even if strict criteria were fulfilled only on 
subsequent radiological testing. This means that if a new lesion is not unequivocal at the time 
of initial detection, but later becomes unequivocal, the date of progression will be the date it 
was first detected.
Visit overall response
The response of the target lesions, the response of the non-target lesions, and the presence or 
absence of new lesions are combined into the visit overall response for the entire participant at 
this visit, using the tables below.
Best response
The best overall response is the best visit response recorded from the start of the study 
intervention until the end of intervention. If SD is the best response seen during the study, it 
must be maintained for at least 6 weeks (42 days) after the start of intervention.
Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor 
(both target and non-target). Any pathological lymph nodes (whether target or non-target) 
must have a reduction in short axis to < 10mm (<20 mm for porta hepatis lymph nodes).


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Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions.
Stable Disease (SD): Steady state of disease. Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions 
from 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 or the 
appearance of one or more new lesions also constitute progressive disease. Ascites or pleural 
effusion will be recorded as disease progression only if proven malignant.
In the absence of measurable disease, the same general concepts apply as noted above.
Progression is assessed on the basis of intrahepatic and extrahepatic disease together. Either 
the growth of intrahepatic lesions with typical arterial enhancement, or the growth of 
extrahepatic tumors, can indicate progression, if the sum of diameters (for target lesions) or 
the qualitatively assessed total tumor burden (for non-target lesions) indicates progression.
Response duration
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study).
The duration of overall complete response is measured from the time criteria are first met for 
CR until the first date that recurrent disease is objectively documented.
Stable disease duration
Stable disease is measured from assignment to treatment until the criteria for progression are 
met.
The following text descriptions of the visit response are logically equivalent to the tables 
below.


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Table 10–9: Response for Participants with Target and Non-target Lesions
Target Lesions
Non-Target Lesions
New 
Lesions
Overall 
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
CR = complete response; NE = non-evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease
Participants with a global deterioration of health status requiring withdrawal 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 
withdrawal of intervention.
Table 10–10: Response for Participants with Non-target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/non-PD*
Not evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response; NE = non-evaluable; PD = progressive disease
* Non-CR/non-PD is preferred over “stable disease” for non-target disease.
10.5.3
iRECIST
iRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response 
seen with immunotherapeutic drugs (Table 10–11). If the investigator considers radiographic 
changes secondary to drug-induced inflammation and not to tumor progression (i.e. in case of 
suspected pseudo-progression), the investigator may postpone a diagnosis of progressive 
disease until the next radiographic evaluation in the study, and further confirmation per 
iRECIST criteria. This decision by the investigator should be based on the participant’s 
overall clinical condition.
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.
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 intervention until repeat imaging is obtained 


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using iRECIST for participant management (see Table 10–11 and Figure 10–1). This decision 
by the investigator should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive study 
intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 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 iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response 
of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 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. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively as 
New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:


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
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:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 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.
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 intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
NOTE: If a participant has iCPD as defined above, but the participant is achieving a clinically 
meaningful benefit, an exception to continue study intervention may be considered following 
consultation with the sponsor. In this case, if study intervention is continued, tumor imaging 


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should continue to be performed following the intervals as outlined in this protocol (see 
Section 1.3.1) 
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.
Additional details about iRECIST are provided in the iRECIST publication (Seymour et al. 
2017).


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Table 10–11: Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD by 
RECIST 1.1 
Repeat 
imaging at 
4 to 8 weeks 
at site to 
confirm PD
May continue 
study 
intervention at 
the local site 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site by 
iRECIST.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
per physician 
discretion only
Discontinue study 
intervention
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
at the local site
No additional 
imaging 
required
Discontinue 
study 
intervention
(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 
intervention at 
the 
investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
per 
investigator’s 
discretion only.
Discontinue study 
intervention
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
intervention at 
the local site 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. The next 
tumor image should 
occur according to 
the schedule 
outlined in the SoA
(Section 1.3.1).
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = 
modified RECIST 1.1 for immune-based therapeutics; iPR = iRECIST partial response; iSD = 
iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; N/A = not 
applicable; PD = progressive disease; RECIST 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 RECIST; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1; PD = 
progressive disease


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10.6
Appendix 6: CYP3A4 Inhibitors and Inducers
CYP3A4 inducers and inhibitors 
Table 10–12 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. 
Grapefruit juice (CYP3A4 inhibitor) should also be avoided.
Table 10–12: 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
CYP3A4 = cytochrome P450 3A4
Strong CYP3A4 inhibitors are NOT allowed during this clinical trial.
CYP3A4 inducers are NOT allowed during this clinical trial.
The CYP3A4 inducers and strong CYP3A4 inhibitors in Table 10–12 were identified using 
the Bayer-World Health Organization’s Drug Dictionary (WHO-DD) and Bayer drug 
groupings for CYP3A4 inducers and CYP3A4 inhibitors.


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10.7
Appendix 7: New York Heart Association Functional Classification
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
10.8
Appendix 8: Barcelona Clinic Liver Cancer (BCLC) Classification
Figure 10–2: BCLC Staging and Treatment Strategy
HCC = hepatocellular carcinoma; MELD = model for end-stage liver disease; PS = performance 
status; TACE = transarterial chemoembolization
Source: (Bruix et al. 2016)
The BCLC classification divides HCC patients in 5 stages (0, A, B, C and D) according to 
pre-established prognostic variables, and allocates therapies according to treatment-related 
status. Thus, it provides information on both prognostic prediction and treatment allocation. 
Prognosis prediction is defined by variables related to tumor status (size, number, vascular 
invasion, N1, M1), liver function (Child–Pugh’s) and health status (ECOG). Treatment 
allocation incorporates treatment dependent variables, which have been shown to influence 


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therapeutic outcome, such as bilirubin, portal hypertension or presence of symptoms-ECOG 
(EASL-EORTC Clinical Practice Guidelines) (EASL-EORTC 2012).
10.9
Appendix 9: Child-Pugh Classification
Points Scored for Observed Findings
1
2
3
Encephalopathy grade a
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin, mg/dL
< 2
2 to 3
> 3.0
Serum albumin, g/dL
> 3.5
2.8-3.5
< 2.8
Prothrombin time-international normalized ratio (INR)
< 1.7
1.7 - 2.3
> 2.3
a
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Assessment as good operative risk (A) if 5 or 6 points; moderate risk (B) if 7 to 9 points, and 
poor operative risk (C) if 10 to 15 points (developed for surgical evaluation of alcoholic 
cirrhotics).
10.10
Appendix 10: Guideline for Diagnosing Esophageal Varices
    
Source: (WGO 2014)


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10.11
Appendix 11: AASLD Practice Guideline (Diagnostic Algorithm for 
HCC)
                 
CT = computed tomography; HCC = hepatocellular carcinoma; MDCT = multidetector CT; MRI = 
magnetic resonance imaging; US = ultrasound
Source: (Bruix et al. 2011)
10.12
Appendix 12: Abbreviations
AASLD
American Association for the Study of Liver Diseases
ABC
Absolute basophil count
ADA
Anti-drug-antibody
AE
Adverse event
AEC
Absolute eosinophil count
AESI
Adverse event of special interest
AFP
Alpha-fetoprotein
AG
Joint stock company, Aktiengesellschaft
ALC
Absolute lymphocyte count
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AMC
Absolute monocyte count
ANC
Absolute neutrophil count
Ang1
Angiopoietin 1
Anti-HBc+
Hepatitis B core antibody positive
Anti-HBe
Hepatitis B e-antigen
Anti-HBs-
Hepatitis B surface antibody negative
Anti-HCV
Anti-hepatitis C virus antibody
Anti-HDV
Hepatitis D antibody
aPTT
Activated partial thromboplastin time


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AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
BCG
Bacillus Calmette-Guérin
BCLC
Barcelona Clinic Liver Cancer staging;
BCRP
Breast cancer resistance protein
BM
Biomarker
BP
Blood pressure
BRAF
Proto-oncogene BRAF
BSC
Best supportive care
BUN
Blood urea nitrogen
Cavg
Average concentration over the dosing interval
CBC
Complete blood count
CCL3/CCL4
Chemokine ligand 3 / 4 
CCR5
Chemokine receptor 5
CD
Compact disk
CD28 / CD3 / CD8
Cluster of differentiation 28 / 3 / 8
CFR
Code of Federal Regulations
CG
Cockcroft-Gault (equation)
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum/peak concentration
Cmin
Minimum/trough concentration
CMV
Cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CP
Child-Pugh (score)
CR
Complete response
CRC
Colorectal cancer
CrCl
Creatinine clearance
CRF
Case report form
CRO
Contract research organization
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 10
CXCR3
C-X-C Motif Chemokine Receptor 3
CYP
Cytochrome P450 (derivates)
DAA
Direct acting antiviral
DC
Discontinuation of study intervention
DCR
Disease control rate
DICOM
Digital Imaging and Communications in Medicine
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
DPD
2,3-dicarboxypropane-1,1-diphosphonate
DRESS
Drug rash with eosinophilia and systemic symptoms
DVD
Digital versatile disk
EASL
European Association for the Study of the Liver
EBV
Epstein-Barr virus


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ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
eCRF
Electronic case report form
EDC
Electronic data capture
EOI
End of infusion
EORTC
European Organisation for Research and Treatment of Cancer
EoS
End of study
EoT
End of treatment
E-R
Exposure-response
EU
European Union
FDA
Food and Drug Administration 
FGFR
Fibroblast growth factor receptor
FoxP3
Forkhead box P3
FPFV
First patient first visit
FSH
Follicle stimulating hormone
FT3
Free triiodothyronine
FT4
Free thyroxine
FU
Follow-up
GCP
Good clinical practice
G-CSF
Granulocyte colony stimulating factor
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GIST
Gastrointestinal stromal tumor
GM-CSF
Granulocyte-macrophage colony stimulating factor
Hb
Hemoglobin
HBcAb
Hepatitis B core antibody
HBeAg
Hepatitis B e-antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDP
Hydroxyethylene diphosphonate
HDV
Hepatitis D virus
HECI
Hepatic events of clinical interest
HFSR
Hand-foot skin reaction
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HMDP
Hydroxymethylene diphosphonate
HR
Hazard ratio
IB
Investigators brochure
HRT
Hormonal replacement therapy
ICI
Immune checkpoint inhibitor
ICF
Informed consent form
ICH
International Conference on Harmonization
iCPD
Confirmed progressive disease by iRECIST
iCR
iRECIST complete response
IDO1
Indolamine-2,3-dioxygenase
IEC
Independent Ethics Committee
IFN-γ
Interferon gamma
IgG
Immunoglobulin G


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IgM
Immunoglobulin M
IgV
Immunoglobulin variable
ILD
Interstitial lung disease
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International normalized ratio
IO
Immune oncology
iPR
iRECIST partial response
irAE
Immune-related adverse event
IRB
Institutional Review Board
iRECIST
Response evaluation criteria in solid tumors, adapted to account for 
tumor response seen with immunotherapeutic drugs
iSD
iRECIST stable disease
IU/mL
International units per milliliter
IUD
Intrauterine device
iUPD
Unconfirmed progressive disease by iRECIST
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IxRS
Interactive Voice/Web Response System
KIT
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
LDH
Lactate dehydrogenase
LFT
Liver function test
LPLV
Last patient last visit
LSH
Life Sciences Data Hub
M-2, M-5
Metabolites of regorafenib
M&S
Modeling and simulation
mAb
Monoclonal antibody
MAD
Maximum administered dose
mCRC
Metastatic colorectal cancer
MDCT
Multidetector computed tomography
MDP
Methylene diphosphonate
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MHC1
Major histocompatibility complex 1
miRNA
Micro RNA
MKI
Multi-kinase inhibitor
mRECIST
Modified response evaluation criteria in solid tumors
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
MVI
Macrovascular invasion
NCI
National Cancer Institute
NE
Non-evaluable
NIMP
Non-investigational medicinal product
NOACs
Novel oral anticoagulants
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
p.o.
Per os (oral)
PBMC
Peripheral blood mononuclear cells


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PD
Progressive disease
PD-1
Programmed cell death 1
PDGFR
Platelet-derived growth factor receptor
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PFS
Progression-free survival
PI/ICF
Patient information / informed consent form
PID
Participant identification number
PK
Pharmacokinetics
PKCθ
Protein kinase C-theta
PR
Partial response
pRBC
Packed red blood cell
PS
Performance status
PT
Partial thromboplastin
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q4W
Every 4 weeks
Q6W
Every 6 weeks
QD
Once daily
QOD
Every other day
QRS
QRS interval in ECG
QT
QT interval in ECG
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected using Fridericia’s formula
RAF
Rat fibrosarcoma
RANKL
Receptor activator of nuclear factor kappa-Β ligand
RAVE
Electronic data capture software
RBC
Red blood cell count
RCC
Renal cell carcinoma
RECIST
Response evaluation criteria in solid tumors
RET
Rearranged during transfection
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical software suite developed by SAS Institute
SD
Stable disease
SDLL
Source data location list
SHP-1, SHP-2
Src homology region 2 domain-containing phosphatase-1 / 2
SIM
Site imaging manual
SJS
Stevens-Johnson Syndrome
SmPC
Summary of Product Characteristics
SN-38
Active metabolite of irinotecan
SoA
Schedule of activities
SRC
Sarcoma
SUSAR
Suspected unexpected serious adverse reactions
sVEGFR
Soluble vascular endothelial growth factor receptor-1
SVR
Sustained virological response
T1DM
Type 1 Diabetes Mellitus
TACE
Transarterial chemoembolization
TEAE
Treatment-emergent adverse event
Teff
Effector T cells
TEN
Toxic epidermal necrolysis


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TIE2
Tyrosine kinase with Ig and EGF homology domains
TM
Trademark
TMB
Tumor mutational burden
TMF
Trial master file
Treg
Regulatory T cells
TSH
Thyroid stimulating hormone
UGT1A1, UGT1A9
Uridine 5'-diphospho-glucuronosyltransferase family 1 A1 / A9
ULN
Upper limit of normal
US(A)
United States of America
v.
Version 
VEGF
Vascular endothelial growth factor
VEGFR
Vascular endothelial growth factor receptor
WxDx
Week x, day x
WBC
White blood cell count
WHO-DD
World Health Organization’s Drug Dictionary
WOCBP
Woman of childbearing potential
ZAP70
Zeta-chain-associated protein kinase 70
10.13
Appendix 13: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
11.
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