Clinical trial NCT03397654
Conditions: Primary Liver Carcinoma
Sponsor: Imperial College London
Start date: 2018-01-28; Completion date: 2023-03-23
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open label, single arm, multi-centre study of pembrolizumab following trans-arterial chemoembolization (TACE). Twenty-six to 32 evaluable participants with primary liver cancer (hepatocellular cancer; HCC) will be assessed. The primary objective is to determine the safety and tolerability of pembrolizumab following TACE. The secondary objective is to evaluate the efficacy of pembrolizumab following TACE by improving progression-free survival rates as measured by modified response evaluation criteria in solid tumours (mRECIST) criteria.

Detailed description:

Arms: arm 1: Trans-arterial chemoembolization (TACE) using doxorubicin solution (60 mg dose) and gelatin sponge particles; followed, at least 30 or 45 days later, by pembrolizumab solution (200 mg dose) every 3 weeks for a maximum of 1 year
Interventions: intervention 1: Pembrolizumab intervention 2: Trans-arterial chemoembolization
Intervention descriptions: intervention 1: Pembrolizumab solution intervention 2: Doxorubicin injected through the hepatic blood supply directly to the cancer-affected part of the liver, then gelatin sponge particles injected to block the blood vessels supplying the tumour

Protocol documents:
Prot_SAP_001.pdf: 
 
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A Phase Ib Study of Pembrolizumab following Trans-Arterial Chemoembolization 
in Primary Liver Carcinoma 
 
 
 
 
 
 
Study Acronym:                            Petal 
 
 
Protocol Number: 
 
Petal-1 
 
IMP:    
 
 
Pembrolizumab 
 
Sponsor: 
 
 
Imperial College London 
 
EudraCT Number: 
 
2017-000471-85 
 
IRAS Number:  
 
223814 
 
Development Phase:    
1b 
 
 
Protocol Version no and date:   5.0 29 April 2019 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
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CONTACT LIST 
 
Chief Investigator  
Dr. David James Pinato, MD MRes MRCP (UK) PhD 
 
Imperial College London 
Level 2 IRD Building 
Hammersmith Hospital 
Du Cane Road 
London 
Email: David.Pinato@imperial.ac.uk 
Tel: 
+44 (0) 207 594 2804 
Fax: 
+44 (0) 203 311 0203 
 
Sponsor 
Ruth Nicholson, Head of Research Governance and Integrity Team Imperial College London 
Room 221 
Medical School Building 
St Mary’s Campus 
Norfolk Place 
London, W2 1PG 
Email: r.nicholson@imperial.ac.uk 
Tel: +44 (0) 20 75941872 
Fax: +44 (0)20 33110203 
 
Funder 
Merck Sharp & Dohme Limited 
West Hill Cottage,  
Hertford Rd, Hoddesdon,  
Hertfordshire EN11 9BU,  
United Kingdom 
Tel: +44 1992 467272 
 
Laboratories  
Frank Lynch, Vice President / COO 
 
QualTek Molecular Laboratories 
300 Pheasant Run 
Newtown, PA 18940 
USA 
Tel: 
(215) 504-7402 
 
Investigational Medicinal Product (IMP)/Device Manufacturing Facilities  
MSD Ireland (Carlow) 
Dublin Road 
Carlow 
Ireland 
Tel: 
 +353 (0) 59917 2600 


 
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ABBREVIATIONS  
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BCLC 
Barcelona Clinic Liver Cancer 
BP 
Blood pressure 
BW 
Body Weight 
CI 
Confidence Interval 
CI 
Chief Investigator 
CrCl 
Creatinine Clearance 
CTC 
Circulating Tumour Cells 
CNS 
Central Nervous System 
CR 
Complete Response 
CRP 
C reactive Protein 
CT 
Computed Tomography 
DBL 
DEB 
Database Lock 
Drug-eluting beads  
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DRAE 
Drug Related Adverse Events 
EASL 
European Association for the Study of the Liver 
EC50 
Half maximal effective concentration 
eCRF 
electronic Case Report Form 
ECI 
event of clinical interest 
ECG 
Electrocardiogram 
ECI 
Evidence of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Collection 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End Of Treatment 
EOT 
End Of Trial 
EPO 
Erythropoietin 
FBC 
Full Blood Count 
FDA 
Food and Drug Administration 
FIH 
First In Human 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GMP 
Good Manufacturing Practice 
GPC3 
Glypican-3 
HCC 
Hepatocellular Cancer 
HCV 
Hepatitis C Virus 
HCV- RNA 
Hepatitis C Virus - Ribonucleic Acid 
Hif-1a 
Hypoxia-inducible factor 1-alpha 
HIV 
Human Immunodeficiency Virus 
HRA 
Health Research Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 


 
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ICH 
International Conference on Harmonisation 
ICH GCP 
International Conference on Harmonisation for Good Clinical Practice 
ITT 
Intention to Treat 
IDSMC 
Independent Data & Safety Monitoring Committee 
Ig 
Immunoglobulin 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse events 
irECI 
ITIM 
iTMF 
ITSM 
ISF 
Immune-Related Evidence of Clinical Interest 
Immunoreceptor Tyrosine-based Inhibition Motif 
Investigator Trial Master File 
Immunoreceptor Tyrosine-based Switch Motif 
Investigator Site File 
IV 
Intravenous 
L 
Litre 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
m 
Metre 
m2 
Metre2 
mAb 
Monoclonal Antibody 
mcL 
Microlitre 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 
Melanoma 
mg 
Milligramme 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
µM 
microMolar 
min 
Minute 
mL 
Millilitre 
mM 
Millimolar 
mmol/L 
Millimoles per litre 
mRECIST 
modified Response Evaluation Criteria In Solid Tumours 
MSD 
Merck Sharp & Dohme Limited 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute –Common Terminology Criteria for Adverse Events 
NIMP 
Non Investigational Medicinal Product 
NICE 
National Institute for Health and Clinical Excellence 
nmol 
Nanomoles 
nmol/L 
Nanomoles per litre 
NSCL 
Non-Small Cell Lung 
NSCLC 
Non-Small Cell Lung Cancer 
OL 
Open Label 
ORR 
Overall Response Rate 
OR 
Odds Ratio 
OS 
Overall Survival 
OTC 
Over-the-counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD 
Pharmacodynamic 
PFS 
Progression-Free Survival 
PFSR 
Progression-Free Survival Rate 
PI 
Principal Investigator 


 
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PIS 
Participant Information Sheet 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time 
PT 
Preferred term 
QOL 
Quality Of Life 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q8W 
Every 8 weeks 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell 
REC 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria In Solid Tumours 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SD 
Stable Disease  
SFU 
Safety Follow Up 
SJS 
Stevens-Johnson Syndrome 
SOC 
Standard of Care 
SOC 
System Organ Class 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TAA 
Tumour Associated Antigens 
TACE 
Trans-Arterial Chemoembolization 
TB 
Tuberculosis 
TEN 
Toxic Epidermal Necrolysis 
T3 
Triiodothyronine 
T4 
Thyroxine 
TILs 
Tumour-infiltrating lymphocytes 
TK 
Toxicokinetic 
TMG 
Trial Management Group 
TSH 
Thyroid-Stimulating Hormone 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WHO DD 
World Health Organisation Drug Dictionary 
 
 
 


 
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Contents 
TRIAL SUMMARY 
9 
1.0 
INTRODUCTION 
13 
 
Background 
13 
 Hepatocellular Carcinoma and trans-arterial chemoembolization. ............................................. 13 
 Pharmaceutical and Therapeutic Background .............................................................................. 13 
 
Preclinical and Clinical Trial Data 
15 
 Preclinical Safety and Efficacy Summary. ...................................................................................... 15 
 Clinical Safety and Efficacy Summary. ........................................................................................... 15 
 
Rationale for the study 
17 
 Rationale for the Trial and Selected Subject Population .............................................................. 17 
 Rationale for Dose Selection/Regimen/Modification. .................................................................. 18 
 
Rationale for Endpoints 
20 
 Safety Endpoints ............................................................................................................................. 20 
 Efficacy Endpoints .......................................................................................................................... 20 
 Biomarker Research. ...................................................................................................................... 20 
 
Risk / Benefit Assessment. 
21 
2.0 
OBJECTIVES AND ENDPOINTS 
22 
 
Primary Objective 
22 
 
Secondary Objective 
22 
 
Tertiary Objective 
22 
 
Primary Endpoint 
22 
 
Secondary Endpoints 
22 
 
Tertiary Endpoints 
22 
 To identify biomarkers of immune response to Pembrolizumab using high-throughput 
technologies. .................................................................................................................................. 22 
 To evaluate the efficacy of Pembrolizumab following TACE by improving PFS rates as measured 
by standard RECIST criteria v 1.1 at pre-defined 12-weekly timepoints. ....................................... 22 
3.0 
STUDY DESIGN 
23 
 
Design 
23 
 Part One .......................................................................................................................................... 23 
 Part Two ......................................................................................................................................... 23 
 
Treatment regimens 
24 
4.0 
PARTICIPANT ENTRY 
25 
 
Study population 
25 
 Inclusion criteria ............................................................................................................................. 25 
 Exclusion criteria ............................................................................................................................ 26 
5.0 
PROCEDURES AND MEASUREMENTS 
27 
 
Screening evaluations 
27 
 
Trial Procedures 
28 
5.1.1 Administrative Procedures ............................................................................................................. 32 
5.1.2 Clinical Procedures/Assessments ................................................................................................... 33 
 Guidance on the interpretation of hepatitis serology for the purpose of eligibility. ................... 36 
 Total Blood Volume ........................................................................................................................ 36 
 
Treatment 
37 
 
Post Treatment Follow-up 
38 
 Safety Follow-Up Visit .................................................................................................................... 38 
 Follow-up Visits .............................................................................................................................. 38 
6.0 
TREATMENT 
38 
 
TACE. 
38 
 
Investigational Medicinal Product Details 
39 
 Product Preparation ....................................................................................................................... 39 
 
Labelling and Packaging 
39 
 
Storage and Dispensing 
40 


 
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 Storage............................................................................................................................................ 40 
 Handling ......................................................................................................................................... 40 
 Returns and Reconciliation ............................................................................................................ 40 
 
Dosage, Duration and Compliance 
40 
 Timing of Dose Administration ...................................................................................................... 40 
 Trial Blinding/Masking................................................................................................................... 40 
 
Dose Modifications for Toxicity 
41 
 
Drug interactions/Precautions 
42 
 Concomitant Medications/Vaccinations (allowed & prohibited) ................................................. 42 
 Acceptable Concomitant Medications ........................................................................................... 43 
 Prohibited Concomitant Medications ............................................................................................ 43 
 
Rescue Medications & Supportive Care 
43 
 Supportive Care Guidelines ............................................................................................................ 43 
 Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-related 
Events of Clinical Interest (irECI). .................................................................................................. 47 
 Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest. ...................... 49 
 
Diet/Activity/Other Considerations 
53 
 Diet .................................................................................................................................................. 53 
 Contraception ................................................................................................................................. 53 
 Use in Pregnancy ............................................................................................................................ 54 
 Use in Nursing Women ................................................................................................................... 54 
 
Overdose of IMP 
54 
 
Permanent Discontinuation of Study Treatment and Withdrawal from Study 
55 
 Permanent discontinuation of study treatment ........................................................................... 55 
 Withdrawal from Study ................................................................................................................. 55 
 Procedures for Withdrawal from Study ........................................................................................ 56 
 
Non-IMP details 
56 
7.0 
PHARMACOVIGILANCE 
56 
 
Adverse Event (AE) 
56 
 Disease Progression ....................................................................................................................... 56 
 New Cancers ................................................................................................................................... 56 
 Abnormal Laboratory Test Results ................................................................................................ 56 
 Pregnancy and Lactation ............................................................................................................... 57 
 
Adverse Event recording 
57 
 Evaluating Adverse Events ............................................................................................................. 57 
 Reporting of Pregnancy and Lactation .......................................................................................... 58 
 
Serious Adverse Events (SAE) 
58 
 Definition of SAE ............................................................................................................................. 58 
 
Definitions of Evidence of Clinical Interest 
59 
 Reporting of SAEs ........................................................................................................................... 61 
 Events exempt from being reported as SAEs ................................................................................. 62 
 Determining SAE Causality and Expectedness .............................................................................. 62 
 
Reporting of ECIs 
62 
 
Reporting of an Overdose 
62 
 
Definition of a Serious Adverse Reaction (SAR) 
62 
 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
63 
 
Reporting of SUSARs 
63 
 
Annual Reporting of Serious Adverse Events 
63 
8.0 
STATISTICAL ANALYSES 
63 
 
Sample Size and power considerations 
63 
 
Data Analysis 
64 
 
Primary and Secondary Endpoint Analysis 
64 
 
Exploratory Endpoint Analysis 
64 
9.0 
REGULATORY, ETHICAL AND LEGAL ISSUES 
64 


 
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Declaration of Helsinki 
64 
 
Good Clinical Practice 
65 
 
Research  Ethics Committee Approval 
65 
 Initial Approval ............................................................................................................................... 65 
 Approval of Amendments .............................................................................................................. 65 
 Annual Progress Reports ................................................................................................................ 65 
 Annual Safety Reports and End of Trial Notification .................................................................... 65 
 
Regulatory Authority Approval 
65 
 
Insurance and Indemnity 
65 
 
Trial Registration 
66 
 
Informed Consent 
66 
 
Contact with General Practitioner 
66 
 
Subject Confidentiality 
66 
 
Data Protection 
66 
 
End of Trial 
66 
 
Study Documentation and Data Storage 
67 
10.0 
DATA MANAGEMENT 
67 
 
Source Data 
67 
 
Language 
67 
 
Database & Data Management 
67 
 
Data Collection 
67 
11.0 
STUDY MANAGEMENT STRUCTURE 
68 
 
Independent Data & Safety Monitoring Committee 
68 
 
Trial Management Group 
68 
 
Early Discontinuation of the Study 
68 
 
Risk Assessment 
68 
 
Monitoring 
68 
 
Quality Control and Quality Assurance 
69 
 
Disclosure of Data and Publication 
69 
12.0 
REFERENCES 
70 
Appendices 
73 
Appendix 1: Diagnostic Criteria for HCC. 
73 
Appendix 2: ECOG Performance Status 
73 
Appendix 3: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
74 
Appendix 4: Modified Response Evaluation Criteria in Solid Tumours (mRECIST*) Criteria for Evaluating 
Response in Hepatocellular Carcinoma. 
74 
Appendix 5: Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria for Evaluating Response in 
Solid Tumours 
74 
SIGNATURE PAGE 1 (Chief Investigator) 
75 
SIGNATURE PAGE 2 (SPONSOR) 
76 
SIGNATURE PAGE 3 (principal INVESTIGATOR) 
77 
 
 
 


 
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TRIAL SUMMARY 
Title 
A 
Phase 
Ib 
Study 
of 
Pembrolizumab 
following 
Trans-Arterial 
Chemoembolization in Primary Liver Carcinoma (PETAL). 
Trial Phase 
Ib 
Clinical Indication 
Primary Liver Cancer  
Trial Type 
Open label (OL), Single arm 
Route of administration 
Intravenous (IV) 
Trial Blinding 
None 
Treatment Groups  
1 
Number 
of 
Trial 
Participants/ Sites 
26-32 evaluable participants / 1-4 UK sites 
Estimated duration of trial 
3 Years 3 Months 
Duration of Participation 
Until disease progression or intolerance, withdrawal or completion of 1 year 
of treatment. 
Study Objectives 
Primary Objective 
• 
To determine the safety and tolerability of Pembrolizumab following 
Trans-Arterial Chemoembolization (TACE). 
Secondary Objective 
• 
To evaluate the efficacy of Pembrolizumab following TACE by improving 
progression-free survival rates (PFSR) as measured by modified 
Response Evaluation Criteria In Solid Tumours (mRECIST) criteria at pre-
defined 12-weekly timepoints. 
Exploratory Objective 
• 
To evaluate predictive correlates of response to Pembrolizumab in 
hepatocellular cancer (HCC). 
Study Endpoints 
Primary Endpoint 
• 
To assess the safety and tolerability of Pembrolizumab using National 
Cancer Institute Common Terminology Criteria for Adverse Events 
version 4 (NCI CTCAE v4). 
Secondary Endpoints 
• 
To evaluate the efficacy of Pembrolizumab following TACE using PFSR at 
12 weeks (every 4 cycles) based on mRECIST criteria.  
Exploratory Endpoints 
• 
To evaluate the efficacy of Pembrolizumab following TACE by improving 
PFSR as measured by standard Response Evaluation Criteria In Solid 
Tumours (RECIST) criteria v 1.1 at pre-defined 12-weekly timepoints. 
• 
To identify biomarkers of immune response to Pembrolizumab using 
high-throughput technologies. 


 
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Summary of Main Inclusion 
Criteria 
In order to be eligible for participation in this trial, the participant must: 
1. Be willing and able to provide written informed consent/assent for 
the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have a diagnosis of Hepatocellular Cancer (HCC) based on AASLD 
criteria (Appendix 1).  
4. Have at least one uni-dimensional lesion measurable by Computed 
Tomography (CT)-scan or Magnetic Resonance Imaging (MRI) based 
on mRECIST criteria.    
5. Patients who received prior TACE treatment (conventional or DEB-
TACE) are eligible, provided they have at least one previously 
untreated lesion that is measurable based on mRECIST criteria. 
6. Be ineligible for surgical resection or liver transplantation. 
7. Have a performance status of 0 or 1 on the Eastern Cooperative 
Oncology Group (ECOG) Performance Scale  
8. Demonstrate adequate organ function  
9. Have an overall Child-Pugh score <7 
10. Female subject of childbearing potential should have a negative 
urine or serum pregnancy.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
11. Women of childbearing potential must be willing to use a highly 
effective method of contraception as outlined in Section 6.9.2 for 
the course of the study through 120 days after the last dose of 
Investigational Medicinal Product (IMP). 
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. 
12. Sexually active males must agree to use an adequate method of 
contraception as outlined in Section 6.9.2 starting with the first dose 
of IMP through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. 
Summary of Main Exclusion 
Criteria 
The participant must be excluded from participating in the trial if the 
participant: 
1. Has extrahepatic metastasis. 
2. Systemic anticancer treatment for HCC. 
3. Has any contraindication for TACE including portosystemic shunt, 
hepatofugal blood flow, known severe atheromatosis. 
4. Has history of bleeding within the 4 weeks preceding study 
enrolment.  
5. Has hepatic encephalopathy. 
6. Has ascites that is refractory to diuretic therapy. 
7. Has documented occlusion of the hepatic artery or the main portal 
vein (segmental portal vein thrombosis does not represent 
exclusion criterion provided this does not contraindicate TACE). 


 
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8. Is currently participating and receiving therapy or has participated 
or is participating in a study of an IMP or used an investigational 
device within 4 weeks of the first dose of IMP. 
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy. 
 
10. Has a known history of active Bacillus Tuberculosis (TB) 
11. Hypersensitivity to Pembrolizumab or any of its excipients. 
12. Has a known additional malignancy that is progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the skin 
or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 
13. Has active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is 
not considered a form of systemic treatment.  
14. Has known history of, or any evidence of active, non-infectious 
pneumonitis. 
15. Has an active infection requiring systemic therapy. Exceptions 
relating to Hepatitis B and C virus infection are documented in 
Section 5.3.1, Table 5.  
16. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating Principal Investigator (PI).   
17. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
18. Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
screening visit through to 120 days after the last dose of IMP. 
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-
L2 agent. 
20. Has a known history of Human Immunodeficiency Virus (HIV; HIV 
1/2 antibodies). 
21. Has received a live vaccine within 30 days of first dose of IMP 
administration. 
Note:  Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
Treatment / Main Study 
Procedures 
TACE. Trans-arterial chemoembolization will be performed as a background 
treatment and as such is classed as a Non Investigational Medicinal Product 
(NIMP) for the purpose of this study. Treatment will consist of the infusion 
of cytotoxic chemotherapy after arterial hepatic angiogram, followed by 


 
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either selective or super-selective embolization of the arterial vascular bed 
perfusing the tumour with gelatin/sponge particles. TACE procedure will be 
standardised across sites and will consist of  conventional or drug-eluting 
beads (DEB) transcatheter superselective arterial chemoembolization 
utilising doxorubicin at either a fixed dose of 60 mg (for conventional TACE) 
or a dose ranging from 75-150mg depending on the size of the tumour (for 
DEB-TACE) followed by tumour vasculature embolization with gelatin 
sponge particles.  TACE is normally administered as a short elective inpatient 
treatment to allow for monitoring of immediate post-procedural 
complications. Radiologic follow up after TACE with contrast-enhanced CT 
or MRI scan will be performed approximately 30 days after TACE as part of 
SOC prior to IMP administration. Participants who fail to achieve complete 
tumour devascularisation after the first session of TACE as assessed by 
follow-up contrast-enhanced scan may be allowed up to 1 further TACE 
session as per European Association for the Study of the Liver 
(EASL)/European Organisation for Research and Treatment of Cancer 
(EORTC) clinical guidelines unless clinical or technical factors preclude repeat 
treatment. In patients requiring re-treatment, re-screening is not required 
and time intervals for commencement of IMP and subsequent Dose Limiting 
Toxicity (DLT) window will remain unchanged.  
 
Pembrolizumab. IMP administration will begin no earlier than 30 + 3 days 
following TACE administration. IMP should be administered on an outpatient 
basis on Day 1 ± 3 days of each cycle after all procedures/assessments have 
been completed. Pembrolizumab will be administered at the pre-planned 
dose as a 30 (-5/+10) minute (min) IV infusion every 3 weeks (Q3W).   


 
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1.0 
INTRODUCTION  
 
Background 
 Hepatocellular Carcinoma and trans-arterial chemoembolization. 
Hepatocellular carcinoma is the sixth commonest and third most lethal solid malignancy on a global scale[1]. 
Approximately 60% of patients who are newly diagnosed with HCC do not qualify for curative treatments 
including liver resection or transplantation[2]. Patients presenting with liver-confined HCC, preserved liver 
function and performance status cluster into “intermediate stage” or Barcelona Clinic Liver Cancer (BCLC) B 
stage.  In this patient subgroup, where overall survival (OS) often extends beyond 2 years, guidelines 
recommend TACE with the intent of prolonging OS by achieving local disease control and prevent systemic 
spread of the disease [3]. 
 
The use of TACE in unresectable HCC as a palliative measure to improve survival whilst maintaining quality 
of life (QOL) is supported by level I evidence stemming from 2 primary randomized controlled trials and 
subsequent meta-analyses. The efficacy of TACE relies on the dual ischaemic and cytotoxic effect stemming 
from the sequential intra-arterial delivery of cytotoxic chemotherapy (doxorubicin, epirubicin or cisplatin) 
followed by direct occlusion of the arterial neo-vascular supply to the tumour. Clinically, this translates into 
radiologically measured responses in 35% of patients (range, 16%-61%), which correlate with a 14% 
improvement of patients’ survival at 2-years (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; 
P =.017)[3]. 
 
 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been 
known for decades. Accumulating evidence shows a correlation between tumour-infiltrating lymphocytes 
(TILs) in cancer tissue and favourable prognosis in various malignancies.  In particular, the presence of CD8+ 
T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumours. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours 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 CD28 and CTLA-4 which has 
been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).  The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is 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 (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the 
tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to 
be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double 


 
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negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic 
tissues as well as in various tumours. Both ligands are type I transmembrane receptors containing both IgV- 
and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumour-specific T-cell expansion 
in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumour 
immune evasion and should be considered as an attractive target for therapeutic intervention[4]. 
 
Anti-tumour immunotherapy with monoclonal antibodies blocking the PD-1/PD-L1 “immune synapse” is 
gaining momentum in the treatment of a growing number of malignancies, where immune checkpoint 
inhibitors directed against PD-1 including nivolumab (OpdivoTM, BMS) or Pembrolizumab (KeytrudaTM, MSD) 
have, amongst others, received accelerated regulatory approval for the treatment of solid tumours[5-7].  
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  
Pembrolizumab has recently been approved in the United States of America (USA) for the treatment of 
patients with unresectable or metastatic melanoma and disease progression following ipilumumab and, if 
BRAF V600 mutation positive, a BRAF inhibitor. 
 
In the specific setting of HCC, immunotherapy represents an appealing treatment strategy in view of inherent 
property of HCC to evoke spontaneous, although exhausted immune responses. The process of oncogenic 
transformation that leads to the onset of HCC is in fact characterised by a continuum between inflammation-
fibrosis and carcinoma, where the innate and adaptive immune response exert a synergistic pathogenic 
role[8, 9].      
 
In this context, chronically inflamed hepatocytes up-regulate the expression of a repertoire of tumour 
associated antigens (TAAs) including alpha-fetoprotein, glypican-3 (GPC3) and many other proteins 
pertaining, amongst others, to the cancer/testis antigen family[10, 11]. A number of studies have 
demonstrated that T cell responses against immune-dominant epitopes from these proteins exist in a 
suppressed state in HCC patients, suggesting they might be amenable to therapeutic modulation to overcome 
immune-evasion of cancer [12, 13].  
 
In addition, the high mutational burden of HCC, which amounts to 2 mutations per Mb, with a median of 45 
non-synonymous events, makes this disease particularly neoantigen-rich, therefore expanding the overall 
antigenicity of HCC[14, 15]. Unsurprisingly, in keeping with this view, evidence of dense lymphocytic 
infiltration is in fact commonly found in histological specimens of human HCC and is often mirrored by 
discernible CD8+, tumour-antigen specific T-cell responses in peripheral blood[16]. Taken together, these 
data suggest that anti-cancer immune response exists in HCC patients and is crucially down-regulated by 
different mechanisms during the clonal evolution of HCC[17]. 
 


 
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Cancer immunogenicity is not a static determinant, but rather a dynamic process that can be positively 
influenced by treatment. Clinical studies have shown that TACE can modulate both the innate and specific 
immune response in HCC and that the differential activation of the adaptive immunity may underlie the 
heterogeneity observed in patients’ survival following TACE[18, 19].  
 
In aggregate, the evidence presented so far and the accumulating data from ongoing phase I trials of 
immunotherapy agents in HCC sustain the combination between TACE, a potential loco-regional inducer of 
immunogenic cell death with the restoration of a functional and antigenically broader antitumour immune 
response achieved by sequential PD-1 directed checkpoint inhibition. 
 
 
Preclinical and Clinical Trial Data 
 Preclinical Safety and Efficacy Summary. 
Pre-clinical toxicology studies on Pembrolizumab were conducted in accordance to the International 
Conference on Harmonisation (ICH) S6 Guidance for Biopharmaceuticals. 
 
The 1- and 6-month toxicity and toxicokinetic (TK) studies in Cynomolgus monkeys showed no 
Pembrolizumab–related effects on any parameter evaluated [electrocardiograms (ECG), general veterinary 
and physical examinations with body temperature and blood pressure (BP), clinical observations, and 
histopathology of tissues from the cardiovascular, respiratory, renal, and nervous systems]. 
 
Pre-clinical efficacy studies have shown that Pembrolizumab enhances T-cell responses in human donor 
blood cell cultures, with a half-maximal effective concentration (EC50) of approximately 0.1 to 0.3 nanoMoles 
(nM). Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer patients, and Cynomolgus monkeys. The antibody potentiates existing 
immune responses only in the presence of antigen-receptor stimulation and does not specifically activate all 
T-cells. 
 
PD-1 blockade using the anti–mouse PD-1 surrogate antibody J43, is demonstrated to significantly inhibit 
tumour growth in a variety of syngeneic murine tumour models. 
 
Importantly, Pembrolizumab does not bind to superfamily members CD28, CTLA-4, and ICOS. Although 
Pembrolizumab acts as an immunomodulatory agent, it is distinct from agents such as those targeting CD3 
or CD28 because it does not inadvertently activate immune responses. Pembrolizumab was evaluated in an 
assay described by Stebbings et al, 2007, used to assess the risk of acute cytokine release in participants 
following treatment with immune-modulatory agents. Unlike an agonist anti-CD28 mAb, incubation of 
human peripheral blood mononuclear cell (PBMC) with Pembrolizumab in the absence of additional 
stimulation did not induce production of IL-2, to further prove its specificity. 
 
 Clinical Safety and Efficacy Summary. 
To date, approximately 11,000 patients in clinical trials and 27,000 patients in the post-marketing setting 
have been treated with KEYTRUDA®.  
 
The clinical safety profile of Pembrolizumab as monotherapy has emerged from a number of clinical studies 
including P001/P002, P012, P013, and P028, plus the P011 monotherapy arm. 


 
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In the Pembrolizumab monotherapy trials, in general, the most commonly reported Adverse Events (AEs) 
included fatigue, diarrhoea, decreased appetite, nausea, dyspnoea, and anaemia. The incidence of drug-
related AEs (DRAEs) ranged from 39.8% (35 of 88 subjects in P013) to 80.0% (8 of 10 subjects in P011). The 
incidence of Grade 3-5 DRAEs across studies ranged from 6.8% (6 of 88 in P013) to 12.0% (187 of 1562 
subjects) in P001/P002. 
 
The most commonly reported Grade 3-5 DRAEs were anaemia, alanine aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) increased, and colitis. 
 
The majority of subjects who experienced an AE continued in the study, with the incidence of AEs leading to 
discontinuation ranging from 4.2% (18 of 430 subjects in P028) to 12.3% (192 of 1562 subjects in P001/P002). 
The majority of AEs leading to discontinuation were not considered drug related. Discontinuations due to a 
DRAE were infrequent and ranged from 0% (no subjects in P011) to 4.5% (4 of 88 subjects in P013). The most 
commonly reported DRAE leading to discontinuation was pneumonitis. 
 
Hepatotoxicity, a clinically important safety concern in this study, is overall infrequent as a Pembrolizumab-
related AE. Out of a total of 1562 subjects with advanced malignancies treated with Pembrolizumab 
monotherapy across a wide range of clinical trials, hepatic, drug-related autoimmune toxicity was identified 
in 8 subjects (0.5%), with 2 subjects qualifying for grade 3 toxicity (0.1%). Data from the use of Pembrolizumab 
in other indications, in absence of background hepatic impairment, suggest that liver toxicity did not appear 
to be a dose-dependent, but rather a stochastic immune-related AE. Management with oral corticosteroids 
for a median duration of 7 days has proven beneficial to antagonise this AE. 
 
Efficacy data are available for a total of 655 P001 melanoma subjects treated with Pembrolizumab and 540 
P002 melanoma subjects treated with either Pembrolizumab or chemotherapy. For both clinical studies, 
assessment of overall response rate (ORR) was based on RECIST 1.1 and performed by blinded central 
reviewers. 
 
The P001 ORR demonstrated the antitumour activity of Pembrolizumab in subjects with melanoma 
(ipilimumab-naïve and previously treated with ipilimumab). 
 
P002 demonstrated superior Progression Free Survival (PFS) for both Pembrolizumab treatment arms 
compared to the chemotherapy control arm. Treatment with Pembrolizumab lead to an ORR that was >4 fold 
higher than the response rate of the chemotherapy control arm. This difference was highly statistically 
significant, with a one sided p-value of <0.0001. The overall response rates for Pembrolizumab treatment in 
P001 and P002 compared favourably to historical response rates for available treatments for melanoma, 
particularly in subjects who had progressed after multiple prior therapies. For example, the largest 
randomised clinical trial in previously treated advanced melanoma subjects, in which carboplatin and 
paclitaxel were used in the control arm, and sorafenib plus carboplatin and paclitaxel in the experimental 
arm, produced a response rate of 11% and 12%, respectively. 
 
One fatal case of Stevens-Johnson Syndrome (SJS) in a clinical trial and one fatal case of Toxic Epidermal 
Necrolysis (TEN) in the post-marketing setting have been reported in patients treated with KEYTRUDA®. 
Including these cases, there have been 8 cases of SJS (6 in clinical trials, and 2 post-marketing) and 2 cases of 
TEN (both post-marketing) all of which were serious.  
• 
The risk of SJS and TEN is reported at approximately 0.4 - 7 cases per million patient years in the general 
adult population.  


 
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• 
Independent risk factors include certain medications such as anticonvulsants, sulfonamides, 
aminopenicillins, allopurinol, and NSAIDs. Non-medication triggers include infection, contrast media, and 
vaccinations.  
• 
Malignancy is associated with an increased mortality rate in patients with SJS and TEN.  
 
A total of 6 cases of myocarditis have been reported in patients treated with KEYTRUDA® in clinical trials or 
in an expanded access program. There were was 1 fatal case reported in a clinical trial.  
• 
A search of the literature identified neither background incidence rates nor prevalence of myocarditis 
specifically among cancer patients.  
• 
Immune-mediated myocarditis should be suspected if other causes of myocarditis, such as infection 
or prior radiation therapy, have been excluded.  
• 
Risk factors include certain medications and treatment modalities such as radiation, anthracycline, 
alkylating agents and most recently checkpoint inhibitors.  
 
A comprehensive summary of the pre-clinical and clinical development of Pembrolizumab is available in the 
IB. 
 
 
Rationale for the study 
 Rationale for the Trial and Selected Subject Population 
In the clinical context of HCC, TACE is indicated by current guidelines as first-line treatment in asymptomatic 
patients with compensated cirrhosis, a Child-Pugh score <8, ECOG of 0 and lack of portal vein thrombosis or 
extra-hepatic spread[3].  
 
However, it is widely accepted that the survival benefit deriving from loco-regional therapies is not evenly 
distributed across all the patients receiving TACE. Despite meeting eligibility criteria for TACE, a subset of 
patients do not respond to therapy[20]. Furthermore, patients with initial radiological response to treatment 
may subsequently become ineligible to repeat TACE due to further disease progression either within or 
outside the liver[21]. The paucity of effective systemic treatments for HCC further limits therapeutic options, 
where the only approved orally active multi-kinase inhibitor sorafenib has produced a 2.8 months 
improvement in survival in advanced disease but has failed to show benefit in the adjuvant setting[22]. 
 
Immune checkpoint blockade targeted to PD-1 has emerged as promising anticancer therapy across a 
growing variety of malignancies. Preliminary results from the CA209-040 study, a Phase I/II dose-ranging trial 
evaluating the safety and tolerability of the anti-PD-1 antibody nivolumab (Opdivo, BMS), has confirmed an 
OS rate of 62% at 12 months in HCC, with established radiologic responses in 8 (19%) of 42 evaluable patients. 
Whilst treatment responders achieved duration of response ranging between 1.4 – 12.5 months, a total of 
26 patients (62%) ultimately experienced progression of their disease, to suggest underlying biologic 
heterogeneity in the disease-modulating effects from treatment[23]. 
 
Increasing evidence has suggested a role for the activation of both the innate and specific branches of the 
immune system as a key prognostic determinant in patients undergoing TACE, with chronic modulation of 
the T-helper-2 lymphocyte response playing a role in influencing long-term survival [24-26]. Similarly, studies 
in HCC patients undergoing TACE have suggested a differential regulation of T-cell suppressive responses in 
relation to the efficacy of TACE, making restoration of an effective anti-tumour adaptive immunity an 
appealing therapeutic strategy in HCC [18, 27].  


 
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A key question now is to understand whether the ischaemic and cytotoxic damage imposed by TACE to the 
tumour may facilitate priming of the antigen-specific branch of the immune system to a broad range of 
previously inaccessible neo-epitopes, potentially enabling an enhanced activity of PD-1/PD-L1 inhibitors. 
Mechanistic evidence suggests PD-L1 expression to be under the transcriptional control of the Hif-1a[28], 
which further strengthens the rationale of combining TACE with PD-1/PD-L1 inhibitors in light of the 
documented role of TACE in activating a sustained hypoxic response and promote the release of circulating 
Vascular Endothelial Growth Factor (VEGF) levels and other pro-antiogenic cytokines[29]. 
 
Whilst optimal dosing of Pembrolizumab has been established in advanced solid tumours[30], the immune-
mediated adverse event profile of the compound and the potential interaction with TACE warrants 
preliminary safety and tolerability evaluation in BCLC-B stage disease, a subgroup of HCC patients who have 
by definition optimal performance status and liver functional reserve, rendering them normally able to 
tolerate liver ischaemia following selective intra-arterial targeting of the tumour nodules up to Child-Pugh B7 
criteria. 
 
 Rationale for Dose Selection/Regimen/Modification.  
Pembrolizumab has been studied in doses ranging from 2 mg/kg Q3W to 10 mg/kg Q2W, with the maximum 
dose that has been studied being 10 mg/kg Q2W. 
 
The rationale for dose selection originates from the results of an OL, Phase I trial (Protocol 001) conducted 
to evaluate the safety and clinical activity of single agent Pembrolizumab. The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered Q2W in participants with 
advanced solid tumours.  All three dose levels were well tolerated and no DLTs were observed.  This first in 
human (FIH) study of Pembrolizumab showed evidence of target engagement and objective evidence of 
tumour size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No Maximum Tolerated Dose 
has been identified to date. Recent data from other clinical studies within the Pembrolizumab program has 
shown that a lower dose of Pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of Pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic (PD) data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and PD data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population PK analysis has been performed using serum concentration time data from 476 patients. Within 
the resulting population PK model, clearance and volume parameters of Pembrolizumab were found to be 
dependent on body weight (BW). The relationship between clearance and BW, with an allometric exponent 
of 0.59, is within the range observed for other antibodies and would support both BW normalised dosing or 
a fixed dose across all BW.  Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W BW based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 
for Pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-
fold higher dose and exposure). The population PK evaluation revealed that there was no significant impact 
of tumour burden on exposure. In addition, exposure was similar between the Non-Small Cell Lung Carcinoma 


 
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(NSCLC) and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of Pembrolizumab in solid tumours is 
based on: 1) similar efficacy and safety of Pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W 
in melanoma participants, 2) the flat exposure-response relationships of Pembrolizumab for both efficacy 
and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumour burden or 
indication on distribution behaviour of Pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of Pembrolizumab target engagement will not vary meaningfully with tumour 
type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations 
performed using the population PK model of Pembrolizumab showing that the fixed dose of 200 mg Q3W 
provides exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose Q3W, 2) will 
maintain individual  exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual participants exposure in the exposure range established in 
melanoma that are well tolerated and safe. A fixed dose regimen simplifies the dosing regimen to be more 
convenient for physicians and to reduce potential for dosing errors. A fixed dosing scheme reduces 
complexity in the logistical chain at treatment facilities and reduces wastage. 
 
There are currently no clinical data illustrating the safety and tolerability of Pembrolizumab following TACE. 
Whilst TACE is expected to produce low-grade hepatitis, occasionally amounting to post-embolisation 
syndrome with fevers and abdominal pain, these events are self-resolving and clinical studies have shown 
that the peak of cytokine as well as AST/ALT release happens approximately 7 days after TACE and 
subsequently spontaneously resolves [31]. 
 
There are limited data to define the safety of PD-1 directed therapies in the context of chronic viral infection. 
Preliminary data reporting on the use of the anti-PD-1 antibody nivolumab have reassuringly shown no 
evidence of hepatitis flares in virally infected HCC patients[23]. Interim results from the ongoing CA209-040 
study have demonstrated Grade 3 and 4 AST and ALT increase in approximately 10-12% of participants with 
advanced HCC as potential DRAEs. However, drug discontinuation rates secondary to all-cause DRAEs was 
low at interim analysis amounting to only 5%[23].  
 
Similar safety signals emerge from the appraisal of immunotherapy trials of anti-CTLA-4 checkpoint 
inhibitors, which – although different by mechanism of action – might have toxicity overlap with anti-PD1 
antibodies due to the potential of evoking undesired immune-pathology. 
 
Reassuringly, a clinical trial of tremelimumab in 20 participants with Hepatitis C-virus (HCV) related advanced 
HCC has similarly shown no evidence of hepatitis flares. Conversely, the majority of participants with active 
HCV viraemia at baseline demonstrated falling HCV- Ribonucleic Acid (RNA) levels following tremelimumab 
treatment to suggest dual anti-viral and anti-tumoural immune-reconstitution. The same trial has however 
confirmed an acute, transient transaminase (ALT, AST) release in up to 45% of the participants, which 
however did not warrant treatment discontinuation [32]. A similar pilot trial tremelimumab following TACE 
or radiofrequency ablation in hepatobiliary tumours has shown good tolerability of the combination both in 
terms of viral kinetics and risk of acute hepatotoxicity following treatment. A dual anti-viral and anti-tumour 
activity was again confirmed and importantly, no DLTs were reached in the combination study[33].  
 


 
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Critical appraisal of the safety data of pembolizumab across all indications seem to suggest the lack of a strict 
dose-dependent correlation between drug exposure and DRAEs. For these reasons, this study will evaluate 
the safety and tolerability of Pembrolizumab following TACE at 200 mg Q3W, which equates to the currently 
recommended therapeutic dose of Pembrolizumab in other indications. Pending evaluation of DRAEs in a 
first subset of 6 subjects within the pre-specified DLT evaluation period of 21 days, the treatment schedule 
of Pembrolizumab may be changed to extend the pembrolizumab to TACE interval from 30 (+3 days) to at 
least 45 days (+3 days) of TACE in an expansion cohort of maximum 26 patients.  
 
At least 1 participant will be mandated to meet Child-Pugh B7 criteria in the safety run-in phase to ensure 
wide generalisability of the safety outcomes to the full spectrum of severity of background liver dysfunction. 
 
 
Rationale for Endpoints 
 Safety Endpoints 
Safety and tolerability of Pembrolizumab following TACE represent the primary endpoints of this study and 
will be recorded and presented descriptively. Adverse events will be graded according to NCI CTCAE v4  and 
other safety data (e.g. ECG, vital signs, laboratory results etc) will be collected. 
 Efficacy Endpoints 
Efficacy outcome measures will represent a secondary study endpoint and will be recorded and presented 
with an exploratory intent. The efficacy of treatment will be evaluated radiologically in terms of PFSR defined 
as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) at 12 weeks 
post treatment according to mRECIST. Contrast-enhanced CT of the chest abdomen and pelvis will be 
mandated at study baseline and at subsequent study endpoints. Baseline CT/MRI scans do not need to be 
repeated if obtained within 35 days of first IMP administration. MRI of the liver is allowed to analyse 
intrahepatic tumour response following TACE at the discretion of the PI. However, if this method is elected 
for the baseline evaluation of the disease, the same modality must be used for all follow-up assessments and 
coupled with full CT restaging of extrahepatic disease. Radiologic evaluation of the disease will be performed 
centrally to ensure maximal reproducibility. The efficacy of treatment will also be evaluated by PFS rate at 
12-weekly timepoints (as assessed by mRECIST), defined as the proportion of participants who did not fulfil 
the criteria of progressive disease. Tumour reassessments will be concurrently captured using standard 
RECIST criteria v. 1.1. 
 Biomarker Research. 
A biomarker tumour sample will be mandated at screening. For all other biomarker samples, participants 
enrolled into this study will be invited to donate additional blood, urine and stool biomarker samples for the 
discovery of immune-response biomarkers. A separate biomarker consent form for these optional biomarker 
samples will be provided to participants. Refusal to consent to these optional biomarker sample collections 
will not exclude the participant’s participation in the trial.  
Biomarker samples will be collected at screening, throughout treatment (predose) and at end of treatment 
(EOT) as indicated in the Time & Events table. Stool and urine samples may be collected up to 3 days prior to 
the visit.  
 


 
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The overall aim of this project is to initiate an exhaustive, multi-technology, high-throughput analysis of 
prospectively collected tissue and bio-fluid samples to explore the molecular and immunological 
determinants underlying the anti-tumour response to Pembrolizumab in HCC and investigate the escape 
mechanisms that characterise resistance to treatment.  
   
Participant samples will be stored for future correlative research which may be in collaboration with MSD. 
 
 
Risk / Benefit Assessment. 
Whilst PD-1/PD-L1 blockade has been extensively characterised for safety outcomes in hundreds of patients 
with advanced malignancies, intermediate-stage HCC represents a special population, for which the main 
safety questions are represented by the concomitant presence of chronic hepatitis and the underlying liver 
functional impairment stemming from liver cirrhosis. Furthermore, there are no clinical data to support 
combination of PD-1 directed checkpoint inhibitors with TACE. Whilst TACE is expected to produce low-grade 
hepatitis, occasionally amounting to post-embolisation syndrome with fevers and abdominal pain, these 
events are self-resolving and clinical studies have shown that the peak of cytokine as well as AST/ALT release 
happens approximately 7 days after TACE and subsequently spontaneously resolves.  
 
Whilst the safety data available to date show Pembrolizumab to be a generally safe and well tolerated 
treatment, confirmatory studies to support the use of the compound in the context of HCC are required prior 
to efficacy testing. 
 
In the present study the protocol has been designed to mitigate the risks potentially arising as a result of the 
combination of Pembrolizumab with TACE: 
• 
A long interval of at least 30 + 3 days between TACE and systemic treatment has been adopted to 
guarantee full resolution from the ischaemic/cytotoxic damage to the healthy liver parenchyma 
following loco-regional treatment. 
• 
Accounting for the great heterogeneity of participants presenting with intermediate-stage HCC, at 
least 1 participant will be selected to correspond to Child Pugh B7 class criteria. This guarantees that 
participants at the worse end of the liver functional reserve spectrum are adequately captured at each 
dose level.  
• 
An initial safety run-in phase (Part 1) will allow for preliminary safety characterisation of the IMP before 
subsequent expansion. Pending evaluation of DRAEs in the first cohort of 6 subjects within the pre-
specified DLT evaluation period, the Independent Data Safety Monitoring Committee (IDSMC) will 
review the DRAE profile and agree on a recommended interval between TACE and  Pembrolizumab to 
be adopted in the subsequent expansion phase. 
• 
Due to the peculiar immune-mediated toxicity related to Pembrolizumab and the kinetics of liver 
functional recovery following TACE a time window of 21 days is deemed biologically adequate to 
characterise acute liver-related toxicity emerging from Pembrolizumab treatment and will be 
considered as the DLT window of the study. In Part 1 and Cycle 1 only study participants will attend 
weekly for laboratory evaluations (Viral load if indicated, PT/INR and aPTT, haematology, biochemistry, 
T3, T4 & TSH, cortisol). 


 
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• 
In the case that DLTs are observed only in the Child Pugh B7 participants but not in the Child Pugh A 
participants, only Child Pugh A participants will be recruited to the expansion cohort as determined by 
the IDSMC. 
• 
The overall safety profile of Pembrolizumab will be fully characterised during the whole study period, 
including a safety follow up (SFU) visit 30 ± 7 days post-discontinuation and a telephone follow-up visit 
130 ± 7 days after the last IMP dose. 
• 
A review will be conducted at the end of Part I by the IDSMC. A final analysis will be conducted at the 
end of the study.  Analyses will include an intention to treat (ITT) analysis including all participants 
enrolled and a per protocol analysis using all participants who complete the study without major 
protocol violations.   
 
2.0 
OBJECTIVES AND ENDPOINTS  
 
 
Primary Objective 
To determine the safety and tolerability of Pembrolizumab following TACE in participants with intermediate-
stage HCC. 
 
 
Secondary Objective 
To determine the efficacy of Pembrolizumab following TACE in participants with intermediate-stage HCC. 
 
 
Tertiary Objective 
To identify predictive correlates of immune response to Pembrolizumab in HCC.  
 
 
Primary Endpoint 
To assess the safety and tolerability of Pembrolizumab using NCI CTCAE v4. 
 
 
Secondary Endpoints  
To evaluate the efficacy of Pembrolizumab following TACE using PFS rates at 12 weeks (every 4 cycles) using 
mRECIST and standard RECIST v. 1.1 criteria.  
 
 
Tertiary Endpoints 
 To identify biomarkers of immune response to Pembrolizumab using high-throughput technologies.  
Biomarker blood, tissue urine and stool sample collection connected to this study will be established for 
biomarker research using high throughput proteomic and genomic analysis. Functional characterisation of 
circulating lymphocyte populations will be performed in parallel. The biomarker biopsy tissue sample taken 
at screening is optional. Participants will be invited to provide all other additional biomarker blood, urine and 
stool sample samples for research as well as provide consent for research to be performed on all leftover 
samples and tissue taken for diagnostic purposes.  
 To evaluate the efficacy of Pembrolizumab following TACE by improving PFS rates as measured by 
standard RECIST criteria v 1.1 at pre-defined 12-weekly timepoints.  
 


 
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3.0 
STUDY DESIGN   
 
Design 
The study will be performed at 1-4 sites in the UK and will recruit up to a maximum of 32 evaluable 
participants. This study is an OL, single arm, sequential phase study evaluating safety, tolerability and 
preliminary efficacy of sequential TACE followed by Pembrolizumab and will be conducted in two parts. 
 Part One 
Part 1 of the study will consist of a safety run-in of up to 6 participants treated with Pembrolizumab at the 
clinically recommended dose of 200 mg Q3W. Subjects will be observed for determination of DLTs over a 21 
day time window with weekly laboratory assessments in Cycle 1 only (Viral load if indicated, PT/INR and aPTT, 
haematology, biochemistry, T3, T4 & TSH, cortisol). Particular attention will be given to liver function tests 
(LFT). Whilst no DLTs were observed nor Maximum Tolerated Dose (MTD) was defined in dose escalation 
studies of Pembrolizumab monotherapy, the safety run-in phase of this study will allow us to verify protocol 
procedures and assess the safety of the combination with TACE. The decision to undertake the main 
feasibility trial for the TACE followed by 200 mg dose with at least 30 days interval or to increase the window 
between TACE and Pembrolizumab to at least 45 days will be made by the IDSMC who will consider the 
general safety profile with a particular focus on acutely occurring liver-related toxicity.  
 
If there are zero DLTs and no other safety concerns the feasibility trial with be undertaken using the standard 
200 mg Q3W dose with at least 30 days window between TACE and Pembrolizumab. If there are one to two 
DLTs, the IDSMC will then advise to continue with either at least 30 days interval or to increase the window 
between TACE and Pembrolizumab to at least 45 days for the expansion cohort based on additional 
information and general safety profile. If three or more DLTs are observed in the six participants of the safety 
run-in the trial will be stopped. 
 
In the safety run-in and at the start of the feasibility trial, as a safety measure, participants 2-6 will be dosed 
after an interval of one week following the first dose received by the first participant. 
 
Accounting for the great heterogenecity of participants presenting with intermediate-stage HCC, at least 1 
participant in Part 1 will be mandated to correspond to Child Pugh B7 class criteria which will ensure wide 
generalisability of the safety outcomes to the full spectrum of severity of background liver dysfunction.  
 
If a participant withdraws or is withdrawn from the study prior to completion of the first 21 day treatment 
period, in the absence of a DLT, that subject must be replaced and the replacement dosed at the current 
dose level under evaluation. In addition, if a participant is withdrawn for any reason before receiving 
Pembrolizumab, replacement with an additional will be allowed. Participants in Part 1 will be screened after 
providing written informed consent a maximum of 28 days prior to receiving TACE. Once recruited to the 
study and after having completed a 30 + 3 days interval post TACE they will be given Pembrolizumab at 200mg 
Q3W until radiologically confirmed disease progression, unacceptable toxicity, participant withdrawal or a 
maximum of 1 year of treatment has been completed. 
 Part Two  
Once the data for 6 patients are reviewed by the IDSMC in part 1 a further 26 evaluable participants will be 
recruited to the study with the same regimen - TACE followed by 200 mg Pembrolizumab after at least 30 


 
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days window or with TACE followed by 200 mg after at least 45 days. This will further characterise the safety 
and tolerability of Pembrolizumab in this population.  
In this part of the study, if a participant withdraws or is withdrawn from the study prior to completion of the 
first 21 day treatment period, in the absence of a DLT, that participant must be replaced. If a participant is 
withdrawn for any reason before receiving Pembrolizumab, replacement with an additional participant will 
be allowed. 
 
Participants entering part two of the study must be assessed up to 28 days prior to TACE to confirm eligibility 
and be recruited onto the trial. They will be scheduled for Pembrolizumab dosing as per agreed time window 
determined by IDSMC and will be given Pembrolizumab every Q3W ± 3 days until radiologically confirmed 
disease progression, unacceptable toxicity, withdrawal or a maximum of 1 year of treatment has been 
completed.  
 
If the pembrolizumab dosing scheduled is set at 45 days after TACE, at least 1 participant will be mandated 
to meet Child-Pugh B7 criteria in the safety run-in phase to ensure wide generalisability of the safety 
outcomes to the full spectrum of severity of background liver dysfunction. 
 
 
Treatment regimens  
 
All participants entered into the study will receive Pembrolizumab 200 mg every Q3W ± 3 days until 
radiologically confirmed disease progression, unacceptable toxicity, withdrawal or a maximum of 1 year of 
treatment has been completed. The study will first assess safety and tolerability of the standard dose level 
of 200 mg Q3W at least 30 days post TACE. This window may be increased to at least 45 days in Part 2 pending 
assessment of the safety profile of Pembrolizumab in sequential combination with TACE.  
 
Table 1: Study Dosing Schedule 
 
TACE 
Treatment Window 
Dosage 
Frequency 
No 
of 
evaluable 
participants 
Part 1 
As per 
SOC 
At least 30 days  
200 mg 
Every 3 Weeks 
6 
Part 2 
As per 
SOC 
Either at least 30 days or 45 
days 
as 
per 
IDSMC 
recommendation 
200 mg 
Every 3 Weeks  
26 
 
 
 
Total 
number 
of 
evaluable participants 
32 


 
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This study will be conducted following the proposed flow chart.  
Figure 1: Study flow chart 
 
4.0 
PARTICIPANT ENTRY 
 
Study population 
This is a phase Ib, open label, single arm trial designed to evaluate safety and preliminary efficacy of 
sequential combination of TACE followed by Pembrolizumab in participants with intermediate-stage HCC. 
 
 Inclusion criteria 
In order to be eligible for participation in this trial, the participant must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have a diagnosis  of Hepatocellular Cancer (HCC) based on AASLD criteria (Appendix 1). 
4. Have at least one uni-dimensional lesion measurable by CT-scan or MRI based on mRECIST criteria.   
Begin Pembrolizumab at 200mg every 3 weeks at least after 30* days of TACE 
*This window might be increased to at least 45 days in Part 2 depending on IDSMC 
recommendation 
Eligible participants with HCC receiving TACE as per standard of care (SOC) 
Participants will be recruited prospectively a maximum of 28 days prior to TACE. 
Follow – Up Telephone Visits  
Every 8 weeks ± 7 days to check survival status, confirm Post-study anticancer therapy 
status and AE/SAEs (up to 130 ± 7 days post last dose).  
Weekly follow up for first cycle (Part I only) and then 3 weekly thereafter for a 
maximum of 1 year of treatment or until disease progression, occurrence of 
unacceptable toxicities or withdrawal 
Safety Follow – Up Visit. 
To be conducted 30 ± 7 days after the discontinuation of treatment.  


 
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5. Patients who received prior TACE treatment (conventional or DEB-TACE) are eligible, provided they 
have at least one previously untreated lesion that is measurable based on mRECIST criteria. 
6. Be ineligible for surgical resection or liver transplantation.Have a performance status of 0 or 1 on the 
ECOG Performance Scale (Appendix 2). 
7. Demonstrate adequate organ function as defined in the table below.   
 
System 
Laboratory Value 
Haematological 
 
Absolute neutrophil count (ANC) 
≥1,500 mcL 
Platelets 
≥60,000  mcL 
Haemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
Erythropoietin (EPO) dependency  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(CrCl) calculated by Cockcroft Gault criteria 
[Glomerular Filtration Rate (GFR) can also be 
used in place of creatinine or CrCl] 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
ULN 
Hepatic 
 
Serum total bilirubin 
≤ 3 X ULN (level of normality <21 µmol/L) 
AST and ALT  
≤ 5 X ULN  
Albumin 
>2.5 mg/dL 
Coagulation 
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless participant is receiving 
anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCrCl should be calculated per institutional standard. 
Table 2 Adequate Organ Function Laboratory Values 
8. Have an overall Child-Pugh score <7 
9. Female subject of childbearing potential should have a negative urine or serum pregnancy.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
10. Female subjects of childbearing potential must be willing to use an adequate method of 
contraception as outlined in Section 6.9.2 – Contraception for the course of the study through 120 
days after the last dose of IMP. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
11. Sexually active males must agree to use an adequate method of contraception as outlined in Section 
6.9.2- Contraception, starting with the first dose of IMP through 120 days after the last dose of IMP. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
 Exclusion criteria  
The subject must be excluded from participating in the trial if the subject: 


 
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1. Has extrahepatic metastasis. 
2. systemic anticancer treatment for HCC. 
3. Has any contraindication for TACE including portosystemic shunt, hepatofugal blood flow, known 
severe atheromatosis. 
4. Has history of bleeding within the 4 weeks preceding screening.  
5. Has hepatic encephalopathy. 
6. Has ascites that is refractory to diuretic therapy. 
7. Has documented occlusion of the hepatic artery or the main portal vein (segmental portal vein 
thrombosis does not represent exclusion criterion provided this does not contraindicate TACE). 
8. Is currently participating and receiving IMP or has participated in a study of an IMP and received IMP 
or used an investigational device within 4 weeks of the first dose of IMP. 
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy. 
 
10. Has a known history of active TB  (Bacillus Tuberculosis) 
11. Hypersensitivity to Pembrolizumab or any of its excipients. 
12. Has a known additional malignancy that is progressing or requires active treatment.  Exceptions 
include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
14. Has known history of, or any evidence of active, non-infectious pneumonitis. 
15. Has an active infection requiring systemic therapy. Exceptions relating to Hepatitis B and C virus 
infection are documented in Section 5.3.1, Table 5.  
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the participant to participate, in the opinion of the PI.   
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting from screening through to 120 days after the last dose of IMP. 
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
20. Has a known history of HIV (HIV 1/2 antibodies). 
21. Has received a live vaccine within 30 days of first dose of IMP. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
5.0 
PROCEDURES AND MEASUREMENTS  
 
Screening evaluations 
Written informed consent will be obtained before the participant undergoes any study-specific procedures. 
Each participant will undergo screening during the 28 days prior to receiving TACE to confirm eligibility. 
Clinical data obtained as SOC prior to consent may be used for the study provided they comply with the 
protocol-defined criteria and protocol-specified timelines. Baseline CT/MRI scans do not need to be repeated 
if obtained within 35 days of first dose.  


 
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Each eligible participant enrolled into the trial will be assigned a unique participant number for use during 
the trial.  A screening and enrolment log will be completed for all participants who enter screening for the 
study. A subject identification log will be completed for all participants who go on to be enrolled. This subject 
identification log will include the allocated participant number as well as the participant identifiable data 
including name, hospital number and date of birth. These logs will be maintained at each site.  
 
 
Trial Procedures  
The Time & Events Table (Table 3) summarises the trial assessments and procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically or logistically necessary by the PI or delegate. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor, PI or delegate and/or 
MSD for reasons related to subject safety. In some cases, such evaluations/testings may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the participant. In these cases, such evaluations/testings will be 
performed in accordance with those regulations. 
 


 
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Table 3: Time & Events 
 
Screening  TACE 
Treatment Cycles1 
End of 
Treatment 
Post-
Treatment 
Treatment Cycle Nos 
Week Nos 
 
Screening  
 
Day 1 
11, 10 
Wk 
 0, 27 
2 & 11 
Wk 
3, 30 
3, 12 
Wk 
6, 33 
4, 13 
Wk 
9, 36 
5, 14 
Wk 
12, 39 
To be repeated beyond 9 cycles 
and up to 17  
Discontinuation  
Safety Follow-up 
(SFU)
Follow Up Tel 
Visits10 
6, 15 
Wk 
15, 42 
7, 16 
Wk 18, 
45 
8, 17 
Wk 
21, 48 
9 
Wk 
24 
Scheduling Window (Days): 
Pre- TACE 
 -28 to -1 
 
N/A 
Post TACE 
30 + 3 (Part 
1)  
Or Post 
TACE 45 + 3 
(Part 2) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
30 ± 
7 
post 
EOT 
Q8W ± 
7 
post 
SFU 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour Imaging (mRECIST)2 (Chest CT 
and dual phase CT or contrast 
enhanced MRI scan of the abdomen) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
Assessment of Child-Pugh Score 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs, Weight & Height12 
X12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12 – Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL Assessment: EORTC QLQ-C30 and 
QLQ-HCC18  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Pregnancy Test – Urine or Serum beta-
HCG 
X 
 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Serology3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Load (HBV DNA, HCV RNA)4 
X 
 
 
X1 
 
 
 
X 
 
 
 
X 
X 
 
 
PT/INR and aPTT 
X 
 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Alpha fetoprotein 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology5 
X 
 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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Screening  TACE 
Treatment Cycles1 
End of 
Treatment 
Post-
Treatment 
Treatment Cycle Nos 
Week Nos 
 
Screening  
 
Day 1 
11, 10 
Wk 
 0, 27 
2 & 11 
Wk 
3, 30 
3, 12 
Wk 
6, 33 
4, 13 
Wk 
9, 36 
5, 14 
Wk 
12, 39 
To be repeated beyond 9 cycles 
and up to 17  
Discontinuation  
Safety Follow-up 
(SFU)
Follow Up Tel 
Visits10 
6, 15 
Wk 
15, 42 
7, 16 
Wk 18, 
45 
8, 17 
Wk 
21, 48 
9 
Wk 
24 
Scheduling Window (Days): 
Pre- TACE 
 -28 to -1 
 
N/A 
Post TACE 
30 + 3 (Part 
1)  
Or Post 
TACE 45 + 3 
(Part 2) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
30 ± 
7 
post 
EOT 
Q8W ± 
7 
post 
SFU 
Biochemistry6  
X 
 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
T3, T4 and TSH 
X 
 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cortisol 
X 
 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TACE administration8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Archival Tissue Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Biopsy Sample 9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Record of Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE Assessment (NCI-CTCAE v4.03) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xǂ 
Survival and Post-study anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
Optional Biomarker Blood Sample11 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Optional Research Blood Sample – 
Circulating Tumour Cells (CTCs)11 
X 
 
 
X11 
 
 
 
 
 
 
 
 
X 
 
 
Optional Biomarker Urine Sample 11 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Optional Biomarker  Stool Sample 11 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
*A serum pregnancy test will be performed a maximum of seven days before pembrolizumab administration 


 
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ǂ AEs/SAEs will be recorded and reported up to 130 days after last study drug administration. Following completion of 130 days period, AE/SAE monitoring will be 
stopped and patients will continue to be followed up every eight weeks for survival status and commencement of other anti-cancer therapies.  
1. In Parts I & II visits should occur on Day 1 (± 3 days) of every 21 day cycle. In Parts I & II Cycle 1 only, participants will need to come in for weekly visits (± 2 
days) for blood samples. 
2. Tumour assessments may be performed by chest CT and dual phase CT or contrast enhanced MRI scan of the abdomen during screening and every 12 weeks 
thereafter. Baseline CT/MRI scans do not need to be repeated if obtained within 35 days of first dose. Tumour assessment only needs to be conducted during 
EOT visit if participant has come off study for reason other than disease progression and has not had a scan in the previous 6 weeks. 
3. Hepatitis serology is required at screening. This includes HBV DNA, HBsAg, HBeAg, HBCT (anti-HBV core total IgG/IgM), HBeAb (anti-HBV e antibody), HBSab 
(anti-HBV Surface Antibody) as well as full Hepatitis C Virus profile including HCQB (HCV quantitative RNA) and anti-HCV antibodies (IgG) 
4. Participants in part 1 of the study who carry a background of chronic active hepatitis B and/or C will have weekly monitoring of viral load (HCV RNA and/or 
HBV DNA as appropriate in Cycle 1 only). In part 2 only of the study viral load monitoring will be performed every 4 cycles of treatment and at discontinuation 
of Pembrolizumab. 
5. Haematology includes: Haematocrit, Haemoglobin, Platelet count, White Blood Cell (WBC, total and differential) Red Blood Cell (RBC) Count, Absolute 
Neutrophil Count, Absolute Lymphocyte Count 
6. Biochemistry includes: Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), C-reactive protein (CRP), Uric Acid, Calcium, Chloride, Glucose, 
Phosphate, Potassium, Sodium, Magnesium, Total Bilirubin, Direct Bilirubin (If total bilirubin is elevated above the ULN) Total protein, Blood Urea Nitrogen,  
7. Urinalysis includes: Blood, Glucose, Protein Specific gravity, Microscopic exam (If abnormal) 
8. Participants who fail to achieve complete tumour devascularisation after the first session of TACE as assessed by follow-up contrast-enhanced scan may be 
allowed up to 1 further TACE. Re-screening is not required. Conventional and DEB-TACE are both considered accepted modalities for TACE treatment.  
9. The 2-incision tumour biopsy samples at screening and end of treatment are optional. 
10. Participants should be followed up until the last participant comes off study for disease progression, intolerance, withdrawal or completes 1 year of treatment 
11. All other biomarker samples (bar the screening biomarker tumour sample) are optional. All samples taken during treatment cycles are predose. Urine and 
stool collections are -3 days.  
CTCs to be taken at screening, cycle 1 and discontinuation visits only. 
Stool sample to be taken at screening and discontinuation visits only. 
12. Height will be measured at screening only.


 
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5.1.1 Administrative Procedures 
5.1.1.1 
 Informed Consent 
The PI or qualified designee must obtain written informed consent from each potential participant prior to 
any study specific procedures are performed.  
 
Consent must be documented by the participants dated signature on a consent form along with the dated 
signature of the PI or qualified designee conducting the consent discussion. A copy of the signed and dated 
consent form should be given to the participant and placed in the participant’s medical notes. The original 
form should be stored in the investigator site file (ISF). 
 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the subject will have received the Health Research Authority (HRA)/Research Ethics 
Committees (REC) approval/favourable opinion (where required) in advance of use.  Participants should be 
informed in a timely manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures the 
participant’s dated signature. 
 
The informed consent process will adhere to HRA/REC requirements, applicable laws and regulations and 
Sponsor requirements. 
5.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the PI or qualified designee to ensure that the 
participant is eligible to enter the trial.  
5.1.1.3 
 Medical History 
A medical history will be obtained by the PI or qualified designee.  Medical history will include all active 
conditions, and any condition diagnosed that are considered to be clinically significant by the PI or delegate. 
Details regarding the disease for which the participant has enrolled in this study will be recorded separately 
and not listed as medical history however under disease status.   
5.1.1.4 
Prior and Concomitant Medications Review 
5.1.1.4.1 Prior Medications 
The PI or qualified designee will review prior and current medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject at screening.  Treatment for the 
disease for which the participant has enrolled in this study will be recorded under prior cancer treatments 
and not listed as a prior medication. 
5.1.1.4.2 Concomitant Medications 
The PI or qualified designee will record all medication taken by the participant from screening through to 
SFU. All medications related to reportable Serious Adverse Events (SAEs) and Event of Clinical Interest (ECIs) 
should be recorded as defined in Section 7. 


 
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5.1.1.5 
Disease Details and Treatments 
5.1.1.5.1 
Disease Details 
The PI or qualified designee will obtain prior and current details regarding disease status.  
 
5.1.1.5.2 
Prior Treatment Details 
The PI or qualified designee will review all prior cancer treatments including systemic treatments, radiation 
and surgeries. 
 
5.1.1.5.3 
Subsequent Anti-Cancer Therapy Status 
The PI or qualified designee will review all new anti-neoplastic therapy initiated after the last dose of IMP.  If 
a participant initiates a new anti-cancer therapy within 30 days after the last dose of IMP, the SFU visit must 
occur before the first dose of the new therapy. Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  
5.1.2 Clinical Procedures/Assessments 
5.1.2.1 
Adverse Event (AE) Monitoring 
The PI or qualified designee will assess each participant to evaluate for potential new or worsening AEs as 
specified in the visit schedule and more frequently if clinically indicated.  Adverse events will be graded and 
recorded from informed consent until safety follow up according to NCI CTCAE Version 4.0 (see Appendix 3).  
Toxicities will be characterised by seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
All AEs of unknown etiology associated with Pembrolizumab exposure should be evaluated to determine if it 
is possibly an ECI of a potentially immunologic etiology (termed immune-related adverse events, or irAEs); 
see section 6.8.24 regarding the identification, evaluation and management of potential irAEs.   
 
Please refer to section 7 for detailed information regarding the assessment and recording of AEs and ECIs.   
 
5.1.2.2 
Full Physical Exam 
The PI or qualified designee will perform a complete physical exam at screening.  Clinically significant 
abnormal findings should be recorded as medical history.   
 
5.1.2.3 
Directed Physical Exam 
At all other times as indicated in the visit schedule, the PI or qualified designee will perform a directed 
physical exam as clinically indicated prior to IMP administration as specified in the visit schedule.  Clinically 
significant abnormal findings should be recorded as an AE.   
 
5.1.2.4 
Vital Signs 
The PI or qualified designee will take vital signs as indicated in the visit schedule. Vital signs will be taken 
predose on treatment cycles.  Vital signs will include temperature, pulse, respiratory rate, weight and blood 
pressure. Height will be measured at screening only. 


 
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5.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The PI or qualified designee will assess ECOG status (see Appendix 2) as indicated in the visit schedule.   
 
5.1.2.6 
Tumour Imaging and Assessment of Disease 
Tumour imaging may be performed by chest CT, dual phase CT or contrast enhanced MRI scan of the 
abdomen at screening and every 12 weeks thereafter.  Baseline CT/MRI scans do not need to be repeated if 
obtained within 35 days of TACE. Tumour imaging only needs to be conducted during the EOT if participant 
has come off study for reason other than disease progression and has not had a scan in the previous 6 weeks. 
 
Tumour imaging will be assessed centrally as per mRECIST criteria.  
 
5.1.2.7 
Tumour Tissue Collection and Correlative Studies Specimen Sampling 
Optional 2 incision tumour tissue samples will be collected from participants at screening and EOT.  Leftover 
tumour tissue will be snap frozen in liquid nitrogen and preserved at -80 °C until genomic analysis (for details 
of sample collection procedures, please refer to the study Laboratory Manual). Parallel next generation DNA 
and RNA sequencing will be performed in paired clinical samples and correlated with response to treatment. 
Paraffin-embedded diagnostic tissue blocks will be processed for immune-histochemical expression of 
putative markers of immune response including PD-L1. 
 
All other biomarker samples will be optional. Blood sampling will include prospective collection of serum, 
plasma and PBMC. A subset of peripheral blood samples collected at baseline and disease progression will 
undergo CTC enumeration and phenotypic characterization using a standardised Food & Drug Administration 
(FDA)-approved CellSearch system (Janssen Diagnostics). On treatment cycles, all samples will be collected 
predose.  
 
Further correlative studies will be performed on urine samples to characterise the metabolomics 
determinants underlying anticancer immune response. Stool samples will be collected to characterise 
dynamic changes in the host’s microbiome throughout treatment. Urine and stool collections may be 
collected within 3 days of the study’s visit.  
 
Laboratory tests will be performed as defined in the schedule of study assessments (Table 4). Samples will 
be analysed by the local study site laboratory using standard methods for routine tests. The following 
variables (Table 4) will be measured: 
 
 
 


 
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Table 4: Laboratory Tests 
 
 
 
Laboratory tests will be performed as indicated in the visit schedule. In Part I Cycle 1 only, participants will 
need to come in for weekly visits (± 2 days) for blood samples. Samples will be taken pre-dose on Day 1 of 
each Cycle. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Safety lab results (FBC & LFTs) must be reviewed by the PI or qualified designee and found to be acceptable 
prior to each dose of IMP. 
 
Haematology 
Biochemistry 
Urinalysis 
Other 
• Haematocrit 
• Haemoglobin 
• Platelet count 
• White 
Blood 
Cell 
(WBC 
-total 
and 
differential) 
• Red Blood Cell Count 
(RBC) 
• Absolute Neutrophil 
Count (ANC) 
• Absolute 
Lymphocyte Count 
• AlbuminAlkaline 
phosphatase 
• Alanine 
aminotransferase 
(ALT) 
• Aspartate 
aminotransferase 
(AST) 
• Lactate 
dehydrogenase 
(LDH) 
• C-reactive protein 
(CRP) 
• Uric Acid 
• Calcium 
• Chloride 
• Glucose 
• Phosphate 
• Potassium   
• Sodium 
• Magnesium 
• Total Bilirubin 
• Conjugated Direct 
Bilirubin 
(If 
total 
bilirubin is elevated above 
the upper limit of normal) 
• Total protein 
• Blood 
Urea 
Nitrogen 
• Cortisol 
 
• Blood 
• Glucose 
• Protein 
• Specific 
gravity  
• Microscopic 
exam 
(If 
results 
abnormal)  
• Urine 
pregnancy 
test † 
• Serum 
β-human 
chorionic 
gonadotropin† 
• PT (INR) 
• aPTT 
• Total thriiodothyronine (T3) 
• Free tyroxine (T4) 
• Thyroid stimulating hormone 
(TSH) 
• Alpha- fetoprotein 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.  A serum pregnancy test will be performed a maximum of seven days before 
pembrolizumab administration 


 
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Participant treatment and overall management decisions will be based on local laboratory data. Laboratory 
values that are considered to be of clinical concern must be recorded as an AE as described in section 7. 
Unless explained by a clinical condition, these tests must be followed up at appropriate intervals until they 
reach a level deemed acceptable by the PI or delegate. 
 
 Guidance on the interpretation of hepatitis serology for the purpose of eligibility. 
Participants will require a full hepatitis serology screen prior to enrolment into the study. This will include a 
full Hepatitis B Virus profile (HBV DNA, HBsAg, HBeAg, HBCT (anti-HBV core total IgG/IgM), HBeAb (anti-HBV 
e antibody), HBSab (anti-HBV Surface Antibody) as well as a full Hepatitis C Virus profile including HCQB (HCV 
quantitative RNA) and anti-HCV antibodies (IgG). Participants are eligible to the trial if they fulfil the following 
serological criteria illustrated in Table 5. 
Table 5. Interpretation of hepatitis serology. 
Test 
Participant Status 
Eligibility Any HBV Treatment Needed? 
HBsAg 
(–) 
Total 
anti-HBc 
(+) 
HBsAb (+) 
Immune 
after 
natural 
infection 
Yes 
No 
HBsAg 
(–) 
Total 
anti-HBc 
(–) 
HBsAb (+) 
Immune after vaccination Yes 
No 
HBsAg 
(+) 
Total 
anti-HBc 
(+) 
IgM 
anti-HBc 
(+) 
HBsAb (–) 
Acute infection 
No 
— 
HBsAg 
(+) 
Total 
anti-HBc 
(+) 
IgM 
anti-HBc 
(–) 
HBsAb (–) 
Chronic infection 
Yes 
Yes, need to be on a HBV treatment 
for at least 12 weeks prior to start of 
treatment Exclude if: (a) <12 weeks 
of therapy; (b) HBV viral load not 
under control during this time frame; 
(c) Documented HBV flare in the past 
12 weeks 
HBsAg 
(–) 
Total 
anti-HBc 
(+) 
IgM 
anti-HBc 
(–) 
HBsAb 
(–) 
HBV viral load (negative) 
Unclear.  Could be: 
  Resolved infection 
  False positive anti-HBc 
  Low level infection 
  Resolving acute infection 
Yes 
No 
HBsAg 
(–) 
Total 
anti-HBc 
(+) 
IgM 
anti-HBc 
(–) 
HBsAb 
(–) 
HBV viral load (+) 
  Low level infection 
  Resolving acute infection 
Yes 
Yes (as above) 
 
 Total Blood Volume 
The total volume of blood that will be drawn from each participant in Part I and Part II are shown in Table 6 
a: Part I Volume of blood to be drawn from each participant for the duration of the trial; calculations based 


 
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on 1 year on treatment including screening, end of treatment visit  and post- treatment safety visit. These 
include optional biomarker samples. 
 
Approximate 
Sample 
volume 
(mL) 
No. of samples 
Approximate 
Total volume (mL) 
Haematology (including coagulation) 
101 
22 
220 
Biochemistry 
81 
22 
176 
Total  
396 
Biomarker CTC Sample  (optional) 
10 
3 
30 
Biomarker Blood Sample (optional) 
6 
5 
30 
Total: 
4562 
Table 6 a: Part I Volume of blood to be drawn from each participant for the duration of the trial; calculations 
based on 1 year on treatment including screening, end of treatment visit  and post- treatment safety visit. 
These include optional biomarker samples. 
 
Approximate 
Sample 
volume 
(mL) 
No. of samples 
Approximate 
Total volume (mL) 
Haematology (including coagulation) 
101 
20 
200 
Biochemistry 
81 
20 
160 
Total  
360 
Biomarker CTC Sample (optional) 
10 
3 
30 
Biomarker Blood Sample (optional) 
6 
5 
30 
Total: 
4202 
Table 6 b: Part II Volume of blood to be drawn from each trial participant for the duration of the trial; 
calculations based on 1 year on treatment including screening, end of treatment visit and post- treatment 
safety visit. These include optional biomarker samples. 
1 Blood volumes for haematology and biochemistry may vary according to local practice 
2 The total volume of blood drawn from each participant for the duration of the trial depends on the time to progression 
for each participant. 
 
 
Treatment 
All participants enrolled on the study will receive Pembrolizumab every Q3W until disease progression, 
occurrence of unacceptable toxicities, withdrawal or the participant has completed 1 year of IMP 
administration. Scheduled visits are described within the visit schedule (Table 4). Observations and 
assessments required during the study visits are also summarised in visit schedule (Table 4).  
 


 
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Time windows for visits are listed in the Visit Schedule. Assessment days will all be relative to the start of IMP 
administration, i.e.Cycle 1 Day 1. .  
 
 
Post Treatment Follow-up 
 Safety Follow-Up Visit 
There will be an early and a late Safety Follow-Up (SFU) visit. The early SFU should be conducted 
approximately 30 days (± 7 days) after the last dose of IMP or before the initiation of a new anti-cancer 
treatment, whichever comes first. A late SFU visit will 130 days after the last dose of the IMP (+/-7 days) by 
a telephone call. All AEs that occur prior to the SFU Visit should be recorded.  Participants with on-going AE’s 
at the SFU visits should be followed up by PI or delegate until resolution or stabilisation of the event but there 
will be no further need to record details of the AE, whichever comes first, including all study assessments to 
monitor the event.  
 
 Follow-up Visits 
Participants who discontinue will move into the Follow-Up Phase and should be assessed by telephone follow 
up every 8 weeks (+/-7 days) to collect information regarding disease status, survival status, and details of 
new anti-cancer therapy initiated.  For up to 130 days post last dose, their AE/SAE will be followed up as well. 
Follow-up will continue until the last participant has completed the study, either with disease progression, 
unacceptable toxicities, withdrawal or completion of 1 year of treatment. 
 
6.0 
TREATMENT 
Treatment will consist of a maximum of 1 year of Pembrolizumab Q3W following TACE.  
  
 
 
TACE. 
TACE will be performed as per SOC and will classify as a NIMP for the purpose of this study. Treatment will 
consist in the infusion of cytotoxic chemotherapy after arterial hepatic angiogram, followed by either 
selective or super-selective embolization of the arterial vascular bed perfusing the tumour. The procedure 
will be standardised across sites and will consist of conventional transcatheter arterial chemoembolization 
(conventional TACE) or drug-eluting beads TACE (DEB TACE) approach. The chemotherapeutic agent of choice 
will be doxorubicin delivered intra-arterially at the fixed dose of 60 mg for patients who receive conventional 
TACE. In patients receiving DEB TACE, the dose of doxorubicin will be ranging from 75-150 mg depending on 
the size of the tumour and according to the standard of care.  Doxorubicin should be stored, prepared and 
disposed of in accordance with the relative Summary of Product Characteristics (SmPC) and hospital 
procedures. In addition to conventional TACE, drug-eluting beads (DEB) TACE is also considered an acceptable 
modality for TACE treatment. The local study team site personnel will maintain a dispensing record for each 
participant. Doxorubicin will be sourced for use in this clinical trial as per normal hospital procedures. Poly-
vinyl alcohol particles will be the embolizing agent of choice. TACE is normally administered as a short elective 
inpatient treatment to allow for monitoring of immediate post-procedural complications. Contrast-enhanced 
CT or MRI scan will be performed approximately 30 days after TACE as part of SOC. Reports will be recorded.  
Participants who fail to achieve complete tumour devascularisation after the first session of TACE as assessed 


 
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by follow-up contrast-enhanced scan may be allowed up to 1 further TACE session as per EASL/EORTC clinical 
guidelines unless clinical or technical factors preclude repeat treatment. In participants requiring re-
treatment, time intervals for commencement of Pembrolizumab and subsequent DLT window will remain 
unchanged. No re-screening is required. 
 
 
 Investigational Medicinal Product Details 
The IMP for this study is Pembrolizumab. A potent and highly-selective humanized mAb of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pembrolizumab potentiates existing immune responses only in the presence of antigen and does not non-
specifically activate T-cells. 
Pembrolizumab will be manufactured by MSD according to Good Manufacturing Practice (GMP) and will be 
provided in the formulation as described in Table 7. Additional information about the IMP can be found in 
the IB. 
 
Table 7: IMP Product Description 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Infusion 
 
The PI or delegate shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of IMP in accordance with the protocol 
and any applicable laws and regulations. 
 
 
Product Preparation 
The IMP will be prepared as per the Pharmacy Manual. 
 
 
Labelling and Packaging  
Pembrolizumab will be supplied by MSD as specified in table 7; ready for injection. Pembrolizumab will be 
packaged, labelled and delivered to the participating sites by MSD. The IMP will be supplied specifically for 
the trial and should not be used for any other purpose than that stated in this protocol. The drug will be 
labelled in accordance to GMP Annex 13. As a minimum the labels will include the following information: 
a. name of the Sponsor; 
b. name of drug, dose, quantity of dose units and route of administration; 
c. batch number to identify the contents and packaging operation; 
d. blank space for recording the trial ID; 
e. directions for use; 
f. PI name; 
g. trial EudraCT number and protocol number; 
h. storage conditions; 
i. 
expiry date; 
j. 
“for clinical trial use only”; 
k. “keep out of reach of children”. 


 
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Storage and Dispensing  
 Storage  
Details on storage of the IMP can be found in the pharmacy manual. 
 
 Handling 
Further details on the preparation of the drug product can be found in the pharmacy manual.  
At each site the PI/designee e.g. pharmacist is responsible for ensuring that all IMP is stored in a secure, 
limited-access location under the storage conditions specified on the label.  Receipt and dispensing of the 
IMP must be recorded by an authorised person at the trial site. IMP may not be used for any purpose other 
than that stated in the protocol. 
 
 Returns and Reconciliation 
The PI/designee is responsible for keeping accurate accountability records for Pembrolizumab including the 
amount dispensed to and returned for each participant and the amount remaining on site at the conclusion 
of the trial. Upon completion or termination of the study, it is the PI/designee responsibility to ensure 
all unused drug is returned to MSD and partially used IMP will be destroyed at the site per local guidelines 
and provide appropriate records of disposal to the sponsor with a copy being stored in the ISF. 
 
 
Dosage, Duration and Compliance 
In Part 1 of the study, participants will be recruited to the safety run-in phase of the trial and will receive the 
IMP after having received prior TACE as per SOC. Participants will receive 200mg of Pembrolizumab Q3W 
with an interval from TACE of at least 30 days.  If there are zero DLTs and no other safety concerns Part II 
with be undertaken using the standard 200 mg Q3W dose 30 days post TACE. If there is one to two DLTs, the 
IDSMC will then advise to continue with either 200 mg dose Q3W 30 days post TACE or to consider increasing 
the TACE-pembrolizumab interval prior to Cycle 1 to 45 days for the expansion cohort based on general safety 
profile. If three or more DLTs are observed in the six participants of the safety run-in the trial will be stopped. 
In Part 2 of the study, participants will be recruited prior to TACE and prospectively followed up. Participants 
will be recruited at the schedule determined in part 1 with either a 30 or a 45-days (+3 days) interval from 
TACE to the first cycle of pembrolizumab. Pembrolizumab will be administered at the standard dose of 200 
mg Q3W until disease progression, unacceptable toxicities, withdrawal or completion of 1 year of treatment.  
 
 
Timing of Dose Administration 
Pembrolizumab will be administered on an outpatient basis on Day 1 (± 3 days) of every 21 day cycle after all 
procedures/assessments have been completed as detailed on the schedule of study assessments (Table 4).  
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals or infusion length 
may be increased due to toxicity).  Due to the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).  
 
 
Trial Blinding/Masking 
This is an OL trial; therefore, the Sponsor, CI, PI and participant will know the IMP is being administered. 
 


 
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Dose Modifications for Toxicity  
Adverse events (both non-serious and serious) associated with Pembrolizumab exposure may represent an 
immunologic etiology.  These AEs may occur shortly after the first dose or several months after the last dose. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs as per Table 
8 below. See Section 6.8 for supportive care guidelines, including use of corticosteroids. 
Treatment discontinuation for AST, ALT deterioration in participants who present with Grade 2 AST or ALT 
will be triggered only if AST or ALT increases by greater than or equal to 50% relative to the measurement 
taken at initiation of systemic treatment (Cycle 1 Day 1) and lasts for at least 1 week. 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing 
for 
Restarting 
Treatment 
Treatment Discontinuation 
Diarrhoea/ 
Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 Toxicity does not resolve within 12 weeks 
of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycaemia 
T1DM or  
3-4 
Hold Pembrolizumab for new 
onset 
Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia 
associated 
with evidence of beta cell 
failure 
Resume 
Pembrolizumab 
when 
participants 
are 
clinically 
and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-
1. 
Therapy 
with 
Pembrolizumab 
can 
be 
continued while endocrine 
replacement 
therapy 
is 
instituted 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with Pembrolizumab 
can 
be 
continued 
while 
thyroid replacement therapy 
is instituted 
Therapy with Pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing 
for 
Restarting 
Treatment 
Treatment Discontinuation 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  Permanently 
discontinue 
if 
toxicity 
develops 
despite 
adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening 
event. 
a For participants who begin treatment with Grade 2 AST or ALTat Cycle 1 Day 1 of treatment, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then participants 
should be discontinued. 
b If symptoms resolve within one hour of stopping IMP infusion, the infusion may be restarted at 50% of the 
original infusion rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms 
resolve and the participant should be pre-medicated for the next scheduled dose. 
c Participants with intolerable or persistent Grade 2 drug-related AE may hold study medication at PI/delegate 
discretion.  Permanently discontinue IMP for persistent Grade 2 adverse reactions for which treatment with 
IMP has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
Table 8: Dose Modification Guidelines for Drug-Related Adverse Events 
 
 
Drug interactions/Precautions 
 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed during the 
on-going trial. If there is a clinical indication for one of these or other prohibited medications or vaccinations 
then discontinuation from the study may be required.  The PI/delegate should discuss any questions 
regarding this with the CI/designee.  The final decision on any supportive therapy or vaccination rests with 


 
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the CI and/or the participant's primary physician. However, the decision to continue the participant on the 
study requires the mutual agreement of the PI/delegate, CI/designee, and the participant. 
 
 Acceptable Concomitant Medications 
All treatments that the PI/delegate considers necessary for a participant’s welfare may be administered at 
the discretion of the PI/delegate in keeping with the community standards of medical care.  All concomitant 
medication will be recorded including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date will be documented. Drugs to be recorded where possible using World Health Organisation 
Drug Dictionary (WHO DD) classification. 
All concomitant medications received from screening until discontinuation should be recorded.   
 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the screening and treatment cycles: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than Pembrolizumab 
• 
Live vaccines within 30 days prior to the first IMP administration and while participating in the 
trial.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor & CI/delegate. 
Participants who, in the assessment by the PI/delegate, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Participants may receive other 
medications that the PI/delegate deem to be medically necessary. The exclusion criteria describes other 
medications which are prohibited in this trial. There are no prohibited therapies during the follow-up phase. 
 
Rescue Medications & Supportive Care 
 Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by the PI/delegate.  
Suggested supportive care measures for the management of AEs with potential immunologic etiology are 
outlined below. 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 


 
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supportive care. The treatment guidelines are intended to be applied when the PI/delegate determines the 
events to be related to Pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the PI/delegate does not need to 
follow the treatment guidance (as outlined below). Refer to Section 6.6 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
6.8.1.1 
Pneumonitis:  
• 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional anti-
inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
6.8.1.2 
Diarrhoea/Colitis:  
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhoea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal 
signs and ileus).   
• 
All participants who experience diarrhoea/colitis should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion.  For Grade 2 or higher diarrhoea, consider GI consultation and endoscopy to confirm or rule 
out colitis. 
• 
For Grade 2 diarrhoea/colitis, administer oral corticosteroids.  
• 
For Grade 3 or 4 diarrhoea/colitis, treat with i.v. steroids followed by high dose oral steroids.   
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
6.8.1.3 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
• 
For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycaemia associated with metabolic acidosis or ketonuria.  
o Evaluate participants with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
6.8.1.4 
Hypophysitis: 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
• 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 


 
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less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
6.8.1.5 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor participants for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
• 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• 
Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
6.8.1.6 
Hepatic: 
• 
Comprehensive guidance on the diagnosis and management of hepatic events of interest are 
reported in Section 6.8.3.  
• 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline values 
(consider weekly). 
o Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks. 
6.8.1.7 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.   
6.8.1.8 
Immune-related adverse events:  
Please see Section 6.8.2 below regarding diagnosis and management of adverse experiences of a potential 
immunologic etiology.   
6.8.1.9 
Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion.  
 
Table 9 below shows treatment guidelines for participants who experience an infusion reaction associated 
with administration of Pembrolizumab. 


 
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NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent dosing 
Grade 1 
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the PI. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 
toxicity 
despite 
adequate 
premedication should be permanently 
discontinued 
from 
further 
IMP 
administration. 
Participant may be pre-
medicated 1.5h (± 30 
minutes) 
prior 
to 
infusion 
of 
Pembrolizumab 
(MK-
3475) with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 
500-
1000 
mg 
po 
(or 
equivalent 
dose 
of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
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) 
Grade 4: 
Life-threatening; 
pressor 
or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the participant 
No subsequent dosing 


 
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NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent dosing 
is deemed medically stable in the opinion 
of the PI. 
Hospitalisation may be indicated. 
Participant is permanently discontinued 
from further IMP administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
Table 9: Infusion Reaction Treatment Guidelines 
 
 
Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-related Events 
of Clinical Interest (irECI).  
Immune-related Adverse events (IrAEs) may be defined as an AE of unknown etiology, associated with IMP 
exposure and is consistent with an immune phenomenon. IrAEs may be predicted based on the nature of the 
Pembrolizumab compound, its mechanism of action, and reported experience with immunotherapies that 
have a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive of 
potential irAEs.  An irAE can occur shortly after the first dose or several months after the last dose of IMP.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes prior to labelling an AE as an irAE.  Participants who develop a Grade 2 or higher irAE should 
be discussed immediately with the CI/designee.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 10. 
 
irAE 
Withhold/Discontinue Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold Pembrolizumab 
Consider systemic corticosteroids in addition 
to appropriate symptomatic treatment. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
Grade 3 
and 
Grade 4 
Withhold Pembrolizumab 
Discontinue if unable to reduce corticosteroid 
dose to < 10 mg per day prednisone 
equivalent within 12 weeks of toxicity 
Systemic corticosteroids are indicated in 
addition 
to 
appropriate 
symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
Table 10: General Approach for Handling irAEs 
 
Details for managing specific irAEs are summarised below: 
Immune-mediated pneumonitis 
Monitor participants for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with 
radiographic imaging. Exclude other causes of pneumonitis, and manage treatment in accordance with the 


 
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guidelines above. Administer corticosteroids, withhold Pembrolizumab for moderate (Grade 2) pneumonitis, 
and permanently discontinue Pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) pneumonitis. 
Immune-mediated colitis 
Monitor participants for signs and symptoms of colitis. Exclude other causes of colitis, and manage treatment 
in accordance with the guidelines above. Administer corticosteroids, withhold Pembrolizumab for moderate 
(Grade 2) or severe (Grade 3) colitis, and permanently discontinue Pembrolizumab for life-threatening (Grade 
4) colitis. 
Immune-mediated hepatitis 
Monitor participants for changes in liver function (at the start of treatment, periodically during treatment 
and as indicated based on clinical evaluation) and symptoms of hepatitis. Exclude other causes of hepatitis, 
and manage treatment in accordance with the guidelines above. Administer corticosteroids and, based on 
severity of liver enzyme elevations, withhold or discontinue Pembrolizumab. 
Immune-mediated nephritis 
Monitor participants for changes in renal function. Exclude other causes of nephritis, and manage treatment 
in accordance with the guidelines above. Administer corticosteroids, withhold Pembrolizumab for moderate 
(Grade 2), and permanently discontinue Pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) 
nephrits. 
Immune-mediated endocrinopathies 
Monitor participants for signs and symptoms of hypophysitis (including hypopituitarism and secondary 
adrenal insufficiency). Exclude other causes of hypophysitis, and manage treatment in accordance with the 
guidelines above. Administer corticosteroids, withhold Pembrolizumab for moderate (Grade 2), withhold or 
discontinue Pembrolizumab for severe (Grade 3) and for life-threatening (Grade 4) hypophysitis. 
 
Monitor participants for hyperglycaemia or other signs and symptoms of type 1 diabetes. Exclude other 
causes of diabetes. Administer insulin for type 1 diabetes, and withhold Pembrolizumab in cases of severe 
hyperglycaemia until metabolic control is achieved. 
 
Thyroid disorders have been reported in participants receiving Pembrolizumab and can occur at any time 
during treatment; therefore, monitor participants for changes in thyroid function (at the start of treatment, 
periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms 
of thyroid disorders. Administer corticosteroids, withhold Pembrolizumab for severe (Grade 3) 
hyperthyroidism, and permanently discontinue Pembrolizumab for life-threatening (Grade 4) 
hyperthyroidism. Treat symptoms of hyperthyroidism as appropriate. Isolated hypothyroidism may be 
managed with replacement therapy without treatment interruption and without corticosteroids. For 
participants with severe (Grade 3) or life-threatening (Grade 4) endocrinopathy that resolved and is 
controlled with hormone replacement, continuation of Pembrolizumab may be considered. 
 
Other immune-mediated adverse events 
Across clinical studies with Pembrolizumab in approximately 5000 participants, the following additional 
clinically significant, immune-mediated adverse reactions were reported in less than 1% of participants: 
uveitis and severe skin reactions. 


 
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In addition a set of irAEs have also been classified as immune-related events of clinical interest (irECI) a full 
list of these can been found in Table 12 in section 7.4. Participants with symptomatic irECIs should 
immediately stop receiving Pembrolizumab and be evaluated to rule out non treatment related causes of the 
event. All irECIs irrespective of relationship to the IMP should be reported within 24 hours of the PI/delegate 
being aware to the Sponsor/CI who will in turn notify MSD. If the irECI is determined to be associated please 
refer to section 6.8.3. If the event is not considered to be related with the IMP the PI/delegate should exercise 
individual clinical judgment on the event management based on the participant.  Any additional questions of 
the collection or information on management of irECIs should be directed to the CI/delegate. 
 
 
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest.  
In addition to overdose, hepatic ECIs will include any of the following events.  All of these events will require 
holding Pembrolizumab treatment, notification of the Sponsor, CI/delegate within 24 hours, and a 
hepatology consultation.  Refer to Section 7 for reporting guidelines. 
All cases of retreatment and permanent discontinuation must be reported to the Sponsor, CI/delegate and 
recorded in the eCRF. 
a. ALT: 
i. 
Among participants with Day 1 ALT <2×ULN:  ALT ≥5×ULN 
ii. 
Among participants with Day 1 ALT ≥2×ULN:  ALT >3× the Day 1 level 
iii. 
ALT >500 U/L regardless of baseline level 
b. AST: 
i. 
Among participants with Day 1 AST <2×ULN:  AST ≥5×ULN 
ii. 
Among participants with Day 1 AST ≥2×ULN:  AST >3× the Day 1 level 
iii. 
AST >500 U/L regardless of baseline level 
c. Total Bilirubin: 
i. 
Among participants with baseline levels <25.65 µmol/L :  a value of >34.2 µmol/L . 
ii. 
Among participants with baseline levels that are ≥25.65 µmol/L :  a value ≥2× the baseline level  
iii. 
Total bilirubin >51.3 µmol/L regardless of baseline level 
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, including: 
i. 
New onset clinically detectable ascites 
ii. 
Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal or gastric varices) 
iii. 
Encephalopathy 
(Participants with clinically apparent ascites or encephalopathy, or untreated varices are not eligible for 
enrolment) 
Immediate assessment 
All participants 
• 
All participants should be evaluated according to directions below within 72 hours of alert for non-
overdose ECI  
• 
Procedures: 
o 
Obtain a consultation with a hepatologist 


 
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o 
Obtain a work-up for hepatitis if there is no underlying hepatitis, including hepatitis A, B,C, D, E, 
Epstein-Barr virus, and cytomegalovirus 
o 
Assess for ingestion of drugs/supplements with hepatotoxic potential  
o 
Assess for alcohol ingestion 
o 
Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal bleeding 
o 
Repeat ALT, AST, Tbil, Dbil, ALP, -glutamyl transpeptidase (GGT), INR, and FBC with differential  
o 
Other laboratories or imaging studies as clinically indicated 
o 
Consider liver biopsy if indicated by hepatologist 
Hepatitis C-Infected Subjects (including subjects who previously achieved SVR 12) 
• 
In addition to the above, measure HCV RNA viral load 
Hepatitis B-infected Subjects 
• 
HBV DNA, HBsAg, HBeAg, HBCT (anti-HBV core total IgG/IgM), HBeAb (anti-HBV antibody), HBSab 
(anti-HBV Surface Antibody) 
• 
Participants should be questioned about compliance with the use of anti-viral agents. 
Permanent Discontinuation Criteria for Subjects with Non-overdose Hepatic ECI 
Therapy should also be permanently discontinued for any of the following:  
• 
ALT >20×ULN 
• 
Child-Pugh score of ≥9 points 
• 
Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal or gastric varices) 
• 
New onset clinically detectable ascites 
• 
Encephalopathy  
• 
Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities listed 
above, that are presumed to be immune-related. 
Other participants may be eligible for treatment interruption (and potential re-start) of 
Pembrolizumab after discussion with the Sponsor, CI/delegate.   
Diagnosis and Management of Non-Overdose Hepatic ECIs 
HCC subjects are at risk for a range of complications that can cause hepatic laboratory abnormalities with or 
without clinical decompensation.  Those with a history of chronic HCV or HBV infection also have the potential 
to experience virologic flares.  Immune-related hepatitis has been observed in ~1% of subjects who received 
Pembrolizumab.  The following section provides further guidance on the diagnosis and management of 
potential hepatic complications among HCC subjects.  
a. 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 anti-
viral therapy should have continued suppression of HBV DNA at the time of flare; thus, detection of HBV 
DNA should prompt questioning of subjects for compliance.  Laboratory abnormalities secondary to flare 
are typically observed for 3-5 weeks.   


 
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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 anti-viral therapy. 
• 
If the participant is clinically stable, Pembrolizumab dosing may be interrupted for up to 12 
weeks.  Subjects 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. 
• 
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 participants are clinically stable, participants may restart 
Pembrolizumab treatment. If these conditions are not met, then Pembrolizumab treatment 
should be permanently discontinued. 
b. Hepatitis C Recurrence or Flare 
Participants who achieved a sustained virologic response at 12 weeks on specific antiviral treatment (SVR 
12) and subjects with on-going HCV infection are eligible for enrolment.  In rare circumstances, HCV 
participants who achieve SVR 12 may relapse at later time points.  Relapse is characterised 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: 
i. Recurrent 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 subject 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 
• 
Measure AST, ALT, ALP, Tbil, Dbil, and INR weekly 
• 
Measure HCV RNA levels every 2 weeks 
• 
Therapy with HCV anti-viral treatments should be strongly considered. 
ii. HCV Flare: 
• 
At the time of first detection of HCV RNA, send a specimen for HCV genotyping 
• 
Measure AST, ALT, ALP, Tbil, Dbil, INR weekly 
• 
Measure HCV RNA levels every 2 weeks 
• 
Therapy with HCV anti-viral treatments should be strongly considered.  


 
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iii. For both recurrent infection and HCV flare:  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 participants are clinically stable, 
participants may restart Pembrolizumab treatment.  If these conditions are not met, then 
Pembrolizumab treatment should be permanently discontinued. 
c. Immune-related hepatitis  
i. Description:  Immune-related hepatitis due to Pembrolizumab should be suspected if any of the 
following is seen: 
• 
AST or ALT baseline values are less than 2×ULN, and AST or ALT laboratory values increase to 
≥5×ULN 
• 
Among participants with Day 1 ALT or AST ≥2×ULN, levels increase to >3× the Day 1 level 
• 
AST/ALT >500 U/L regardless of baseline level 
• 
Among participants with Day 1 Tbil levels <1.5 mg/dL:  a value of >2.0 mg/dL 
• 
Among participants with Day 1 Tbil levels that are ≥1.5 mg/dL:  a value of ≥2× the Day 1 level 
• 
Total bilirubin >51.3 µmol/L  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). 
ii. Management 
• 
Interrupt Pembrolizumab treatment and alert the sponsor/CI or delegateas per ECI criteria above 
for ALT, AST, bilirubin, and hepatic decompensation.   
• 
Start IV corticosteroid (methylprednisolone 125 mg) followed by oral corticosteroid (1-2 
mg/kg/day).   
• 
Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, ALP, and INR. 
• 
If symptoms and laboratory tests resolve to Grade ≤1 or baseline (if abnormal at baseline), taper 
steroids over 28 days.  Pembrolizumab treatment may be restarted after steroid treatment has been 
tapered to prednisone ≤10 mg/day (or equivalent dose of another agent).  Treatment and 
laboratory results must be documented. 
• 
If laboratory abnormalities do not resolve within 3 weeks, or steroids cannot be lowered to ≤10 
mg/day (or prednisone equivalent) within 12 weeks, or participants show evidence of 
decompensation to Child-Pugh C status or have esophageal or variceal bleeding at any point, 
treatment must be permanently discontinued.  This must be documented. 
d. Other Hepatic Events of Clinical Interest 
• 
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 Tbil is elevated above baseline, magnetic resonance cholangiopan-creatography or ultrasound 
with doppler should be obtained to rule out vascular compromise, biliary obstruction, and/or 
tumour 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.    


 
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• 
For all of these cases, participants may resume Pembrolizumab treatment if they are clinically stable 
after appropriate therapy or discontinue the causative agent, as long as laboratory values have 
returned to Grade 1 or baseline (if normal or Grade 1 at start) or to baseline grade within 3 weeks.   
• 
Treatment must be permanently discontinued if the participant is off Pembrolizumab therapy for 
infection, obstruction, or drug/alcohol-related toxicity for more than 3 weeks, or if they have 
oesophageal bleeding, or become Child-Pugh C at any point. 
 
 
Diet/Activity/Other Considerations 
 Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhoea, nausea or vomiting. 
 
 Contraception 
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.  For this trial, male participants will be considered 
to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or 
due to an underlying medical condition).   
Female participants will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in 
women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating 
a partner, respectively, while receiving study drug and for 120 days after the last dose of IMP by complying 
with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 


 
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Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (oestrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it 
is consistently employed as the participants preferred and usual lifestyle.  Periodic abstinence (e.g. 
calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not 
acceptable methods of contraception.  
Participants should be informed that taking the IMP may involve unknown risks to the fetus (unborn baby) if 
pregnancy were to occur during the study. In order to participate in the study participants of childbearing 
potential must adhere to the contraception requirement (described above) from the day of IMP 
administration (or 14 days prior to the initiation of study medication for oral contraception) for the duration 
of the study and for 120 days after the last dose of IMP. 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 entered into the study. 
 Use in Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with Pembrolizumab, the participant will 
immediately be removed from the study. 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, CI/delegate without delay and within 24 hours if the outcome is 
a SAE (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The Sponsor, CI/delegate will notify MSD of all events within 48 hours. The PI 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, CI/delegate.  If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the Sponsor, CI/delegate 
and followed as described above and in Section 7. If the pregnancy continues to term, the outcome (health 
of infant) must also be reported for up to 3 months. 
 Use in Nursing Women 
It is unknown whether Pembrolizumab 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 
breast-feeding are not eligible for enrolment. 
 Overdose of IMP 
For purposes of this trial, an overdose of Pembrolizumab will be defined as any dose of 1,000 mg or greater 
(≥5 times the indicated dose). No specific information is available on the treatment of overdose of 
Pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event of 
overdose, the participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. Details of reporting an overdose can be seen in section 7.6. 
 


 
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 Permanent Discontinuation of Study Treatment and Withdrawal from Study  
 Permanent discontinuation of study treatment 
A participant must be discontinued from the trial for any of the following reasons: 
• 
The participant withdraws consent. 
• 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression. 
Note: A participant may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved. IMP will be provided off-study 
and as a special. 
• 
Unacceptable AEs. 
• 
Intercurrent illness that prevents further administration of IMP 
• 
PI’s decision to withdraw the participant 
• 
The participant becomes pregnant 
• 
Noncompliance with trial treatment or procedure requirements 
• 
Administrative reasons 
Trial participants will not be replaced once completing 21 days of treatment or enrolled more than once. The 
primary reason for discontinuation should be recorded. Once the trial medication has been discontinued the 
participant should complete the end of treatment and safety follow-up visit procedures as listed in the 
schedule of study assessments (Table 3). After the end of treatment, participants will continue to be assessed 
for AE and SAE monitoring until the SFU visit. 
 
Participants will continue onto follow-up after the safety follow up, their details will be reviewed every 8 
weeks ± 7 days for details of disease status, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up. Follow-up will continue until the last participant has completed treatment or 
comes off study for disease progression or unacceptable toxicities. 
 Withdrawal from Study 
Withdrawal from the study refers to discontinuation of IMP and study procedures and can occur for the 
following reasons: 
• 
Participant decision 
• 
Loss to follow-up 
• 
Death 
• 
PI/delegate Decision 
Participants may withdraw consent at any time for any reason or be dropped from the trial at the discretion 
of the PI/delegate should any untoward effect occur.  In addition, a participant may be withdrawn by the 
PI/delegate or the Sponsor if enrolment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.  Specific details regarding discontinuation or withdrawal are 
provided in below. 


 
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 Procedures for Withdrawal from Study 
When a participant withdraws prior to trial completion, all applicable activities scheduled for the final trial 
visit should be performed at the time of discontinuation.  Any AEs which are present at the time of withdrawal 
should be followed in accordance with the safety requirements outlined in Section 7 
 
 Non-IMP details 
Trans-arterial chemoembolization will be performed as a background treatment and as such is classed as a 
NIMP for the purpose of this study 
 
7.0 
PHARMACOVIGILANCE 
 
 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a participant administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the IMP, whether or not considered related to the IMP. 
 
Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing 
condition that is temporally associated with the use of the Pembrolizumab and/or radiotherapy, is also an 
AE. 
 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered AEs.   
 
Disease Progression 
Disease progression of the cancer under study is not considered an AE unless the investigator deems that it 
is at least possibly related to the Pembrolizumab.  
 
New Cancers 
The development of a new cancer should be regarded as an SAE and reported accordingly.  
 
Abnormal Laboratory Test Results 
All clinically significant abnormal laboratory test results occurring during the study will be recorded as AEs 
from after first administration of the IMP until for at least 30 days following the last dose of IMP or the 
discontinuation visit; whichever is the sooner. The clinically significant abnormal laboratory tests will be 
repeated at appropriate intervals until they return either to baseline or to a level deemed acceptable by the 
PI/delegate, or until a diagnosis that explains them is made.   
 
Note: AEs seen at screening should be recorded as part of the participant’s medical history. 


 
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Pregnancy and Lactation 
Pregnancy and lactation are not considered AEs, however these events should be reported to the CI/delegate 
and subsequently to the Sponsor following guidance in below section. 
 
Adverse Event recording 
All AEs will be recorded from the time of signing the consent form and will be followed up for up to130 days 
following the last dose of IMP. All adverse events will be recorded in the electronic Case Report Form (eCRF).  
 
Any unresolved AEs at the participant’s last visit should be followed up for as long as medically indicated, but 
without further recording in the eCRF.  
 
If a PI/delegate learns of any SAEs, including death, at any time after a participant has completed the study 
and he/she considers there is a reasonable possibility that the event is related to Pembrolizumab, the 
PI/delegate should notify the Sponsor and CI/delegate 
 
The following details will be collected for each AE: 
• 
AE description / diagnosis 
• 
Date and time of onset and resolution (if applicable) 
• 
NCI-CTCAE grade (including any changes) 
• 
Seriousness  
• 
PI/delegate causality rating against the IMP  
• 
Action taken with regard to IMP 
• 
Outcome 
 
Evaluating Adverse Events 
AEs will be evaluated by a medically qualified physician. 
7.2.1.1 Determining AE Severity and Grade 
AE severity and grade will be evaluated according to the NCI CTCAE version 4.0. Any AE which changes CTCAE 
grade over the course of a given episode should be closed at the date and time the severity changed and a 
new AE recorded from the date and time of the new NCI CTCAE grade. 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalisation 
or prolongation or hospitalisation indicated; disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
 


 
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7.2.1.2 Determining AE Causality 
The PI/delegate must endeavour to obtain sufficient information to determine the causality of the AE (i.e. 
IMP, other illness, progressive malignancy etc.) and must provide his/her opinion of the causal relationship 
between each AE and the IMP.  This may require instituting supplementary investigations of significant AEs 
based on their clinical judgement of the likely causative factors and/or include seeking a further opinion from 
a specialist in the field of the AE. 
 
Causality is the relationship of an AE to the IMP and will be determined as follows. 
Definite: 
• There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
Probable:  
• There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely 
Possible:  
• There is some evidence to suggest a causal relationship (e.g. because the event 
occurs within a reasonable time after IMP administration. However, the influence 
of other factors may have contributed to the event (e.g. the participant’s clinical 
condition, other concomitant treatments). 
Unlikely:  
• There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the trial medication). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition, other concomitant treatment).  
Not related:  
• No evidence of any causal relationship. 
Not assessable: 
• There is insufficient or incomplete evidence to make a clinical judgement of the 
causal relationships 
Table 11: Assessment of Causality between AE and exposure to the IMP. 
 
Reporting of Pregnancy and Lactation  
It is the responsibility of PI/delegate to report any pregnancy or lactation in a participant (spontaneously 
reported to them), including the pregnancy of a male participant's female partner that occurs during the trial 
or 30 days following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier.  All participants and female partners of male participants who become pregnant must be followed to 
the completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as SAEs. Consent to report information regarding these pregnancy outcomes from female 
partners of any males who took IMP will be obtained from the mother. If the pregnancy continues to term, 
the outcome (health of infant) must also be reported for up to 3 months.  
Such events must be reported within 24 hours of learning of its occurrence to the Sponsor and CI/delegate 
who will subsequently inform MSD. 
 
 
Serious Adverse Events (SAE) 
 Definition of SAE 
An SAE is an AE occurring during any part of the study that meets one or more of the following criteria: 
• 
Results in death; 
• 
Is life threatening; or places the participant, in the view of the PI/delegate, at immediate risk of death 
from the event as it occurred1 


 
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• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalisation2;  
• 
Is a congenital anomaly/birth defect(in offspring of participant taking the product regardless of time 
to diagnosis);  
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose (whether accidental or intentional). Any AE associated with an 
overdose is considered a SAE.  
• 
Is an important medical event that may not result in death, not be life threatening, or not require 
hospitalisation but may be considered a serious adverse event when, based upon appropriate 
medical judgment, the event may jeopardise the participant and require medical or surgical 
intervention to prevent such an outcome. 
1 This does not include an AE which hypothetically might have caused death if had it occurred in a more severe 
form. 
2 Hospitalisation is defined as an unexpected inpatient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. It does not usually apply to scheduled 
admissions that were planned before study inclusion or visits to causality (without admission). 
 
 
Definitions of Events of Clinical Interest (ECI)  
Selected non-serious and SAE can also be classified as ECI and must be reported as described in the below 
section. 
Events of clinical interest for this trial include: 
1. An overdose of Pembrolizumab, as defined in Section 7.6 that is not associated with clinical symptoms 
or abnormal laboratory results.  
2. A Drug induced liver injury defined as elevated AST or ALT lab value that is greater than or equal to 3X 
the ULN  
AND / OR    
An elevated total bilirubin lab value that is greater than or equal to 2X ULN AND / OR 
An alkaline phosphatase lab value that is less than 2X ULN, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.  
 
3. Any AEs identified in the below table can be classified as ir-ECI. A detailed narrative of the event should 
be documented: 


 
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Pneumonitis  - (reported as ECI if ≥ Grade 2) 
Acute interstitial Pneumonitis 
Interstitial Lung Disease  
Pneumonitis 
Colitis  - (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat 
the AE) 
Intestinal Obstruction 
Colitis  
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine  - (reported as ECI if ≥ Grade 3 or  ≥ Grade 2 and resulting in dose modification or use of systemic steroids 
to treat the AE) 
Adrenal Insufficiency  
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis 
(DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
Hematologic - (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids 
to treat the AE) 
Autoimmune haemolytic anaemia 
Aplastic anaemia 
Thrombotic thrombocytopenic 
purpura 
Idiopathic thrombocytopenia 
purpura 
Disseminated intravascular 
coagulation 
Haemolytic uraemic  
syndrome 
Any grade 4 anaemia regardless of underlying mechanism 
Hepatic  - (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to 
treat the AE) 
Hepatitis 
Autoimmune hepatitis  
Transaminase elevations (ALT and/or 
AST) 
Infusion reactions - (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome  
Serum sickness 
Infusion reactions  
Infusion-like reactions  
Neurologic - (reported as ECI for any grade) 
Autoimmune neuropathy  
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndromw 
 
 


 
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Ocular  - (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat 
the AE) 
Uveitis 
Iritis 
 
Renal - (reported as ECI for ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations - (report as ECI if ≥ Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin - (reported as ECI for any grade) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (reported as ECI for ≥ Grade 3) 
Pruritus 
Rash 
Rash generalised  
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other  - (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Percarditis 
Vasculitis 
Sclerosing cholangitis 
 
Any other grade 3 event which is considered immune-related by the physician. 
Table 12: Immune related AEs considered ECIs. 
 
Participants should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and 
participants should be asked for signs and symptoms suggestive of an immune-related event.  Participants 
who develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible ir ECI, then additional testing should be performed to 
rule out other etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
 
 Reporting of SAEs 
Any SAE whether or not related to Pembrolizumab, occurring from informed consent until 130 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, must be reported 
on an SAE report form within 24 hours of the PI or designee becoming aware of the event to the Sponsorand 
CI/delegate who will then inform MSD.  
 
Please find below Sponsor details: 
Imperial College Joint Research Compliance Office 
Email address: jrco.ctimp.team@imperial.ac.uk  
 
All SAEs regardless of causality, pregnancy or overdose should be documented and each episode of an SAE 
must be recorded on a separate SAE report form.  The NCI CTCAE Version 4 must be used to grade each SAE, 
and the worsening of the grade is to be recorded.   
 
If new or amended information on a previously reported SAE becomes available, the PI or delegate should 
update the SAE and report this to the Sponsor, CI/delegate. Follow up information about a previously 
reported SAE must be reported within 24 hours of receiving it. If the SAE has not been reported within the 
specified timeframes, a reason for lateness must be included when sending the SAE.  
 


 
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Additionally, any SAE, considered by a PI/delegate who is a qualified physician to be related to 
Pembrolizumab that is brought to the attention of the PI at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor and CI. The CI/delegate will then 
inform the MSD.  
 
These AEs will be followed up until resolved or stabilised at a level acceptable to the CI even if this is after 
the study reporting period. 
 
Events exempt from being reported as SAEs 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is prolonged 
for any reason and then an SAE form must be completed.  The events must still be recorded. 
1. Elective admissions to hospital for procedures which were planned and documented in the medical 
records at the time of consent are not SAEs, and do not require SAE reporting.   
2. Hospitalisation for administration of the IMP, or to facilitate study procedures according to the trial 
protocol, is also exempt from being reported as an SAE. 
 
 
Determining SAE Causality and Expectedness 
Assessment of causality and expectedness for all SAEs will be made by the PI/designee against the current 
approved version of the IB.  If updated versions of the IB are released during the course of the trial then 
assessment of expectedness will be made against the current regulatory approved version. 
 
 
Reporting of ECIs 
Any ECIs whether or not related to the Pembrolizumab, occurring from the first dose until 30 days following 
the last treatment dose, or the initiation of a new anticancer therapy, whichever is earlier, must be recorded 
on the AE log and reported using the eCRF report form within 24 hours of the PI/designee becoming aware 
of the event to the CI or delegate who will then inform MSD. 
 
 
Reporting of an Overdose 
In the event of overdose, Pembrolizumab should be discontinued and the participant should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an AE(s) is associated with (“results from”) the overdose of Pembrolizumab, the AE(s) should be recorded 
on the AE eCRF and reported as a SAE, even if no other seriousness criteria are met. 
If an overdose is taken without any associated clinical symptoms or abnormal laboratory results, the 
overdose is again recorded as an AE on the eCRF and reported as a non-serious ECI, using the terminology 
“accidental or intentional overdose without adverse effect.” 
All reports of overdose either SAE or ECI must be reported within 24 hours of the PI/ designee becoming 
aware of the event to the Sponsor, CI/delegate by email who will inform MSD. 
 
 
Definition of a Serious Adverse Reaction (SAR) 
A SAR is defined as a SAE that is judged to be related to any dose of the IMP administered to the participant. 
 


 
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Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any SAR that is NOT consistent with the applicable product information as set out in the IB. 
 
 
Reporting of SUSARs 
The Investigator and local study team will report all SUSARs to the Sponsor, CI/delegate within 24 hours of 
becoming aware of the event.   
The Sponsor, CI/delegate will ensure that SUSARs are notified to the appropriate regulatory authority, the 
relevant Independent Research Ethics Committee (REC), MSD and the participating PIs in accordance with 
regulatory requirements and within the timelines specified in legislation (SI 2004/1031 as amended). 
 
The Sponsor has delegated the responsibility for notifying the MHRA and REC of all SUSARs occurring during 
the study to the CI/delegate. All SAEs and SUSARs must be reported in accordance with local regulatory 
guidelines: 
 
Life threatening SUSARs should be reported to the MHRA and REC no later than 7 days after the CI has 
first knowledge of the minimum criteria for expedited reporting. Further relevant information should 
be given within a further 8 days. 
 
Non-fatal and non-life threatening SUSARs should be reported to the MHRA and REC no later than 15 
days after the CI has first knowledge of the minimum criteria for expedited reporting. Further relevant 
information should be given as soon as possible. 
 
Follow up of participants who have experienced a SUSAR should continue until recovery is complete or the 
condition has stabilised. 
 
 Annual Reporting of Serious Adverse Events 
Annual reports will be submitted to regulatory authorities and REC by the CI or delegate in accordance with 
all applicable global laws and regulations. Copies will be forwarded to the Sponsor. 
 
8.0 
STATISTICAL ANALYSES 
 
Sample Size and power considerations 
Since this is the first time that Pembrolizumab is given to participants with chronic viral infection and limited 
functional liver reserve, we designed the study as a safety-oriented trial and considered enrolling a 
subsequent cohort of up to 26 participants following an initial safety run-in of 6 subjects to: 1) satisfy the 
safety aims of the study; 2) preliminarily document the efficacy of treatment to inform subsequent efficacy-
testing in a future adequately powered trial; 3) obtain adequate information regarding the disease-
modulating effects from treatment reflected by the proposed translational endpoints.  
 
With primary endpoints being safety, no power calculation for hypothesis testing is required to formally 
power the study: the upper 95% confidence interval for toxicity events will inform the decision to proceed to 
a future, adequately powered phase II trial. Using the rule of three, if zero events are observed in 26 
participants the upper 95% confidence interval will be 15%.   


 
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Data Analysis 
The clinical data will be entered and stored in InFormTM database.  Statistical analysis will be conducted.   
A safety review will be conducted by the IDSMC after Part I. A final analysis will be conducted at the end of 
the study.  Analyses will include an intent to treat (ITT) analysis including all participants enrolled and a per 
protocol analysis using all participants who complete the study without major protocol violations.   
Histograms and boxplots will be used to check the distribution and possible outliers for continuous variables.  
Continuous variables that follow a normal distribution will be summarised using means and standard 
deviations. Skewed continuous variables will be summarised using medians and inter-quartile ranges. 
Categorical variables will be summarised using frequencies and percentages. 
 
Primary and Secondary Endpoint Analysis 
All participants who receive at least one dose of Pembrolizumab will be included in the safety analysis set.  
The frequency of AEs will be assessed for severity (NCI CTCAE v4), expectedness, seriousness and causal 
relationship to IMP.  In addition, AEs will be summarised by toxicity type, impact on IMP and by timing.  
All participants who receive at least one dose of Pembrolizumab and undergo disease re-evaluation as per 
protocol will be included in the efficacy analysis. 
Due to sample size constraints, for the primary outcome of assessing the safety and tolerability of 
Pembrolizumab following TACE and secondary outcomes of ORR every 3 months and QOL, we will use 
descriptive measures such as frequencies and percentages for categorical variables and means and standard 
deviations for normally distributed continuous variables, as specified above in section 8.1. 
The secondary endpoint of PFSR will be estimated by the Kaplan-Meier method. This rate estimates the 
proportion of participants who do not progress and are alive at a given time of 12 weekly timepoints. The 
PFSR is calculated from the start of Imp administration until the date of progression or death from any cause. 
Univariate models will be performed for all demographic and other study variables, as statistically 
appropriate, as well as to test for confounding due to sample size constraints, with models such as Fisher’s 
exact test or the Chi-square test utilised for categorical variables and t-tests or the Wilcoxon test (if the 
continuous variable does not follow a normal distribution) for continuous ones. For all estimates, 95% 
confidence intervals will be calculated. 
 
Exploratory Endpoint Analysis 
The sample collection will be used for future ethically approved research.  For the translational/exploratory 
endpoints, appropriate descriptive measures as well as univariate models will be shown as dependent on 
whether the relevant measure is categorical or continuous, whether the test is paired or not and whether is 
it normally or non-normally distributed as indicated above.   
 
9.0 
REGULATORY, ETHICAL AND LEGAL ISSUES 
 
Declaration of Helsinki 
The CI will ensure that this study is conducted in full conformity with the principles of the 1964 Declaration 
of Helsinki and any subsequent revisions. 


 
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Good Clinical Practice  
The study will be conducted in accordance with the guidelines laid down by the International Conference on 
Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines).  
 
Research Ethics Committee Approval  
 Initial Approval 
Prior to the shipment of IMP and the enrolment of subjects, the REC must provide written approval of the 
conduct of the study at named sites, the protocol and any amendments, the Participant Information Sheet 
(PIS) and Informed Consent Form (ICF), any other written information that will be provided to the 
participants.  
 
 Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted to the HRA/REC 
and Medicines Healthcare Regulatory Agency (MHRA) (as required) for approval as instructed by the Sponsor.  
 
Amendments that are intended to eliminate an apparent immediate hazard to participants may be 
implemented prior to receiving Sponsor or REC approval. However, in this case, approval must be obtained 
as soon as possible after implementation. 
 
 Annual Progress Reports 
The REC will be sent annual progress reports in accordance with national requirements. 
 
 Annual Safety Reports and End of Trial Notification 
The REC will be sent annual safety updates in order to facilitate their continuing review of the study 
(reference. ICH GCP E6 Section 3.1.4) and will also be informed about the end of the trial, within the required 
timelines. 
 
 
Regulatory Authority Approval 
The study will be performed in compliance with the regulatory requirements of the UK. 
Clinical Trial Authorisation from the appropriate Regulatory Authority will be obtained prior to the start of 
the study. In addition, the Regulatory Authority must approve amendments (as instructed by the Sponsor), 
receive Suspected Unexpected Serious Adverse Reactions (SUSAR) reports, Development Safety Update 
Reports and be notified of the end of the trial. 
 
 
Insurance and Indemnity 
Imperial College holds Public Liability ("negligent harm") and Clinical Trial ("non-negligent harm") insurance 
policies which apply to this trial.  
 


 
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Trial Registration 
The study will be registered on the clinicaltrials.gov trial database in accordance with requirements of the 
International Committee of Medical Journal Editors (ICMJE) regulations. 
 
Informed Consent 
The PI/delegate at each site will: 
• Ensure that each participant is given full and adequate oral and written information about the study 
including the background, purpose and risks/benefits of participation 
• Ensure that each participant is notified that they are free to withdraw from the study at any time 
• Ensure that each participant is given the opportunity to ask questions and allowed sufficient time to read 
and understand the ICF 
• Ensure each participant provides signed, dated ICF before undergoing any study specific procedure 
• Ensure the original copy of the signed, dated ICF is stored in the ISF and a copy is also filed in the 
participant’s medical records 
• Ensure that each participant receives a copy of the signed, dated ICF 
 
 
Contact with General Practitioner  
It is the PI/delegate responsibility to inform the participant’s General Practitioner by letter that the 
participant is taking part in the study provided the participant agrees to this, and information to this effect is 
included in the PIS and ICF.  
 
 
Subject Confidentiality 
The PI/delegate must ensure that the subject’s confidentiality is maintained. On all documents submitted to 
the Sponsors, participants will be identified by a trial ID number only. Documents that are not submitted to 
the Sponsor (e.g. signed ICF) should be kept in a strictly confidential file by the PI/delegate. 
 
The PI/delegate shall permit direct access to participant’s records and source document for the purposes of 
monitoring, auditing, or inspection by the Sponsor, authorised representatives of the Sponsor, Regulatory 
Authorities and RECs. 
 
 Data Protection 
Precautions will be taken to ensure that participant confidentiality is preserved at all times. The PI/delegate 
will identify those individuals who will require access to participant data and identifiable details and obtain 
appropriate permission from the consenting participant. 
 
 End of Trial 
The EOT is defined as the last participant last visit (LPLV). 
 


 
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 Study Documentation and Data Storage 
The PI must retain essential documents until notified by the Sponsor, and for at least 25 years after study 
completion. Participant files and other source data (including copies of protocols, original reports of test 
results, IMP dispensing logs, correspondence, records of informed consent, and other documents pertaining 
to the conduct of the study) must be retained. Documents should be stored in such a way that they can be 
accessed/data retrieved at a later date. Consideration should be given to security and environmental risks. 
 
No study document will be destroyed without prior written agreement between the Sponsor and the 
CI/delegate. Should the PI wish to assign the study records to another party or move them to another 
location, written agreement must be obtained from the Sponsor & CI/delegate. 
 
10.0 DATA MANAGEMENT 
 Source Data 
All original records and certified copies of original records of clinical findings, observations, or other activities 
necessary for the reconstruction and evaluation of the trial are classified as source data. 
Source data are contained in source documents; these are defined as: original documents, data, and records 
e.g., hospital records, clinical and office charts, laboratory notes, memoranda, participant’s diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and 
at medico-technical departments involved in the clinical trial.  
 
 Language 
CRFs will be in English. Generic names for concomitant medications should be recorded in the eCRF wherever 
possible. All written material to be used by participants must use vocabulary that is clearly understood, and 
be in the language appropriate for the study site. 
 
 Database & Data Management 
Data will be recorded using the InForm electronic data capture (EDC) and management system where 
possible.  
 
AE data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC) and preferred term (PT), and CTCAE v4.0 grade. 
 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study database will 
be available in an audit trial.  
 
 Data Collection 
Details of procedures for eCRF completion will be provided in a study manual. 
 


 
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11.0 STUDY MANAGEMENT STRUCTURE  
 Independent Data & Safety Monitoring Committee  
This study will employ an Independent Data Safety Monitoring Committee (IDSMC)  
The IDSMC is an independent body that will act in an advisory capacity to monitor the safety of participants 
participating in this study. The IDSMC will review the safety data and recommend modifications to the 
protocol to ensure participant safety, or recommend early termination of the study if major concerns arise 
about the participant’s safety at any time during the course of the study. The IDSMC will review the safety 
profile of the IMP at the completion of Study Part 1 and should any SUSAR occur during the course of the 
study. The roles and responsibilities of the IDSMC will be outlined in a separate charter agreed to by each of 
the members of the IDSMC. 
 Trial Management Group 
A Trial Management Group (TMG) will consist of the Chief Investigator, PIs, the Trial Statistician and Trial 
Coordinator. Other key study personnel may be invited to join the TMG as appropriate to ensure 
representation from a range of sites and professional groups. 
 
Notwithstanding the legal obligations of the Sponsor and Chief Investigator, the TMG will have operational 
responsibility for the conduct of the trial.  
 
 Early Discontinuation of the Study 
Early trial termination can occur for well-documented reasons.  
Further recruitment of participants will not take place under the following conditions:   
• 
Premature termination of the trial.   
• 
Drug-related events, i.e. SUSARs, emerging adverse effects that are serious and the risk/benefit ratio 
is unacceptable.   
• 
Procedure-related events, i.e., the recruitment rate is too low or the number of dropouts for 
administrative reasons is too high 
In the event of MSD decision to no longer supply the IMP, ample notification will be provided so that 
appropriate adjustments to participant treatment can be made. 
 
 Risk Assessment 
A study-specific risk assessment will be performed by the Sponsor prior to the start of the study to assign a 
risk category of ‘low’, ‘medium’ or ‘high’ to the trial. The risk assessment will consider all aspects of the study 
and will be used to guide the monitoring plan. 
 Monitoring  
The study will be monitored periodically by monitors in the UK to assess the progress of the study, verify 
adherence to the protocol, ICH GCP E6 guidelines and other national/international requirements and to 
review the completeness, accuracy and consistency of the data. 
Monitoring procedures and requirements will be documented in a Monitoring Plan. Monitoring will be 
proportionate to the objective, purpose, design, size, complexity, blinding, endpoints and risks associated 


 
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with the clinical trial. The appropriate level and nature of monitoring required for the clinical trial will be 
assessed by undertaking a formal risk assessment analysis of the study.  
 
 Quality Control and Quality Assurance 
Quality Control (QC) will be performed according to internal procedures. The study may be audited by a 
Quality Assurance (QA) representative of the Sponsor. All necessary data and documents will be made 
available for inspection. 
 Disclosure of Data and Publication 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The CI may use this information for the 
purposes of the study only. 
 
It is understood by the CI that the Sponsor will use information developed in this clinical study in connection 
with the development of the IMP and, therefore, may disclose it as required to other clinical investigators 
and to Regulatory Authorities. In order to allow the use of the information derived from this clinical study, 
the CI understands that he/she has an obligation to provide complete test results and all data developed 
during this study to the Sponsor. 
 
Verbal or written discussion of results prior to study completion and full reporting should only be undertaken 
with written consent from the Sponsor. 
 
Therefore all information obtained as a result of the study will be regarded as CONFIDENTIAL, at least until 
appropriate analysis and review by the CI is completed.  
 
The results may be published or presented by the CI/delegate(s). 
 
 


 
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hepatocellular carcinoma: a prospective study. Aliment Pharmacol Ther. 2014; 40(11-12):1270-1281. 
27. Liao Y, Wang B, Huang ZL, Shi M, Yu XJ, Zheng L, Li S and Li L. Increased circulating Th17 cells after 
transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a 
prospective study. PLoS One. 2013; 8(4):e60444. 
28. Chen J, Jiang CC, Jin L and Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. 
Ann Oncol. 2015. 
29. Chao Y, Wu CY, Kuo CY, Wang JP, Luo JC, Kao CH, Lee RC, Lee WP and Li CP. Cytokines are associated with 
postembolization fever and survival in hepatocellular carcinoma participants receiving transcatheter 
arterial chemoembolization. Hepatol Int. 2013; 7(3):883-892. 


 
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30. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith 
L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, et al. Phase I Study of Pembrolizumab 
(MK-3475; Anti-PD-1 Monoclonal Antibody) in Participants with Advanced Solid Tumours. Clin Cancer Res. 
2015; 21(19):4286-4293. 
31. Kim MJ, Jang JW, Oh BS, Kwon JH, Chung KW, Jung HS, Jekarl DW and Lee S. Change in inflammatory 
cytokine profiles after transarterial chemotherapy in participants with hepatocellular carcinoma. 
Cytokine. 2013; 64(2):516-522. 
32. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, 
Alfaro C, Sarobe P, Lasarte JJ, Perez-Gracia JL, Melero I and Prieto J. A clinical trial of CTLA-4 blockade with 
tremelimumab in participants with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013; 
59(1):81-88. 
33. Duffy AG, Makarova-Rusher OV, Kerkar SP, Kleiner DE, Fioravanti S, Walker M, Carey S, Figg WD, Steinberg 
SMS, Anderson V, Abi-Jaoudeh N, Levi E, Wood BJ and Greten TF. A pilot study of tremelimumab – a 
monoclonal antibody against CTLA-4 – in combination with either trans catheter arterial 
chemoembolization (TACE) or radiofrequency ablation (RFA) in participants with hepatocellular 
carcinoma (HCC). ASCO Meeting Abstracts. 2015; 33(18_suppl):abstr 4081. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendices 
Appendix 1: Diagnostic Criteria for HCC. 
 
The diagnosis of HCC may be confirmed by biopsy or by application of the following non-invasive diagnostic 
criteria that have been proposed by the American Association for the Study of the Liver (AASLD), last updated 
in 2011*.  
1. 
Nodules between 1 and 2 cm found on ultrasound screening of a cirrhotic liver should be 
characterized further with two dynamic studies, either multi-detector CT scan or MRI with contrast. If the 
imaging appearances are typical of HCC (i.e. hypervascular, arterial enhancement followed by washout in the 
portal/venous phase) in two independent techniques, then the lesion should be treated as HCC. If the findings 
are not characteristic or the vascular profile is not coincidental among techniques the lesion should be 
biopsied. 
2. 
If the nodule is larger than 2 cm at initial diagnosis and has the typical features of HCC on one dynamic 
imaging technique, biopsy is not necessary for the diagnosis of HCC. However, if the vascular profile on 
imaging is not typical of HCC or if the nodule is detected in a non-cirrhotic liver, biopsy should be performed 
to confirm the diagnosis. 
*As published in: Bruix J, Sherman M; Management of hepatocellular carcinoma: an update. Hepatology. 
2011 Mar; 53(3):1020-2. 
Appendix 2: ECOG Performance Status 
 
Grade 
Description 
0 
sNormal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. 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 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
 


 
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Appendix 3: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
4.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
Appendix 4: Modified Response Evaluation Criteria in Solid Tumours (mRECIST*) Criteria for Evaluating 
Response in Hepatocellular Carcinoma. 
Modified RECIST version criteria will be used in this study for assessment of tumour response. CT is the 
preferred imaging technique in this study. 
* As published in: 
• 
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular Carcinoma. Semin 
Liver Dis 2010; 30:52-60 
 
Appendix 5: Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria for Evaluating Response in 
Solid Tumours 
RECIST version 1.1* will be concurrently recorded in this study for assessment of tumour response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
            E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-
47. 
In addition, volumetric analysis will be explored by central review for response assessment. 


 
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SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol including all 
statements regarding confidentiality. 
 
 
Study Title: 
A 
phase 
Ib 
study 
of 
Pembrolizumab 
following 
Trans-Arterial 
chemoembolization in primary Liver carcinoma (PETAL).  
 
 
 
 
 
Signed:  
___________________________________________ 
 
 
 
 
Dr David James Pinato 
 
 
 
MD MRes MRCP (UK) PhD 
 
 
 
 
 
Date: 
 
_____________________ 
  


 
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SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: 
A 
phase 
Ib 
study 
of 
Pembrolizumab 
following 
Trans-Arterial 
chemoembolization in primary Liver carcinoma (PETAL).  
 
 
 
 
 
 
Signed:  
___________________________________________ 
 
 
 
 
Name of Sponsor’s Representative 
 
 
 
Title 
 
 
 
Sponsor name 
 
 
 
 
 
 
Date: 
 
_____________________ 
 
 


 
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SIGNATURE PAGE 3 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and provides the 
necessary assurance that this study will be conducted at his/her investigational site according to all 
stipulations of the protocol including all statements regarding confidentiality. 
 
 
Study Title: 
A 
phase 
Ib 
study 
of 
Pembrolizumab 
following 
Trans-Arterial 
chemoembolization in primary Liver carcinoma (PETAL).  
 
 
 
 
Address of Institution:  ____________________________________________ 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed:  
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date: 
 
 
_____________________