Clinical trial NCT03316872
Conditions: Hepatocellular Carcinoma
Sponsor: University Health Network, Toronto
Start date: 2018-02-15; Completion date: 2024-02-15
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2 study whose purpose is to assess the efficacy of the combination of pembrolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) who have experienced disease progression after treatment with sorafenib.

Detailed description:
Pembrolizumab will be administered intravenously as a 30-minute infusion at a dose of 200 mg every 21 days, until disease progression or intolerable toxicity.

Stereotactic radiotherapy will commence on day 2 of the first cycle of pembrolizumab, and will be delivered in 5 fractions over 8-15 days in accordance with institutional protocol.

Subjects will be re-evaluated for response every 12 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks following initial documentation of objective response.

Response and progression will be evaluated in this study using both RECIST 1.1and (iRECIST) guideline (Seymor 2017).

Arms: arm 1: Pembrolizumab, intravenously, at a dose of 200 mg, once every 3 weeks

SBRT starting Day 2 of Cycle 1 of pembrolizumab treatment, given in 5 fractions over 10-15 days.
Interventions: intervention 1: Pembrolizumab intervention 2: Stereotactic Body Radiotherapy (SBRT)
Intervention descriptions: intervention 1: Pembrolizumab is a 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. intervention 2: SBRT involves delivery of high doses of radiation therapy in smaller fractions

Protocol documents:
Prot_SAP_000.pdf: 
Protocol ID: PEMRAD 
Version Date: 09-Sep-2021 
 
Page 1 of 83 
 
Protocol ID: PEMRAD 
Protocol Version/ Date:  Initial / 11Apr2017 
 
 
 
      Amendment #1 / 01-May-2018 
 
                                          Amendment #2 / 06-Nov-2019 
 
 
 
      Amendment #3 / 20-Nov-2020 
 
 
 
 
 
 
 
Amendment #4 / 09-Sep-2021 
 
TITLE:  Pembrolizumab and Stereotactic Radiotherapy Combined in Subjects with Advanced 
Hepatocellular Carcinoma – A Phase II Study (PEMRAD) 
 
Coordinating Center: 
 
 
Princess Margaret Cancer Centre 
 
 
 
 
 
 
 
 
 
610 University Avenue 
 
 
 
 
 
 
 
 
 
Toronto, ON M5G 2M9 
 
 
 
 
 
 
 
 
 
Canada 
 
Sponsor-Investigator: 
Jennifer J Knox 
 
 
 
 
 
 
 
 
 
Princess Margaret Cancer Centre 
 
 
 
 
 
 
 
 
 
610 University Avenue 
 
 
 
 
 
 
 
 
 
Toronto, ON M5G 2M9 
 
 
 
 
 
 
 
 
 
 
Canada 
 
Phone: +1-416-946-2399 
 
Fax: 416-946-6546 
 
Email: jennifer.knox@uhn.ca 
 
Radiation Oncology Lead: 
Laura A Dawson 
 
 
 
 
 
 
 
 
 
Princess Margaret Cancer Centre 
 
 
 
 
 
 
 
 
 
610 University Avenue 
 
 
 
 
 
 
 
 
 
Toronto, ON M5G 2M9 
 
 
 
 
 
 
 
 
 
Canada 
 
Phone: +1-416-946-4501 
 
Email: laura.dawson@rmp.uhn.on.ca 
 
Hepatology Lead: 
David K Wong 
 
Princess Margaret Cancer Centre 
 
 
 
 
 
 
 
 
 
610 University Avenue 
 
 
 
 
 
 
 
 
 
Toronto, ON M5G 2M9 
 
 
 
 
 
 
 
 
 
Canada 
 
 
 
 
 
 
 
 
 
Email:dave.wong@uhn.ca 
 
Participating Institutions:  
Princess Margaret Cancer Centre 
 
 
 
 
 
 
 
 
 
610 University Avenue 
 
 
 
 
 
 
 
 
 
Toronto, ON M5G 2M9 
 
 
 
 
 
 
 
 
 
Canada 
 
 
 
NCT03316872


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Statistician: 
 
Central Office Coordinator: 
Lisa Wang  
 
 
 
  
Nitika Solanki 
Department of Biostatistics 
 
 
Drug Development Program 
Princess Margaret Cancer Centre  
 
Princess Margaret Cancer Centre  
610 University Ave   
 
 
700 University Ave  
Toronto, ON M5G 2M9  
 
 
Toronto, ON M5G 1X6  
Phone: 416-946-4501 ext. 4883  
 
Phone: 416-946-4501 ext. 2630 
Fax: 416-946-2048  
 
 
 
Fax: 416-946-2016  
lisawang@uhnres.utoronto.ca  
 
nitika.solanki@uhn.ca 
  
 
 
Investigational Agent: Pembrolizumab 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Advanced HCC post 
sorafenib/Lenvatinib 
-Disease amenable to 
SBRT 
-Measurable disease 
by RECIST 1.1/ 
iRECIST. 
-Fresh tissue biopsy 
for WES, RNAseq 
R
E
G
I
S
T
R
A
T
I
O
N 
D1 
Pembrolizumab treatment 
D2 
SBRT Fraction 
D3 D5 
D8 
D10 
D22 
D43 
To disease 
progression / 
intolerable toxicity 
Blood for ctDNA and methylation profile 
SBRT* 
D85 
First CT assessment at 12 weeks 
*SBRT will be given daily or every 2nd day on weekdays, and therefore cycle days may not correspond. Schema is 
for illustration purposes only. All treatment dates +/- 1 day. 
Blood for cytokine analysis 
Optional 2nd biopsy 


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SYNOPSIS 
 
Title of study:  
 
Pembrolizumab and Stereotactic Radiotherapy Combined in Subjects with Advanced 
Hepatocellular Carcinoma – A Phase II Study (PEMRAD) 
 
Objectives: 
 
Primary:  
 To assess the efficacy of combined SBRT and pembrolizumab in subjects with 
advanced hepatocellular carcinoma (HCC), by measurement of overall response 
rate (ORR). 
 
Secondary:  
 To assess response rate outside irradiated volumes (abscopal effect)  
 Analyze response kinetics 
 Determine progression-free and overall survival 
 Assess safety of combined SBRT and pembrolizumab. 
 
Exploratory: 
 To explore predictors of response to combined SBRT and pembrolizumab in 
HCC, including molecular and imaging biomarkers associated with response 
outside irradiated volumes. 
 
Study Design: 
 
Single-arm, non-comparative, open-label phase II clinical trial of pembrolizumab with 
SBRT delivered during first cycle of systemic therapy. 
 
Number of subjects: 
 
The trial will follow a 2-stage design. During the first stage, 10 evaluable subjects will 
be enrolled. If 2 or more subjects demonstrate a response, the trial will continue to a 
total enrollment of 22 evaluable subjects. We expect to accrue up to 27 patients as some 
of the subjects may not be evaluable. 
 
Main criteria for Inclusion/Exclusion: 
 
1. Histologically- or cytologically-confirmed HCC, unsuitable for locoregional 
therapy (such as TACE, RFA), surgical resection or liver transplantation (BCLC 
stage B or C), with measurable disease by RECIST 1.1/iRECIST. 
2. Disease progression after at least 8 weeks of sorafenib or lenvatinib, or 
discontinuation of sorafenib/lenvatinib due to intolerance with subsequent 
disease progression. 
3. Tumor that is amenable to biopsy for correlative studies at time of study 


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registration, no contraindication to biopsy, and subject willing to undergo 
biopsy. In addition, the subject must consent to give blood for correlative 
studies, and have no contraindications to this. 
4. Adequate liver function: Child-Pugh A5/6, ALT&AST ≤ 5 x upper limit of 
normal (ULN), bilirubin ≤ 34 umol/L, albumin ≥ 25 g/L. 
5. ECOG Performance Status 0-1. 
6. Intrahepatic HCC must be suitable for stereotactic radiotherapy – max 10 lesions 
to be treated, and total tumor diameter <20 cm. Smaller satellites of HCC or 
non-definite HCC need not be encompassed within SBRT volumes if needed to 
respect normal tissue limits. 
7. No prior invasive malignancy, unless treated with curative intent and disease-
free for 2 years prior to study entry. 
8. Subjects with fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma-HCC are excluded. 
9. Subjects with previous liver transplantation will be excluded. 
10. Subjects with prior upper abdominal radiation therapy within planned volumes 
(exceeding standard tolerances) will be excluded. 
11. Liver tumors must not invade main branch bile ducts or extend into adjacent 
organs. 
12. Individual liver tumors must not measure >15cm in diameter 
13. Subjects with contraindications to checkpoint inhibiting immunotherapy will be 
excluded: chronic autoimmune disease, immunosuppressive medications or 
corticosteroids (>10mg/day prednisone), HIV infection, or live/live-
attenuatedvaccine (within prior 30 days). 
14. Subjects with brain metastases will be excluded. 
15. No previous cancer immunotherapy. 
16. Subjects with alcohol related or non-alcoholic steatohepatitis (NASH) related 
cirrhosis will be excluded. 
17.  Subjects with a history of significant, active or unstable heart disease will be 
excluded. 
 
Intervention: 
Pembrolizumab will be administered intravenously as a 30-minute infusion at a dose of 
200 mg every 21 days, until disease progression or intolerable toxicity. 
Stereotactic radiotherapy will commence on day 2 of the first cycle of pembrolizumab, 
and will be delivered in 5 fractions over 5-15 days in accordance with institutional 
protocol, with a preferred schedule of beginning on a Tuesday, if Day 1 is on a Monday. 
 
Correlatives: 
A pre-treatment biopsy will be mandatory. Up to four good core biopsies will be 
obtained if deemed safe by radiologist performing the procedure. These will be banked 
for planned whole exome sequencing, gene expression profiling by RNAseq and DNA 
methylation mapping. Immunohistochemical analysis of PD-L1and tumour infiltrating 
lymphocytes will also be evaluated. 
 
Patients deemed eligible will be presented with the consent to have an optional tumour 


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biopsy will be performed at 3-6 weeks on study. 
 
Whole blood will be drawn on cycle 1, Day 1 and Day 10 and Cycle 5 Day 1 for ctDNA 
analysis and DNA methylation profiling. These markers will also be analyzed at time of 
progression where possible.  
 
Blood will also be collected for peripheral cytokine analysis by 
electrochemiluminescence at Cycle 1, Day 1, Day 5, and Day 10, Cycle 3 Day 1, Cycle 
5 Day 1 and at progression. 
 
Baseline diagnostic imaging and radiation planning imaging will be archived for future 
exploratory analyses, which will explore patterns of enhancement and change in 
responding patients compared with non-responders. 
 
Statistics: 
The primary objective of the study is to assess the ORR of the combination of SBRT 
and pembrolizumab, as measured by RECIST 1.1. /iRECIST. Given the preliminary 
results with nivolumab, we would predict pembrolizumab alone to produce an ORR of 
approximately 15%. We hypothesize that combining pembrolizumab with SBRT will 
increase the ORR to 40%, a clinically meaningful increase in systemic response rate and 
indicative of significant activity. With 90% power, we would need to accrue 22 subjects 
in a two-stage study design, with a one-sided significance level of 10%. If 2 or more 
subjects show response from the first 10, we will continue to accrue to a total of 27, as 
we expect that some subjects will not be evaluable for the primary endpoint. A total 
number of 6 or more responders in 22 evaluable subjects would be considered to reject 
the null hypothesis. Response will be defined as best response at any time on study 
treatment. 
Secondary analyses will be performed without pre-specified assumptions of efficacy, 
given the lack of data in this setting. 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE  
 
Adverse Event  
AFP 
 
Alpha Fetoprotein 
BCLC  
Barcelona Clinic for Liver Cancer (staging) 
BP  
 
Blood Pressure  
CBC   
Complete Blood Count  
CI  
 
Confidence Interval  
CP 
 
Child-Pugh (Score) 
CR  
 
Complete Response  
CT  
 
Computed Tomogram  
CTCAE  
Common Terminology Criteria for Adverse Events  
eCRF   
Electronic Case Report Form  
DDP   
Drug Development Program 
DRESS 
Drug Rash with Eosinophilia and Systemic Symptom 
cfDNA 
Cell-free DNA  
ctDNA  
Circulating Tumor DNA  
ECOG  
Eastern Co-operative Oncology Group  
GCP   
Good Clinical Practice  
GTV  
Gross Tumour Volume 
Gy 
 
Gray 
HCC  
Hepatocellular Carcinoma 
HBV  
Hepatitis B Virus 
HCV  
Hepatitis C Virus 
ICH   
International Conference on Harmonization  
irAE 
 
Immune Related Adverse Event 
iRECIST 
immune related modified RECIST 1.1  
IRB  
 
Institutional Review Board  
LFT 
 
Liver Function Tests 
MRI   
Magnetic Resonance Imaging  
NA  
 
Not Applicable 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NASH  
Non-Alcoholic Steatohepatitis 
NE  
 
Not Evaluable  
NK 
 
Natural Killer 
NTCP  
Normal Tissue Complication Probability 
OAR  
Organs at Risk 
ORR  
Overall Response Rate 
OS  
 
Overall Survival  
OTN  
Ontario Telemedicine Network 
PBMC  
Peripheral Blood Mononuclear Cell  
PD  
 
Progressive Disease  
PD-1   
Programmed Death-1  
PDL-1  
Programmed Death Ligand-1  
PFS  
 
Progression Free Survival  
PTV 
 
Planning target volume 


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PM  
 
Princess Margaret Cancer Centre  
PR  
 
Partial Response  
RECIST  
Response Evaluation Criteria in Solid Tumor  
REB   
Research Ethics Board  
SAE   
Serious Adverse Event  
SBRT  
Stereotactic Body Radiotherapy 
SD  
 
Stable Disease  
SJS 
 
Stevens-Johnson Syndrome 
TEN 
 
Toxic Epidermal Necrolysis 
UHN   
University Health Network  
ULN   
Upper Limit of Normal  
US 
 
Ultrasound  
WES   
Whole Exome Sequencing  
RNAseq 
RNA sequencing  
 
 
 
 


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TABLE OF CONTENTS 
 
SCHEMA......................................................................................................................................... 3 
SYNOPSIS ...................................................................................................................................... 4 
1. 
OBJECTIVES .................................................................................................................... 11 
1.1 
Primary Objectives ................................................................................................ 11 
1.2 
Secondary Objectives ............................................................................................ 11 
1.3 
Exploratory Objectives .......................................................................................... 11 
2. 
BACKGROUND ............................................................................................................... 12 
2.1 
Hepatocellular Carcinoma ..................................................................................... 12 
2.2 
Investigational Agents ........................................................................................... 13 
2.3 
Rationale ................................................................................................................ 18 
2.4 
Correlative Studies Background ............................................................................ 18 
3. 
SUBJECT SELECTION.................................................................................................... 20 
3.1 
Inclusion Criteria ................................................................................................... 20 
3.2 
Exclusion Criteria .................................................................................................. 23 
3.3 
Inclusion of Women and Minorities ...................................................................... 25 
4. 
REGISTRATION PROCEDURES ................................................................................... 25 
4.1 
General Guidelines ................................................................................................ 25 
4.2 
Registration Process .............................................................................................. 25 
5. 
TREATMENT PLAN........................................................................................................ 26 
5.1 
Agent Administration ............................................................................................ 26 
5.2 
General Concomitant Medication and Supportive Care Guidelines ..................... 33 
5.3 
Duration of Therapy .............................................................................................. 33 
5.4 
Duration of Follow Up .......................................................................................... 36 
5.5 
Criteria for Removal from Study ........................................................................... 36 
6. 
DOSING DELAYS/MODIFICATIONS and toxicity management ................................. 37 
6.1 
Pembrolizumab Dose Modification ....................................................................... 37 
6.2 
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest 
(ECIs)..................................................................................................................... 40 
6.3 
Rescue Medications & Treatment of Pembrolizumab-Related Toxicities ............ 44 
6.4 
Radiation Therapy Toxicity Assessment During Therapy .................................... 46 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................ 48 
7.1 
List of Adverse Events and Reporting Requirements ........................................... 48 
7.2 
Adverse Event Characteristics ............................................................................... 50 
7.3 
Serious Adverse Event Reporting .......................................................................... 52 
7.4 
Routine Adverse Event Reporting ......................................................................... 53 
7.5 
Documentation of Adverse Events ........................................................................ 54 
7.6 
Follow-Up of AEs and SAEs................................................................................. 54 


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7.7 
Pregnancy .............................................................................................................. 54 
7.8 
Investigator Notifications ...................................................................................... 55 
7.9 
Data Safety and Monitoring Board ........................................................................ 55 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 55 
8.1 
Investigational Agent - Pembrolizumab ................................................................ 55 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 56 
9.1 
Tumor Biopsies...................................................................................................... 56 
9.2 
Blood withdrawal and biomarker studies .............................................................. 58 
10. 
STUDY CALENDAR ....................................................................................................... 59 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 61 
11.1 
Antitumor Effect – Solid Tumors .......................................................................... 61 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 68 
12.1 
Data Collection and Reporting .............................................................................. 69 
12.2 
Source Documents ................................................................................................. 69 
12.3 
Retention of Subject Records and Study Files ...................................................... 69 
12.4 
Site and Study Closure .......................................................................................... 70 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 70 
13.1 
Study Design/Endpoints ........................................................................................ 70 
13.2 
Sample Size/Accrual Rate ..................................................................................... 71 
13.3 
Analysis of Primary Endpoint ............................................................................... 71 
13.4 
Analysis of Secondary Endpoints .......................................................................... 71 
13.5 
Analysis of Exploratory Endpoints........................................................................ 72 
13.6 
Reporting and Exclusions ...................................................................................... 72 
REFERENCES .............................................................................................................................. 74 
APPENDIX 1 
 PERFORMANCE STATUS CRITERIA ................................................. 78 
APPENDIX 2 
 CHILD-PUGH SCORE ............................................................................ 79 
APPENDIX 3 
HEPATITIS B DEFINITIONS AND TREATMENT CONSIDERATIONS
 
80 
APPENDIX 4 
 VASCULAR THROMBOSIS STAGING ............................................... 81 
APPENDIX 5 
 DATA MANAGEMENT GUIDELINES ................................................ 82 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To assess the systemic efficacy of combined SBRT and pembrolizumab in subjects with advanced 
HCC who have experienced disease progression after sorafenib or lenvatinib therapy, as measured by 
overall response rate (ORR). Both RECIST 1.1 and iRECIST (Seymour 2017) will be used. In addition, 
this study will look at the composite sum of irradiated tumor and other measurable metastatic disease 
as assessed by the following: local radiotherapy response, systemic pembrolizumab response and 
potential abscopal effect on all measurable disease. 
 
1.2 
Secondary Objectives 
 
1. To assess the radiographic response rate in non-irradiated tumor lesions, following the 
combination treatment of pembrolizumab and SBRT in subjects with advanced HCC who have 
experienced disease progression after sorafenib/lenvatinib therapy, as an estimate of the abscopal 
effect. 
2. To measure the duration and timing of radiographic responses following the combination 
treatment of pembrolizumab and SBRT in subjects with advanced HCC who have experienced 
disease progression after sorafenib/lenvatinib therapy. 
3. To determine the progression-free survival (PFS), in subjects receiving combination treatment 
with pembrolizumab and SBRT for advanced HCC who have experienced disease progression 
after sorafenib/lenvatinib therapy. 
4. To determine the overall survival (OS) in subjects receiving combination treatment with 
pembrolizumab and SBRT for advanced HCC who have experienced disease progression after 
sorafenib/lenvatinib therapy. 
5. To evaluate the safety and tolerability profile of combination treatment with pembrolizumab and 
SBRT in subjects with advanced HCC who have experienced disease progression after 
sorafenib/lenvatinib therapy. 
 
1.3 
Exploratory Objectives 
 
1. To investigate genomic signatures that may predict responses to pembrolizumab and radiation. 
This will include Whole Exome Sequencing (WES) and RNA sequencing (RNAseq) on tumor 
tissue from subjects with advanced HCC who have experienced disease progression after 
sorafenib therapy. If deemed safe, a second optional biopsy will be performed in consenting 
patients to compare immune signatures and biomarkers pre and post treatment. 
2. To determine levels of circulating tumor DNA (ctDNA) and evaluate methylation profiles from 
plasma in subjects with advanced HCC who have experienced disease progression after 
sorafenib/lenvatinib therapy. To examine the associations between these profiles with response 
to pembrolizumab and SBRT, and between subgroups of patients with all vs not all tumor 
deposits irradiated.   
3. To explore PD-L1 expression as a biomarker predictive of response to combined pembrolizumab 
and SBRT in subjects with advanced HCC who have experienced disease progression after 
treatment with sorafenib/lenvatinib, and evaluate the ‘immunoscore’ in HCC. 


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4. To determine if peripheral analyses of cytokines using electrochemiluminescence may predict 
the abscopal effect. 
5. To explore imaging features correlated with response.  
2. BACKGROUND 
 
2.1 
Hepatocellular Carcinoma 
 
Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide, but represents the second 
leading cause of cancer related mortality, associated with a 5-year survival of less than 10%. It most 
frequently arises in the setting of chronic liver disease, which may be related to viral hepatitis (Hepatitis 
B or C infection), alcoholic liver disease, or non-alcoholic fatty liver disease. Many subjects are not 
eligible for potentially curative treatment in the form of surgical resection or liver transplant, due to 
either extent of liver dysfunction or advanced tumor stage. Locoregional therapies such as 
radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) can prolong survival, but 
cannot be used in subjects with significant vascular invasion or metastatic disease. HCC is generally 
considered resistant to most traditional chemotherapy regimens, and the median survival of subjects is 
approximately 6-9 months without treatment, or shorter if major portal vascular invasion is present. 
In subjects with advanced HCC unsuitable for local therapies, and with satisfactory liver function, the 
current standard of care in Western populations is the oral tyrosine kinase inhibitor (TKI) sorafenib or 
lenvatinib. The SHARP trial was a phase III study evaluating sorafenib, which randomized 602 subjects 
to either sorafenib or placebo. In subjects treated with sorafenib, median overall survival was 10.7 
months, compared with 7.9 months in those who received placebo (hazard ratio 0.69, 95% CI 0.55-0.87, 
p<0.001).1 A similar study was carried out in an Asian population, and reported a similar hazard ratio 
(HR) for OS of 0.68 (p=0.014), but with shorter median OS times for subjects treated both with sorafenib 
(6.5 months) and placebo (4.2 months).2 This difference in OS may relate to the underlying etiologic 
factors in HCC development in these populations, with the SHARP study enrolling a majority of subjects 
with hepatitis C virus (HCV) infection or alcoholic cirrhosis, whereas the Asia-Pacific study was 
comprised of a majority of subjects with hepatitis B virus (HBV) infection. The recently-reported phase 
III study of sorafenib alone or in combination with doxorubicin was stopped early due to futility, with a 
trend toward decreased survival in subjects treated with the combination (HR 1.06, 95% CI 0.8-1.4).3 
More recently the REFLECT study demonstrated that lenvatinib, another multikinase inhibitor, was non 
inferior to sorafenib. The REFLECT study enrolled patients with BCLC B or C staging, and Childs Pugh 
Class A. Of note those with more than 50% liver invasion or invasion of bile ducts or portal vein were 
excluded. Median overall survival was was 13.6 months on lenvatinib vs 12.3 months on sorafenib, with 
an HR of 0.92 (95% CI = 0.79–1.06), showing non-inferiority of lenvatinib compared to sorafenib.1 
In subjects who have experienced disease progression on sorafenib or lenvatinib a number of new 
therapeutic options have been approved recently.  For decades many randomized trials of numerous 
agents had failed to show improved survival compared with placebo, including brivanib, ramucirumab 
and everolimus.4-6 The RESORCE randomized phase III study of regorafenib in 573 subjects with 
progressive HCC after previous sorafenib therapy has reported positive results. The median OS in the 
regorafenib group was 10.6 months, compared with 7.8 months in the placebo group (HR 0.63, 95% CI 
0.50-0.79, p<0.001).7 Furthermore cabozantanib and ramucirumab (when alpha-feto protein > 400 


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ng/ml) are now approved tyrosine kinase inhibitors but are yet to be reimbursed in Canada. Each provide 
an improvement in survival over placebo of only 2.2 month and 1.2 months respectively.  
2.2 
Investigational Agents 
 
2.2.1 Pembrolizumab (a.k.a. MK-3475) 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
pembrolizumab. 
 
2.2.1.1 
Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades.8 Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.9-12 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 tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 is an 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).13 
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.14 PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T-regulatory 
cells and Natural Killer cells. Expression has also been shown during thymic development on CD4-
CD8- (double 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 tumors.  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.  
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.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment 
of subjects with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. Pembrolizumab was also recently approved 
for the treatment of subjects with metastatic non-small cell lung cancer (NSCLC) whose tumors express 
PD-L1 as determined by a Food and Drug Administration (FDA)-approved test, with disease progression 
on or after platinum-containing chemotherapy. 


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2.2.1.2 
Preclinical and Clinical Trial Data 
 
Therapeutic studies in mouse models have shown that the administration of antibodies blocking the PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor 
rejection, either as a monotherapy or in combination with other treatment modalities. Anti-mouse PD-1 
and anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as monotherapy in models 
of squamous cell carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of 
the PD-1 pathway effectively promotes CD8+ T-cell infiltration into the tumor and the presence of 
interferon-γ, granzyme B and perforin, indicating that the mechanism of action involves local infiltration 
and activation of effector T-cell function in vivo.15,16 Experiments have confirmed the in vivo efficacy 
of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the IB). Clinical trials have demonstrated efficacy using pembrolizumab in subjects 
with advanced melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, 
Hodgkin’s lymphoma, triple-negative breast cancer, and gastric adenocarcinoma. In addition, recent 
data demonstrate emerging evidence of single-agent activity in additional tumor types such as 
mesothelioma, urothelial cancer, ovarian cancer, neuroendocrine carcinoma, and small cell lung cancer.  
 
Immune checkpoint blockade is an attractive therapeutic option in HCC. The majority of HCCs arise in 
the setting of chronic inflammation, usually secondary to chronic infection with Hepatitis B (HBV) and 
C (HCV) viruses. This creates an immunosuppressive state in an organ that naturally promotes immune 
tolerance. Hepatocytes together with other non-parenchymal cells have been shown to express 
programmed death receptor ligand-1 (PD-L1), contributing to the suppression of effector T cells.17,18,19 
Expression levels of PD-1 mRNA have been shown to correlate with disease course in HBV subjects 
and post-operative recurrence in HBV-associated HCC,20,21 and in HCV-associated HCC, infiltrating 
and circulating CD8+PD1+ T cells correlated with progression and recurrence postoperatively.22 In a 
mouse model of HCC, blockade of PD-1 with immunostimulatory monoclonal antibodies extends 
survival.23 The interim analysis of a Phase I/II trial of nivolumab in previously treated subjects with 
HCC demonstrated objective responses in 16% of subjects (n=214) and an estimated survival rate of 
71% at 9 months. Results also show the safety profile of nivolumab to be generally consistent with that 
previously reported in other tumor types.24 
 
2.2.1.3 
Rationale for Dose Selection 
 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose recently 
approved in the United States and several other countries for treatment of melanoma and NSCLC 
subjects is 2 mg/kg Q3W. Information on the rationale for selecting the 200 mg Q3W dose is 
summarized below.  
 
Keynote-001, an open-label Phase I study, was conducted to evaluate the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics, and anti-tumor 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 every 2 weeks (Q2W) and dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg 
Q3W in subjects with advanced solid tumors. All dose levels were well tolerated, no dose-limiting 
toxicities were observed, and no maximum tolerated dose (MTD) identified. This first-in-human study 
of pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels. Additional cohorts at different dose levels and frequencies reported similar 


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results, with all clinical efficacy and safety data demonstrating a lack of important differences across 
doses. 
 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide a similar response to 
2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously, a flat pembrolizumab exposure-
response relationship for efficacy and safety has been found in subjects with melanoma in the range of 
doses between 2 mg/kg and 10 mg/kg. Exposures for 200 mg Q3W are expected to lie within this range 
and will be close to those obtained with 2 mg/kg Q3W dose. 
 
In a population PK model, developed with data from 476 subjects, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body weights.  
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 body weight 
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 tumor burden on exposure. In addition, exposure was similar between the non-small cell lung 
cancer (NSCLC) and melanoma indications. Therefore, there are no anticipated changes in exposure 
between different tumor indications. 
 
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 every 3 weeks will provide exposures that 1) are optimally consistent with those obtained 
with the 2 mg/kg dose every 3 weeks, 2) will maintain individual subject exposures in the exposure 
ranges established in melanoma and NSCLC as associated with maximal clinical efficacy and 3) will 
maintain individual subject exposures in the established safe exposure ranges.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. The existing data suggest 200 mg Q3W as the 
appropriate pembrolizumab dose. 
 
2.2.2 Liver SBRT 
 
Stereotactic Body Radiotherapy (SBRT) has increasingly been shown to have an important role in the 
treatment of HCC. 
 
Historically conventional external beam radiation to the liver was associated with radiation induced liver 
toxicity (RILD).  Classic RILD refers to a syndrome characterized by anicteric hepatomegaly, elevation 
of liver enzymes (ALP>AST) and ascites and can progress to liver failure, despite maximal care. Classic 
RILD is uncommon in modern radiation therapy series, when the dose to the liver can be kept below 
recommended levels. Technological advances in radiation treatment planning, breathing motion 
management and image guided radiation therapy (IGRT), have made it possible for ablative doses of 


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radiation to be delivered safely to focal unresectable HCC, using conformal RT, SBRT or protons. 
However, a decline in liver function (e.g. as assessed using Child Pugh score or ALBI) 3 months 
following radiation therapy is seen in 10 – 30 % of patients.  Presence and progression of main portal 
branch HCC may contribute to this, and subsequent improvement in liver function often follows if the 
vascular HCC responds to radiation therapy (which may be delayed at 3 – 6 months post radiation).   
 
SBRT involves the delivery of high doses of RT in smaller fractions using highly precise techniques 
therefore minimizing injury to surrounding hepatic parenchyma. Furthermore, cell death may be 
enhanced by causing vascular injury together with double-strand DNA breakage. 
SBRT for the treatment of unresectable HCC was first reported in 1995 and recent studies predominantly 
in patients with tumors < 6 cm have demonstrated high local control rates of 70 - 90% at 1-2 years.25-30 
In one study of 38 HCC patients previously treated with TACE, 33 – 57 Gy was delivered in 3 fractions, 
with a 61% 2 year survival.29 Doses > 42 Gy in 3 fractions were associated with improved local control. 
In another study of 48 patients with HCC treated 
with 3-fraction SBRT (30 – 39 Gy), 11% of patients had a decline in Child-Pugh class, which was more 
likely if less volume of liver was spared (<800 cc of liver receiving 18 Gy or more).31 Early studies in 
Japan have reported survival at 1 year of 99% and 100% in patients with small tumors treated with 
SBRT, suggesting a potential curative role in this select population.32,33 
 
In patients with more advanced HCC, SBRT has also been used successfully.  However, 
individualization of the SBRT dose is required to reduce the risk of toxicity.  Interestingly, even non-
ablative SBRT doses have been associated with long term control of the irradiated locally advanced 
HCC, and recanalization of the vascular HCC has been observed.34 Xi et al reported a 50% one year 
survival in 41 patients with vascular HCC following 30 – 48 Gy in 6 fractions.35  
 
An iso-toxic RT schedule that allows patients with HCC unsuitable for standard therapies to be treated 
in 6 fractions over two weeks using SBRT was developed at Princess Margaret Hospital (PMH), 
University of Toronto.36 The dose per fraction was determined based on the effective volume of normal 
liver irradiated (Veff), accounting for differences in dose per fraction. When the effective liver volume 
irradiated was low (Veff < 25%), doses of 54 Gy (9 Gy x 6) were delivered safely to HCCs, with 
excellent local control. For patients requiring higher volumes of liver to be irradiated (Veff 25-80%), 
doses from 24 to 54 Gy (4 to 9 Gy x 6) were delivered safely, although local control was reduced.  An 
analysis of the completed phase I and II Toronto SBRT studies of 102 Child-Pugh A HCC patients 
ineligible for local-regional therapies (38% Hepatitis B, 38% Hepatitis C, 25% alcohol; 55% portal vein 
thrombosis; 12% extrahepatic disease) treated with SBRT (median dose 36 Gy in 6 fractions) from 2004 
to July 2010 found a median survival of 17.0 months and 1 year local control rate of 87%. A dose 
response for local control was observed, with more sustained local control when 30 Gy in 6 fractions or 
more was delivered.34 No classic RILD was seen. However, a decline in Child Pugh score was seen in 
approximately 30% of patients 3 months following SBRT.  Factors significantly associated with toxicity 
were baseline Child Pugh score (A6 versus A5), lower baseline platelet count, mean liver (minus HCC 
volume) dose, and dose to 800cc of liver (minus HCC volume, D800cc). There was no toxicity if the 
mean liver dose (MLD) was < 18 Gy in 6 fractions and the D800cc was < 15 Gy in 6 fractions.37 In 
2012, at Princess Margaret Cancer Centre, a change from 6 fraction SBRT was made to 5 fraction SBRT, 
and 5 fraction SBRT is now our clinical standard of care and is the SBRT fractionation being tested in 
a phase III randomized trial (RTOG1112 - https://clinicaltrials.gov/ct2/show/NCT01730937).   
 


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In summary, although local control (including sustained stable disease) is likely with modest dose 
SBRT, even to large HCCs or those associated with vascular invasion, progression outside the irradiated 
volume is common following SBRT alone (PFS ~ 3-4 months), and there is rationale to combine SBRT 
with systemic therapies. 
 
2.2.3 Combination of SBRT and pembrolizumab 
 
There is significant biologic rationale for synergy between radiotherapy and immunotherapy, as SBRT 
may provide an immunologic “adjuvant” for use with checkpoint blockade.38,39 Early phase II data of 
combination ICI and radiation in melanoma are promising.40 Preclinical data suggests that higher doses 
per fraction, as used with SBRT, are more likely to induce an immune response and abscopal effect.41-
43 The abscopal effect has been seen in several tumor types, including renal cell carcinoma, melanoma 
and anecdotally in several patients with HCC.44-47 The combination strategy of ICI and SBRT in HCC 
has the advantage of inducing locoregional response in liver and vascular disease as well as targeting 
extrahepatic metastases. A recent orthotopic murine model of HCC has demonstrated the superiority of 
combination SBRT and anti-PD-1 blockade compared to either modality alone.48 Other pre-clinical 
models of combinations SBRT and immune checkpoint blockade have revealed similar results with the 
abscopal effect only elucidated when immunotherapy was added.43,49 A mouse model in GBM also 
evaluated sequence of treatment and a number of clinical studies have demonstrated both in field and 
abscopal responses to combination therapy.50-54 Although the most optimal sequencing of treatment is 
not clear, concurrent treatment appears superior in murine models.48,55,56 
 
There is no clinical experience with the combination of anti-PD-1 blockade and SBRT for liver cancer 
and limited experience with combined check point inhibitors and radiation therapy for any type of 
cancer. A retrospective study of 127 patients with melanoma treated with ipilimumab and local therapy 
reported better local control, survival and increased abscopal effects in patients treated with local therapy 
in addition to ipilimumab, with no increase in toxicity in patients treated with local therapies.57 The 
majority of patients received radiation therapy to the brain, the skin or lymph nodes, with 2 receiving 
radiation therapy to the liver.   
 
A phase III study of 799 patients treated with palliative radiation therapy (8 Gy in 1 fraction) for bone 
metastases from prostate cancer (CA184-043) reported grade 3/4 toxicity in 26% versus 3% in patients 
treated with radiation followed by ipilumumab or placebo respectively , consistent with reported toxicity 
from ipilumumab alone.58  In a phase I study of 35 patients treated with Ipilimumab and SBRT (50 Gy 
in 4 fractions), 2 patients treated with concurrent SBRT and ipilumumab developed dose limiting 
toxicity (grade 3 pancreatitis and lipase elevation); one patient with sequential ipilumumab and SBRT 
developed grade 3 increase in bilirubin and AST, and 12 of 35 patients (34%) had grade 3 toxicity (colitis 
in 4), slightly higher than reported grade 3 toxicity post ipilumumab alone (10 – 28%) with no grade 4 
or 5 toxicity observed.59 Clinical benefit was associated with increased peripheral CD8+ T cells, 
CD8+/CD4+ T cell ratio and proportion of CD8+ T cells expressing 4-1BB and PD-1.  There was greater 
T cell activation in patients receiving liver SBRT versus lung SBRT. Another small study of ipilimumab 
with SBRT in metastatic melanoma reported responses in 6 of 22 evaluable patients, and manageable 
toxicity with only 3 patients discontinuing treatment due to adverse events, and grade 3/4 toxicity in 
14% of patients.60 
   
In summary, there has not been a clear indication that toxicity is increased with the combination of 


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radiation and ICI, but there is a need for prospective data, especially in HCC. 
 
2.3 
Rationale 
 
As discussed above, there is significant interest in using immune checkpoint inhibitors in the treatment 
of hepatocellular carcinoma. In addition, the use of SBRT has shown promise in treating subjects with 
hepatocellular carcinoma. 
The combination of SBRT and immune checkpoint inhibition with pembrolizumab aims to capitalize on 
the local control effect of the radiotherapy by combining with a systemically-active agent to increase 
local response within the radiation field and control disease not encompassed by SBRT.  
Objective response rate has been chosen as the primary outcome measure for this study. Although 
overall survival (OS) is the gold standard for measuring efficacy of cancer treatment, measurement of 
radiographic response rate is considered an acceptable endpoint for phase II clinical trials, as an effective 
treatment is considered likely to result in a reduction in tumor size.61 The use of RECIST 1.1 in HCC 
has been problematic in subjects treated with anti-angiogenic therapy such as sorafenib, or treatments 
involving vessel embolization (transarterial chemo-embolization, transarterial radio-embolization, or 
bland embolization) but both PD-1 checkpoint inhibitors and SBRT have separately been associated 
with RECIST responses.24,34 iRECIST adapts RECIST to account for unique response kinetics seen 
following immunotherapy, by allowing for treatment beyond unconfirmed progression (iUPD) in 
clinically stable patients, where there after a response may be seen. New lesions are not counted as the 
sum of measurement (SOM), but are recorded separately and may be considered iUPD until 
confirmatory progression (iCPD) This is explained in further detail in Section 11.1.4. 
 
The selection of overall response rate includes the lesions treated with SBRT as well as systemic disease 
not included in the radiation volume. This composite response aims to evaluate the effect of the 
“treatment package” of pembrolizumab and SBRT, a paradigm in which the SBRT provides high rates 
of local control in the liver and the pembrolizumab controls systemic disease, and there is potential 
synergy and/or abscopal effect of using the two in combination. Assessment of response will be 
performed by a radiologist independent to the conduct of the study. Secondary endpoints will aim to 
measure the response in tumor lesions outside the SBRT field, an assessment of the abscopal effect 
described following radiotherapy. Additional secondary efficacy endpoints will include PFS and OS. 
2.4 
Correlative Studies Background 
 
2.4.1 Correlation between tumor genomic characteristics and response to therapy 
 
Introduction: Immune checkpoint inhibitors (ICIs) are an important novel class of anti-neoplastic agent 
that may act synergistically with radiation. Biomarkers predicting response to immune checkpoint 
inhibition and to the potential abscopal effect when combined with radiation are lacking. Thus, to benefit 
future subjects, we will seek to define novel predictive biomarkers of response. This will require a 
mandatory biopsy, consisting of 4 x core biopsies and blood samples to support genomic and immune 
correlative analyses.  
 
These will include but are not limited to: 
 


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Germline (blood) and tumor genomic analyses  
This research will evaluate whether genetic variation within a clinical trial population correlates with 
response to the combination treatment under evaluation. If genetic variation is found to predict efficacy 
or adverse events, the data might inform optimal use of therapies in the subject population. Furthermore, 
it is important to evaluate germline DNA variation across the genome in order to interpret tumor-specific 
DNA mutations. 
 
Next generation sequencing, has provided scientists the opportunity to identify tumor-specific DNA 
changes (i.e., mutations, methylation status, microsatellite instability etc.), mutational loads and specific 
genomic signatures that may influence response to ICIs, and also to SBRT. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific immune-related gene 
sets (such as those capturing interferon-gamma transcriptional pathways) may be evaluated and new 
signatures may be identified. Tumor DNA and RNA will be extracted from biopsies at diagnosis and 
banked for planned whole exome sequencing (WES) and whole transcriptome gene expression analysis 
by RNA sequencing. In patients consenting for a repeat biopsy at 3-6 weeks, tumor specimens will also 
be banked. This will be offered only when deemed safe by the PI. Specific signatures detected may 
inform responsiveness or resistance to ICIs, and using data from RNAseq it will be possible to evaluate 
gene signatures previously shown to be potentially predictive of response to pembrolizumab.62,63     
 
Blood analyses 
The analysis of circulating tumor DNA (ctDNA) appears to be feasible in early studies in HCC, and 
correlations of ctDNA may provide important insight into the timelines of response or non-response to 
immunotherapy and combination treatment.64 Circulating tumor DNA (ctDNA) will be measured at 
diagnosis, during SBRT, at 12 weeks and at time of disease progression (20ml per time point). The 
absolute concentration of ctDNA within peripheral blood plasma will be calculated from the aggregated 
tumor-specific reads and normalized to the total concentration of cell-free (cf) DNA. At these time points 
DNA methylation profiles in cfDNA will also be evaluated. Samples of cfDNA will be stored at -80C, 
to allow for potential future post-hoc quantitative analyses.  
 
PD-L1 Expression and Immunoscore 
Tumor samples from this study will be analyzed for percentage PD-L1 expression. PD-L1 protein level, 
as assessed by IHC in tumor sections, has been shown to correlate with response to pembrolizumab in 
subjects with NSCLC, and a PD-L1 IHC diagnostic is marketed for use with pembrolizumab in NSCLC. 
Preliminary data indicates that this association may also be true in additional cancer types (i.e., triple-
negative breast cancer, head and neck, and gastric). The burden of tumor infiltrating lymphocytes (TILs) 
may also predict response to ICIs and provide an ‘immunoscore’ which can prognosticate in HCC; 
densities of CD8, CD3, CD45R0 and PD-1 may also be assessed.65,66 
 
 
 
Cytokine analysis 
Predictors of the abscopal effect are of great interest but lacking. Documented rises in antibodies to 
melanoma specific tumor antigens have been reported and in HCC this the abscopal effect has correlated 
with a rise in TNF-alpha.44,50,53 Banked samples may be analyzed using electrochemiluminescence 
assays for dynamic changes in cytokines of interest as a biomarker predictive of the abscopal effect. 
These markers will be compared to gene expression profiles and mutational signatures ascertained from 
tissue analysis.  
 


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Imaging 
Diagnostic and radiation therapy imaging will also be investigated to explore whether imaging features 
are associated with molecular biomarkers or clinical outcomes.  
 
2.4.2 Optional future biomedical research 
 
As much remains unknown about genetic signatures and biomarkers in relation to disease response, any 
remaining samples from consenting patients will be banked for future biomedical research in order to 
give investigators the ability to further probe any notable results found during protocol-defined 
correlatives research. 
 
3. SUBJECT SELECTION 
 
3.1 
Inclusion Criteria  
 
In order to be eligible for participation in this trial, the subject must: 
 
3.1.1 
Be willing and able to provide written informed consent/assent for the trial. 
3.1.2 
Be  18 years of age on day of signing informed consent. 
3.1.3 
Have a histologically or cytologically confirmed diagnosis of hepatocellular carcinoma, 
and at least one measurable lesion as defined by RECIST 1.1/iRECIST. Otherwise 
eligible subjects, with a radiographic diagnosis of HCC, may be enrolled for screening, 
but histological confirmation is mandatory prior to initiation of study therapy. 
3.1.4 
Have current liver function meeting Child Pugh Class A (5-6 points), with no 
encephalopathy or ascites. Child Pugh status must be calculated based on clinical and 
laboratory results during the screening period. 
3.1.5 
Have intrahepatic HCC amenable to SBRT:  
 maximum 10 lesions to be treated, and  
 total tumor diameter to be treated <20 cm 
 No single liver tumor >15 cm in diameter 
 No evidence of common or main branch bile duct invasion 
 No evidence of direct tumor extension into stomach, duodenum, small bowel, large 
bowel or diaphragm 
 Smaller satellites of HCC or non-definite HCC need not be encompassed within 
SBRT volumes if needed to respect normal tissue limits.  
 
3.1.6 
Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior 
to initiation of treatment on Day 1. The subject must have a site of disease amenable to 
biopsy, and be a candidate for tumor biopsy. In addition, the subject must be willing to 
give blood for correlative studies, and have no contraindications to this. 
3.1.7 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 


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3.1.8 
Have demonstrated disease progression, after previous treatment with sorafenib or 
lenvatinib for advanced or metastatic disease, lasting a minimum of 8 week period, 
allowing for appropriate interruptions and dose reductions (i.e. second-line systemic 
therapy for advanced disease after failing 1st line tyrosine kinase inhibitor (TKI)) . 
Individuals who have discontinued sorafenib/lenvatinib for documented grade 3 or 4 
toxicity may be eligible for participation, provided disease progression has been observed 
since discontinuation of sorafenib/lenvatinib. Occasional subject may have been 
switched from sorafenib to lenvatinib early before progression due to intolerance and 
then at progression can be considered eligible having had 1 line of TKI to progression. 
3.1.9 
Have recovered (to ≤ grade 1) from prior toxicities related to previous treatments at the 
time of study enrollment, with the exception of alopecia or skin depigmentation. 
3.1.10 
Be tested for Hepatitis B-Virus surface antigen (HbsAg) status. HBV DNA is not 
mandated for subjects tested negative for Hepatitis B Virus. Subjects may be included in 
the study if they have adequately controlled hepatitis B, defined by: 
 receiving a nucleoside analog anti-viral drug for 4 or more weeks, and 
 serum hepatitis B virus (HBV) DNA level of less than 100 IU/ml via polymerase 
chain reaction quantification assays prior to enrollment. 
 in the case of subjects with known suppressed HBV viral DNA (<100 IU/ml) within 
3 months prior to study entry, 7 days nucleoside analog anti-viral drug prior to study 
inclusion is acceptable. 
 
3.1.11 
Be tested for Hepatitis C-Virus antibody (Anti-HCV) status. Subjects with HCV 
infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) 
or anti-HCV antibody) are allowed on study. In addition, subjects with successful HCV 
treatment (defined as sustained virologic response [SVR] 12 or SVR 24) are allowed as 
long as 4 weeks have passed between completion of HCV therapy and start of study 
treatment. HCV RNA is not mandated for subjects tested negative for Anti-HCV during 
screening.  
 
3.1.12 
Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 14 days of treatment initiation.   
Table 1:  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,200 /mcL 
Platelets 
≥50,000 / mcL 
Hemoglobin 
≥8 g/dL without transfusion or EPO dependency (within 7 days 
of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥50 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 34 umol/l 
AST (SGOT) and ALT (SGPT) 
≤ 5 X ULN  


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Albumin 
>25 g/L 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
 
3.1.13 
Women of child-producing potential must agree to use effective contraceptive methods 
prior to study entry, during study participation, and for at least 30 days after the last 
administration of study medication. A serum pregnancy test within 72 hours prior to the 
initiation of therapy will be required for women of childbearing potential. Men treated or 
enrolled on this trial must agree to use adequate contraception prior to and for 4 months 
after completion of pembrolizumab administration. 
 
 
Highly effective contraception methods include:  
• Total abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception  
• Male or Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment  
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject.  
• Combination of any two of the following (a+b or a+c, or b+c):  
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception  
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)  
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository  
 
In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment.  
Note: Female subjects of childbearing age are defined as follows:  
 
• Subjects with regular menses  
 
• Subjects, after menarche with amenorrhea, irregular cycles, or using a contraceptive 
method that precludes withdrawal bleeding  
 
• Women who have had tubal ligation  
 
Female subjects may be considered to NOT be of childbearing potential for the following 
reasons:  


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• The subject has undergone total abdominal hysterectomy with bilateral salpingo-
oophorectomy or bilateral oophorectomy  
 
• The subject is medically confirmed to be menopausal (no menstrual period) for 24 
consecutive months  
 
• Pre-pubertal females. The parent or guardian of young female subjects who have 
not yet started menstruation should verify that menstruation has not begun. If a young 
female subject reaches menarche during the study, then she is to be considered as a 
woman of childbearing potential from that time forward.  
 
 
3.2 
Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
3.2.1. 
Has received any second-line systemic therapy for advanced HCC after disease 
progression following sorafenib/lenvatinib therapy, or has had prior radiotherapy to the 
proposed treatment field (at the discretion of the Principal Investigators). 
3.2.2. 
Is currently participating and receiving experimental treatment as part of a clinical trial, 
or has participated in a study of an immune checkpoint inhibitor and received study 
therapy, or used an investigational device within 4 weeks of the first dose of treatment. 
3.2.3. 
Has had a previous solid organ transplant, a diagnosis of immunodeficiency, or is 
receiving systemic steroid therapy or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment. 
 
3.2.4. 
Has liver tumor not amenable to SBRT, as per 3.1.5 above, or has had prior upper 
abdominal radiation therapy within planned volumes (exceeding standard tolerances). 
3.2.5. 
Has a histological or cytological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or 
mixed cholangiocarcinoma-HCC. 
 
3.2.6. 
Has had prior radioembolization or other selective internal radiotherapy treatment to the 
liver.  
 
3.2.7. 
Has dual active HBV infection (HBsAg (+) and/or detectable HBV DNA) and HCV 
infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry. 
 
3.2.8. 
Has had esophageal or gastric variceal bleeding within 3 months prior to study 
enrollment. 
 
3.2.9. 
Has had encephalopathy in the past 6 months, or has clinically apparent ascites at the 
time of study enrollment. 
 
3.2.10. 
Has a known history of active TB (Bacillus Tuberculosis). 
 


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3.2.11. 
Hypersensitivity to pembrolizumab or any of its excipients. 
 
3.2.12. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
1 week prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
3.2.13. 
Has a known history of prior invasive malignancy except if the subject has undergone 
curative-intent therapy with no evidence of disease recurrence for 2 years prior to study 
entry.  Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, superficial bladder cancer, low-risk prostate cancer or in situ cervical cancer. 
3.2.14. 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
3.2.15. 
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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy at a dose of ≤ 10 mg/day of prednisone or equivalent) is not considered a form 
of systemic treatment.  
3.2.16. 
Has known history of, or any evidence of active, non-infectious pneumonitis/interstitial
 
lung disease. 
3.2.17. 
Has an active infection requiring systemic therapy. 
3.2.18. 
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 investigator.   
3.2.19. 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.2.20. 
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 


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3.2.21. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
3.2.22. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
3.2.23. 
Has alcohol related or non-alcoholic steatohepatitis (NASH) related cirrhosis.  
 
3.2.24. 
Has had a history of significant active or unstable heart disease  
3.2.25. 
Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of
 
study therapy. Administration of killed vaccines is allowed. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. This study is designed to 
include minorities as appropriate. However, the trial is not designed to measure differences in 
intervention effects. The population of Southern Ontario is ethnically diverse and the proportion of 
different ethnic groups in the community is provided in the table below. Universal access to health 
care will ensure that there is no discrimination on the basis of race or gender (Guide to Canadian 
Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf). Individual hospital registries and 
databases do not routinely collect racial data, under the direction of the Canadian Human Rights Code. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The Central Office Coordinator at the Drug Development Program Central Office will enter eligible 
subjects on study centrally. All sites should call the Central Office Coordinator (listed on cover page) 
to verify dose level availabilities. The required forms (Registration Checklist) will be provided upon 
site activation.   
 
Following registration, subjects should begin protocol treatment within 7 days.  Issues that would cause 
treatment delays should be discussed with the Principal Investigator (cc the Central Office 
Coordinator). If a subject does not receive protocol therapy following registration, the subject’s 
registration on the study may be cancelled. The Central Office Coordinator should be notified of 
cancellations as soon as possible.   
 
4.2 
Registration Process 
 
Prior to registering a subject, each institution must have submitted all necessary regulatory 
documentation to the Drug Development Program Central Office. The registration checklist will only 
be sent once this has been received.   
 
No subject can receive protocol treatment until registration with the Central Office has taken place.  
All eligibility criteria must be met at the time of registration. There will be no exceptions. Any 
questions should be addressed with the Central Office prior to registration.   
 
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manager and sent / faxed to the Central Office Coordinator: 
• 
Signed subject consent form 
• 
Registration Checklist CRF signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility has 
been confirmed: 
• 
Assign a subject study number 
• 
Assign the subject a dose 
• 
Register the subject on the study 
• 
Fax or e-mail the confirmation worksheet with the subject study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
Central Office Coordinator listed on the front sheet. Subject registration will be accepted between the 
hours of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central office 
will be closed. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Appropriate dose delays and management of 
adverse events are described in Section 6. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the subject's malignancy. 
 
Regimen Description 
Agent 
Dose 
Route 
Schedule 
Pembrolizumab 
200 mg 
IV over 30 minutes 
Every 3 weeks 
SBRT administered to dominant hepatic HCC 
Starting day 2 of cycle 1 
pembrolizumab, given in 5 
fractions over 5-15 days 
 
5.1.1 Pembrolizumab Dose Selection 
 
The rationale for selection of the dose to be used in this trial is provided in Section 2.2.1.3 Rationale for 
Dose Selection.   
5.1.1.1 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed in the STUDY CALENDAR (Section 10). Trial treatment may be 
administered up to 1 day before or 3 days after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 
All trial treatments will be administered on an outpatient basis. 


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In general, toxicities from previous cycles of treatment should have returned to Grade 0-1 before the 
next dose of study medication (see Section 6.1 for specific guidance). Pre-existing Grade 2 toxicities, 
which did not result in exclusion from the trial, (for example, liver transaminase abnormalities) should 
be stable. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Every effort 
should be made to target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
 
5.1.2 Stereotactic Body Radiotherapy (SBRT) Dosing and Scheduling  
 
All the definite HCC with vascular invasion should be treated by SBRT when safe, up to a maximum of 
10 lesions and total diameter of ≤20 cm. However, extrahepatic HCC, all satellites of HCC and non-
definite HCC need not be encompassed within the irradiated volumes, especially if normal tissue dose 
limits cannot be met.  
Treatment will be delivered in 5 fractions. The time between fractions should be between 24 and 72 
hours, with treatment delivered to all targets over 5 to 15 days (starting on day 2, as per the schema). 
The preferred inter-fraction interval is 24 hours, with the exception of when luminal OARs are at their 
maximal dose, when it is preferred that the first two fractions are to be delivered on day 2 and 3 and 
other fractions every other day. All lesions may be treated on the same day, or alternative lesions may 
be treated on alternate days, as long as the overall treatment time is 15 days at maximum. 
 
5.1.2.1 
Prescription Dose 
 
Absorbed dose: 27.5 Gy - 50 Gy in 5 fractions. The prescription dose may be 50 Gy, 45 Gy, 40 Gy, 35 
Gy, 30 Gy or 27.5 Gy in 5 fractions, based on normal tissue constraints. The dose to multiple PTVs may 
be different. The goal is to use the highest allowable prescription dose to the primary target, while 
respecting normal tissue constraints. The minimal planned prescription dose to PTVs is 27.5 Gy. 
Given the novelty of this combination, and the potential for overlapping hepatic toxicity, the first 10 
patients will have to meet all the following additional liver dosimetric constraints: 
1) Mean liver (minus gross HCC tumor volume) dose < 15 Gy in 5 fractions. 
2) D800cc ≤ 18 Gy in 5 fractions 
3) Biologically corrected normal tissue complication probability (NTCP) < 0.5% 
 
If 2 or fewer patients of the first 10 patients experience grade 3 hepatic toxicity at this dose, we will 
increase to standard dosing. If 3 or more patients experience grade 3 toxicity, or if any patients 
experience grade 4/5 toxicity in first 3 months following SBRT, these dose constraints will be 
maintained for all patients on study and modification of all SBRT dose constraints will be considered. 
 
 


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5.1.2.2 
Dose Specifications 
 
The prescription isodose should encompass 95% of PTV. The dose to multiple PTVs within the same 
patient may vary. If there are multiple PTVs, each should be planned for one of the prescription doses 
listed above, with each specific covering isodose planned to encompass 95% of each PTV, with 
normalization to the PTV receiving the highest dose. The highest allowable doses to the target volumes 
that maintain normal tissue constraints should be used. A goal is that 100% of the CTV is encompassed 
by the prescription dose. The unit of dose is Gy. 
 
5.1.2.3 
Dose Prescription 
Is based on the volume of normal tissues irradiated (correlated with mean liver dose), as well as 
proximity of stomach, duodenum, small and large bowel (GI luminal structures) to the target volumes, 
as normal tissue constraints must be maintained in this study.  
 
In the absence of adjacent GI luminal structures that may limit dose, the PTV dose prescription should 
be as high as possible based on mean liver dose (MLD, defined as the mean dose to the liver minus all 
GTVs), with 6 potential dose levels.  Note, no variations in mean liver dose are permitted.  
 
Table 2: SBRT Dose Prescription 
 
Priority 
Constraint 
Prescription Dose 
Allowed MLD 
(Gy)* 
Planned 
Prescription Dose 
(Gy) 
If the max allowed MLD in exceeded at this 
planned dose 
13.0 
50 
Reduce to 45 Gy and re-evaluate 
15.0 
45 
Reduce to 40 Gy and re-evaluate 
15.0 
40 
Reduce to 35 Gy and re-evaluate 
15.5 
35 
Reduce to 30 Gy and re-evaluate 
16.0 
30 
Reduce to 27.5 Gy and re-evaluate 
17.0 
27.5 
Ineligible 
*< 15.0 Gy for the first 10 patients, regardless of prescription dose 
 
 Vascular tumor thrombosis (e.g., portal vein thrombosis) dose should be treated to the same 
dose as the parenchymal HCC. However, lower doses are acceptable if required to maintain 
normal tissue limits, since the cancer density may be lower than parenchymal HCC. Non-
tumor bland thrombosis is strongly recommended to NOT be irradiated, to reduce the overall 
volume irradiated. 
 Maximum dose within PTV = 150%. If multiple PTVs exist, 150% of the maximal PTV 
prescription dose is permitted for all PTVs.  Concomitant boost to the GTV to 1-2 dose levels 
above the prescription dose are recommended, and it is desirable to have a hot spot of at least 
40 Gy in the GTV if possible. 


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 Maximum dose outside PTV = 120% of the maximal PTV prescription. 
 Efforts should be made to keep the prescription dose and the 30Gy isodose as conformal as 
possible. 
 Different isodoses may cover different PTVs. If multiple PTVs, the MLD should be 
evaluated with the prescription dose corresponding to the highest dose level that any PTV is 
treated. Queries should be directed to the study PI. 
5.1.2.4 
Technical Factors 
 
Megavoltage equipment with photons of at least 6MV, capable of daily image guidance, with a multileaf 
collimator for intensity modulation is required. Inverse-planned IMRT, forward planned IMRT and 
volumetric modulated arc therapy (VMAT) are to be used for planning. CT based planning is required, 
with a minimum of 5 beam angles. Image guided radiation therapy (IGRT) is mandatory. Breathing 
motion management is recommended if breathing motion is > 5 mm. Breathing motion assessed on 
4DCT and adequately treated with PTV margins < 20mm is permitted.  
 
5.1.2.5 
Localization, Simulation and Immobilization 
 
Custom immobilization is recommended (e.g. With vacuum immobilization, patient positioning boards, 
knee cushions, and/or breath hold immobilization with active breathing control). 
 
Treatment planning CT scans will be required to define GTV. Multi-phasic IV contrast is 
recommended for the planning CT (arterial phase and/or delayed phase imaging recommended for GTV 
delineation, and venous phase for portal vein thrombosis delineation).  
 
Exhale breath hold CT or average phase CT (from 4D CT) may be used as the baseline CT for radiation 
therapy planning. CT scans obtained during free breathing may not be used for planning. CT scans used 
for target delineation are recommended to be multi-phase IV contrast scans obtained in exhale breath 
hold. Exhale breath hold is preferred as it most often is closer to the average position than inhale breath 
hold, and exhale is more reproducible than inhale. If IV contrast scans cannot be obtained at the time of 
radiation planning, IV contrast CT scans from diagnostic radiology may be fused to the primary planning 
dataset to aid in target definition. If contraindications to IV CT contrast exist, IC contrast multiphase 
MR can be used to help define GTV. Diagnostic MR imaging can be imported to the planning system 
to aid in target delineation. 
 
All scans used for target delineation should be fused to each other so that the livers are 
registered to each other for target delineation. Registration will be performed with the best fit liver-to-
liver image registration, focusing on the region of the PTVs if deformation or rotation occurs between 
scans.  
 
Breathing motion assessment. Measurement of target/liver breathing motion is required, unless breath 
hold is to be used for liver immobilization. Motion may be assessed using 4D CT, fluoroscopy and/or 
cine MR. 
 


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4D CT: A 4D, or respiratory sorted, CT may be obtained for assessing motion if breath hold is not used 
for liver immobilization. 
 
All patients will have image guidance at the time of each radiation fraction.  Cone beam CT is the 
preferred image guidance. 
 
5.1.2.6 
Treatment Planning/Target Volumes 
 
The Gross Tumor Volume (GTV) is defined as all suitable parenchymal and vascular HCC 
visualized on contrast enhanced CT and/or MRI, most often best seen on arterial phase (as 
hyperintensity) and/or venous or delayed phase (as hypointensity relative to liver). GTVp1 should 
represent the ‘primary parenchymal (=p) dominant (=1)’ GTV, upon which primary QA will be based. 
Subsequent lesions can be labeled as GTVp2, GTVp3, GTVp4 and GTVp5). If ‘p’ is not included 
following “GTV”, the lesion will be assumed to be parenchymal. Vascular HCC thrombi (GTVv) most 
often are best seen on venous phase imaging as hypointensity relative to the contrast in the vessel. 
Vascular HCC may be combined with parenchymal HCC (labeled as GTVp or GTVpv) if they are to be 
treated to the same dose. 
Non-tumor thrombi should not be considered as GTV; they should be excluded from contouring 
The prescription dose should be annotated to each GTV after the final plan is complete (e.g. GTVp1_50 
for a 50Gy target). 
 
For each GTVp, the Clinical Target Volume (CTV) is defined as the GTV (CTVp1…CTVp5), with 
no expansion. The minimal CTVv is the GTVv, with no expansion. It is expected that there will be no 
expansion from GTV to CTV for the majority of cases. However, CTV expansions to include regions 
at high risk for microscopic disease, including non-tumor vascular (v) thrombi (CTVv), prior TACE (t) 
sites (CTVt), or adjacent RFA (r) (or other ablation) sites (CTVr) are permitted if judged to be at high 
risk of recurrence. Such CTVs may be treated to a microscopic dose (27.5 Gy) or up to as high as the 
prescription dose, at the investigator’s discretion. Separate CTVs should be labeled CTVp1, CTVv2, 
CTVv3, CTVt4…etc. The prescription dose should be annotated to each CTV after the final plan is 
complete (e.g. CTVp1_50 for a 50Gy target, and CTVt2_27.5 for a CTV treated to 27.5 Gy). 
 
The Planning Target Volume (PTV) will provide a margin around each CTV to compensate for set-
up and internal organ motion. PTV nomenclature should follow CTV nomenclature guidelines. For 
example, PTVv for the PTV around the CTVv and PTVp1 and PTVp2 for PTVs around CTVp1 and 
CTVp2. A minimum PTV margin of 4 mm around each CTV is required in all directions (for example 
if active breathing control is used with excellent reproducibility). The maximum permitted PTV margin 
is 20 mm, expected to be used uncommonly. PTV margins ≤ 10 mm are a goal. Asymmetric PTV 
margins are permitted. The actual PTV used will depend on motion management used, the patients’ 
motion and reproducibility. PTVs should not be manually modified due to proximity of adjacent 
organs at risk (OARs). The final PTVs should have dose annotated once the plan is final, e.g. 
PTVp1_50 and PTVv1_27.50 for targets treated to 50 Gy and 27.5Gy, respectively. 
 
Standard target and organ at risk nomenclature will be used. 
 
Heterogeneity Corrections: All dose distributions shall include corrections for tissue heterogeneities. 
Arterial vascular contrast from the planning dataset is recommended to be converted to water equivalent 


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density if used for planning. Planning datasets without intravenous contrast may be used for planning.  
 
Planning target volumes around luminal GI tissues are encouraged so that the steepest dose gradients of 
doses higher than the maximal allowable luminal GI doses are outside the PRV.  PRV magnitude will 
be individualized based on an estimate of expected change day-today (5 mm to 30 mm). 
 
Goals of planning are to maximize dose to the target volumes, while maintaining all normal tissue 
constraints (as defined below). Reducing the maximal dose and lower dose ‘bath’ to all luminal 
gastrointestinal normal tissues should be a planning priority to reduce the risk of gastrointestinal 
toxicity. Conformality of the prescription dose and the 30 Gy isodose are other goals. 
 
Critical Structures Maximal Doses  
Dose values in this section should be read as physical dose in 5 fractions. Note these doses have been 
modestly reduced from our present standard, with the goal of reducing the risk of toxicity. 
 
Esophagus max (to 0.5 cc):   
30 Gy 
Stomach max (to 0.5 cc):  
 
29 Gy 
Duodenum max (to 0.5 cc):   
29 Gy 
Small bowel max (to 0.5 cc):   
29 Gy 
Large bowel max (to 0.5 cc):   
30 Gy 
Cord + 5 mm max (0.5cc):  
 
25 Gy 
Kidneys: Bilateral mean dose          < 10 Gy 
-OR-  
If there is one kidney mean dose > 10Gy, remaining (or only) kidney V10Gy < 10% 
 
The following organ dose constraints are strongly advised to be met, but are not mandatory: 
Stomach (to 5 cc):  
 
 
< 25 Gy 
Duodenum (to 5 cc):   
 
< 25 Gy 
Small bowel (to 5 cc):  
 
< 25 Gy 
Liver minus all GTVs:  
 
>700cc and D800cc ≤ 18 Gy 
Heart max (30cc):  
 
 
< 30 Gy 
Skin (external) max (0.5 cc):   
< 32 Gy 
Chest wall max (0.5 cc):  
 
< 50 Gy 
Gallbladder max (0.5 cc):  
 
< 55 Gy 
Common bile duct max (0.5 cc)  
< 50 Gy*  
 
*Even though the bile duct is not often well visualized, it is always within the portal region and may be 
within high dose volumes for central targets, so efforts to reduce hot spots in this region are warranted. 
 
Peer review of all SBRT plans is required prior to starting SBRT (either one-on-one or at GI or SBRT 
quality assurance rounds) by another radiation oncologist. 
 
Treatment Interruptions 
Treatment interruptions should be clearly documented in the patient’s treatment record. Total 
treatment time is recommended to be 10 days, with allowable total duration between 5 days and 15 days. 
 


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Total Treatment Duration 
Per protocol: All treatment falls within 15 calendar days 
Variation Acceptable: All treatments fall within 16 to 21 calendar days 
Deviation Unacceptable: All treatments that take 22 or more calendar days to complete 
 
PTV Dosimetry 
Target coverage for each PTV should be considered on its own. If there are multiple tumors, the primary 
(dominant) PTV should be labeled #1. The intent is for prescription dose to cover 95% of each PTV. 
If PTVs are not treated as per guidelines, this is a deviation unacceptable. The PTV should be treated to 
as high a dose as possible, respecting normal tissue constraints, as a dose response has been observed. 
Modifying required PTVs due to close proximity of adjacent OARs is not permitted. 
 
The following Table 3 describes variations and deviations in the prescription dose (dose covering 95% 
of the PTV). Treating “per protocol” should always be the planning intent. 
 
Table 3: Variations and Deviations in Prescription Dose 
 
Dose to 95% PTV 
PTVs around GTVs* 
PTVs around non-GTV CTVs* 
Per protocol 
Prescription dose +/- 5% 
Prescription dose +/- 5% 
Variation acceptable 
90-95% or 105-110% of 
prescription dose, and ≥ 25 Gy 
90-95% or 105-110% of 
prescription dose, and ≥ 25 Gy 
Deviation unacceptable 
<90% or >110% of prescription 
dose, or < 25 Gy 
<90% or >110% of prescription 
dose, or < 25 Gy 
Overall plan deviation 
unacceptable 
< 25 Gy 
 
*Note that lower doses than the dose-allocation schedule are acceptable if they are required due to 
adjacent luminal GI structures that may limit the deliverable dose. 
 
Compliance for Critical Structures (organs at risk, OARs) 
If non-hepatic OARs limit the prescription dose, the highest dose (from the 6 prescription doses listed 
in Table 2 above) should be used, while maintaining OAR dose constraints. 
 
Table 4: Variations and Deviations due to Organs at Risk 
 
Non-liver OARs 
Per protocol 
Variation acceptable 
Deviation unacceptable 
Esophagus max (to 0.5 cc): 
Stomach max (to 0.5 cc): 
Duodenum max (to 0.5 cc): 
Small bowel max (to 0.5 cc): 
Large bowel max (to 0.5 cc): 
SpinalCord_05 + 5 mm max (0.5cc): 
Kidneys: Bilateral mean dose 
30 Gy 
29 Gy 
29 Gy 
30 Gy 
30 Gy 
25 Gy 
≤10 Gy 
> 30 but ≤34 Gy 
>29 but ≤32 Gy 
>29 but ≤32 Gy 
>30 but ≤32 Gy 
>30 but ≤34 Gy 
>25 but ≤28 Gy 
>10 but ≤12 Gy 
> 34 Gy 
> 32 Gy 
> 32 Gy 
> 32 Gy 
> 34 Gy 
> 28 Gy 
> 12 Gy 
 
Table 5: Acceptable & Unacceptable Dose Deviations 
Prescription Dose 
Liver (minus GTV) mean dose 
Per protocol (acceptable) 
Deviation (unacceptable) 
50 Gy 
45 Gy 
40 Gy 
35 Gy 
≤13 Gy 
≤15 Gy 
≤15 Gy 
≤15.5 Gy 
> 13 Gy 
> 15 Gy 
> 15 Gy 
> 15.5 Gy 


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30 Gy 
27.5 Gy 
≤16 Gy 
≤17 Gy 
> 16 Gy 
> 17 Gy 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Initiation of Proton Pump Inhibitors (PPIs) prior to starting SBRT should be considered for subjects 
whose treatment plan will contain significant volumes of stomach or duodenum. In these patients, non-
steroidal anti-inflammatory drugs should be avoided where possible. 
  
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy not specified in this protocol for the treatment of HCC. See Section 5.3.2 for 
details on radiotherapy for oligoprogressive disease 
 Live vaccines within 30 days prior to the first dose of trial treatment 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 the following: 
o To modulate symptoms from an event of clinical interest of suspected immunologic 
etiology  
o Physiologic doses of prednisone 10 mg (or equivalent) per day  
o Inhaled steroids for management of asthma 
o Use of prophylactic corticosteroids to avoid allergic reactions (e.g., IV contrast day) 
o Topical steroids for management of skin reactions 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describe other medications which are prohibited in this trial.  
 
Any other medication which is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator.   
 
5.3 
Duration of Therapy 
 
In the absence of treatment delay / discontinuation due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
 Confirmed disease progression by iRECIST, as defined by Section 11.1.4 
 Clinical evidence of disease progression, in the opinion of the Investigator, such that 


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continuing treatment would not be beneficial for the study subject. Note that further SBRT may 
be considered for oligoprogressive disease as per Section 5.3.2, and re-challenge with 
pembrolizumab may be considered in circumstances listed in Section 5.3.1. 
 Women who become pregnant or are breastfeeding  
 Sexually active subjects who refuse to use medically accepted forms of barrier contraception 
(e.g. male condom, female condom) during the study  
 Termination of the protocol by a regulatory agency or Sponsor, or study medication can no 
longer be provided 
 Significant non-compliance with the protocol schedule in the opinion of the investigator 
 Subjects requiring a delay in treatment beyond the allowed timeframe. 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event as defined in Section 7 
 Subject decides to withdraw from the study 
 General or specific changes in the subject's condition which render the subject unacceptable for 
further treatment in the judgment of the investigator. 
 Necessity for treatment with another anti-cancer treatment prohibited by this protocol 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of 
study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. 
5.3.1 Retreatment with Pembrolizumab 
Subjects who stop pembrolizumab with SD/iSD or better may be eligible for up to one year of additional 
pembrolizumab therapy if they progress after stopping study treatment. This retreatment is termed the 
Second Course Phase of this study and is only available if the study remains open (accrual may be 
completed, but patients still in follow-up) and the subject meets the following conditions: 
 
Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-determined 
confirmed CR/iCR according to RECIST 1.1/iRECIST, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy 
 Received at least two treatments with pembrolizumab beyond the date when the initial 
CR/iCR was declared 
 
 
OR 
 
o Had SD/iSD, PR/iPR or CR/iCR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
AND 
 
 Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab 


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 Did not receive any anti-cancer treatment since the last dose of pembrolizumab, except for SBRT 
to oligoprogressive lesion (see Section 5.3.2) 
 Has ECOG performance status of 0 or 1 
 Demonstrates adequate organ function as listed in Inclusion Criteria (Section 3.1) 
 Female subjects of childbearing potential should have a negative serum or urine pregnancy test 
within 72 hours prior to receiving retreatment with study medication.   
 Female subjects of childbearing potential should be willing to use 2 methods of birth control or 
be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 
days after the last dose of study medication. Subjects of child bearing potential are those who 
have not been surgically sterilized or have been free from menses for > 1 year.  
 Male subjects should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.   
 Does not have a history or current evidence of any condition, therapy, or laboratory abnormality 
that might 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 investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when they last 
received pembrolizumab. Treatment will be administered for up to one additional year. 
 
5.3.2 SBRT to Oligoprogressive lesions 
It has been observed that patients with overall stable or responding disease may develop a small number 
of new or progressive tumor deposits during active treatment. Such patients are likely to benefit from 
continuing on study treatment, and may be eligible for additional SBRT to these lesions if the following 
criteria apply: 
 Excepting the oligoprogressive lesions, the best overall response is SD/iSD, PR/iPR or CR/iCR 
by RECIST 1.1/iRECIST 
 The oligoprogressive lesions has been noted at the second or later CT assessment of disease 
 5 or fewer progressive or new lesions are noted 
 The patient has evidence of ongoing clinical benefit – no deterioration in clinical or laboratory 
parameters suggestive of overall worsening of disease or clinical condition 
 The oligoprogressive lesions are amenable to SBRT – not within previous SBRT field, and 
SBRT can be delivered with an acceptable safety profile in the opinion of the Investigator. This 
includes extrahepatic HCC and selected intrahepatic HCC (if the estimates cumulative dose to 
the liver is within specified dose limits) 
 
Patients with oligoprogressive lesions that fit the above criteria may be eligible for further SBRT, and 
should be discussed with the Principal Investigator/Sponsor. 


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5.4 
Duration of Follow Up 
 
Subjects removed from therapy for reasons other than progressive disease/iCPD will be followed at 
intervals of 90 days (±14 days) for disease status until progression or initiation of alternative therapy. 
Follow-up visits can occur remotely via telephone, Ontario Telemedicine Network (OTN), or other 
appropriate virtual communication if it is in patient’s best interest, at the discretion of the Investigator.  
Subjects who withdraw for refusal will no longer be followed. All subjects will be followed for survival 
every 90 days (±14 days) for survival status until death via telephone, in-person visit, or via medical 
records. 
 
Table 6: Follow-up Guideline 
* Confirmed disease progression (iCPD) is defined according to iRECIST. 
** See section 7.6 for Adverse Event Follow-Up details 
 
5.5 
Criteria for Removal from Study 
 
Subjects will be removed from study when any of the following criteria applies:  
 Death 
 Withdrawal of consent 
 Lost to follow-up 
 Sponsor-Investigator termination of the study 
 Termination of the study by a regulatory body 
 
The reason for study removal and the date the subject was removed must be documented in the Case 
Report Form. 
 
 
 
 
 
Follow-Up Period 
Off Treatment 
Visit: 4 weeks ± 7 
days from the End 
of Study Drug 
Administration 
Progression 
Follow-Up: every 
3 months ± 14 days 
after the Off 
Treatment Visit * 
Adverse Event 
Follow-Up: until 
resolution or 
stabilization of 
adverse event(s) 
Survival Follow-
Up: every 3 
months ± 14 days 
after the Off 
Treatment Visit 
Reason Subjects 
Removed from study 
Objective Disease 
Progression 
X 
 
X 
X 
Clinical Progression/ 
Symptomatic 
Deterioration 
X 
X 
X 
X 
Adverse Events  or 
clinically significant lab 
value 
X 
X 
X (weekly FU for 
4-weeks, then 
monthly) 
X 
All other subjects 
X 
X 
X 
X 


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6. DOSING DELAYS/MODIFICATIONS AND TOXICITY MANAGEMENT 
 
6.1 
Pembrolizumab Dose Modification 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology. These adverse events may occur shortly after the first dose or several months 
after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe 
or life-threatening AEs as per Table 7 below. See Section 5.2 for supportive care guidelines, including 
use of corticosteroids.  
Table 7: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated 
with Pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced 
to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE 
does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-
related AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 


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Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
or equivalent) 
followed by taper 
 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
 
Participants with diarrhea/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. 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold1 
 Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
 Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2, 3 or 4 
Continue  
 Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis  
Grade 2 
Withhold  
 Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 


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equivalent) 
followed by taper. 
Neurological 
Toxicities 
Grade 2 
Withhold  
 
Based on severity 
of AE administer 
corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1  
Withhold 
 Based on severity 
of AE administer 
corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
 Based on severity 
of AE administer 
corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
 Based on type and 
severity of AE 
administer 
corticosteroids  
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
NOTE:  
1. For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy 
or achieved metabolic control (in case of T1DM).   
2. Non-irAE will be managed as appropriate, following clinical practice recommendations. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 4 weeks of the scheduled cycle day 
1 delay, unless otherwise discussed with the Sponsor. The reason for interruption should be documented 
in the patient's study record. 
Subjects experiencing a toxicity requiring a dose interruption may be eligible for rechallenge if the above 
criteria are met, at the discretion of the treating investigator. A subject who experiences a recurrence of 
the same toxicity at the same grade or higher should permanently discontinue pembrolizumab. 


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6.2 
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest (ECIs) 
 
In addition to overdose, hepatic ECIs will include any of the following events. All of these events will 
require holding pembrolizumab treatment and notification of the Sponsor within 24 hours. Refer to 
Section 7 for reporting guidelines. 
All cases of retreatment and permanent discontinuation must be reported to the Sponsor and recorded in 
the database. 
 
a) ALT: 
i) Among subjects with baseline ALT <2×ULN: ALT ≥5×ULN 
ii) Among subjects with baseline ALT ≥2×ULN: ALT >3× the baseline level 
iii) ALT >500 U/L regardless of baseline level 
(Subjects with ALT >5×ULN at baseline are not eligible for enrollment) 
 
b) AST: 
i) Among subjects with baseline AST <2×ULN: AST ≥5×ULN 
ii) Among subjects with baseline AST ≥2×ULN: AST >3× the baseline level 
iii) AST >500 U/L regardless of baseline level 
(Subjects with AST >5×ULN at baseline are not eligible for enrollment) 
 
c) Total Bilirubin: 
i) Among subjects with baseline levels <22 umol/L: a value of >34 umol/L 
ii) Among subjects with baseline levels that are ≥22 umol/L: a value ≥2× the baseline level 
iii) Total bilirubin >51 umol/L regardless of baseline level 
(Subjects with total bilirubin >34 umol/L at baseline are not eligible for enrollment) 
 
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 
(Subjects with clinically apparent ascites or encephalopathy, or untreated varices at baseline 
are not eligible for enrollment) 
 
Immediate assessment 
All subjects 
 All subjects should be evaluated according to directions below within 72 hours of alert for non-
overdose ECI 
 Procedures: 
o Obtain an opinion from a hepatologist 
o Obtain a work-up for hepatitis if there is no underlying hepatitis, including hepatitis A, 
B, C, D, Epstein-Barr virus serology, and cytomegalovirus serology 


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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, bilirubin, ALP, INR, and CBC 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, anti-HBs, HbeAg and anti-Hbe 
 Subjects 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 
 CP score of ≥9 points 
 Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal or gastric varices) 
 New onset of clinically detectable ascites that cannot be managed with appropriate treatment 
 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 subjects may be eligible for treatment interruption (and potential re-start) of 
pembrolizumab after discussion with the Sponsor. 
 
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). This is accompanied (or 
preceded) by a detectable rise in HBV viral DNA in serum. An episode of elevated transaminases 
without increase in HBV DNA is not attributable to a viral flare. 
 
Among subjects with HBV, a flare should be considered if this pattern is observed and there is no 
evidence of an alternative etiology. Guidelines for subjects with a diagnosis of HBV flare are as follows: 
 Care should be instituted in consultation with a hepatologist. 
 For subjects who have detectable HBV DNA, re-institute anti-viral therapy. 


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 If the subject is clinically stable, pembrolizumab dosing may be interrupted for up to 12 weeks. 
Subjects should undergo weekly laboratory tests including: AST, ALT, ALP, bilirubin, 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 subjects are clinically stable, subjects may restart pembrolizumab 
treatment. If these conditions are not met, then pembrolizumab treatment should be permanently 
discontinued.  
 
b. Hepatitis C Recurrence or Flare 
Subjects who achieved sustained viral remission for 12 months (SVR 12) and subjects with ongoing 
HCV infection are eligible for enrollment. In rare circumstances, HCV subjects who achieve SVR 12 
may relapse at later time points. Relapse is characterized by detection of HCV RNA, often accompanied 
by ALT elevations to >5×ULN. In the absence of hepatic decompensation, ALT/AST elevations are 
typically isolated (i.e., limited/no elevations of bilirubin/ALP).  
 
Among subjects 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 subjects with recurrent HCV infection or an HCV flare are described below: 
 
1) Recurrent HCV infection: 
If the subject entered the study with undetectable HCV RNA, and has confirmed detectable HCV RNA 
(2 specimens, 1 week apart) at time of event, then the subject has experienced a late HCV relapse or a 
recurrent infection. 
 
 Question the subject 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, bilirubin and INR weekly 
 Measure HCV RNA levels every 2 weeks 
 Therapy with HCV anti-viral treatments should be strongly considered. 
 
2) HCV Flare: 
 At the time of first detection of HCV RNA, send a specimen for HCV genotyping 
 Measure AST, ALT, ALP, bilirubin, INR weekly 
 Measure HCV RNA levels every 2 weeks 
 Therapy with HCV anti-viral treatments should be strongly considered. 
 
3) 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 subjects are clinically 
stable, subjects may restart pembrolizumab treatment. If these conditions are not met, then 
pembrolizumab treatment should be permanently discontinued.  


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c. Immune-related hepatitis 
1) 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 subjects with baseline ALT or AST ≥2×ULN, levels increase to >3× the baseline level 
 AST/ALT >500 U/L regardless of baseline level 
 Among subjects with baseline levels <22 umol/L: a value of >34 umol/L 
 Among subjects with baseline levels that are ≥22 umol/L: a value ≥2× the baseline level 
 Total bilirubin >51 umol/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). 
 
2) Management 
 Interrupt pembrolizumab treatment. 
 Start IV corticosteroid (methylprednisolone 1-2 mg/kg/day) followed by oral corticosteroid (1-
2 mg/kg/day). 
 Monitor with biweekly laboratory tests including AST, ALT, bilirubin, 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).  
 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 subjects show evidence of 
decompensation to CP C status or have esophageal or variceal bleeding at any point, treatment 
must be permanently discontinued.  
 Consultation with a hepatologist is advised 
 
d. Other Hepatic Events of Clinical Interest 
 Infection should 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 bilirubin is elevated above baseline, magnetic resonance cholangiopancreatography or 
Doppler ultrasound should be obtained to rule out vascular compromise, biliary obstruction, 
and/or tumor progression. If biliary obstruction is present, consultation with a gastroenterologist 
and/or an interventional radiologist should be obtained to see if the obstruction may be relieved. 
 A careful review of drugs, including herbal and alternative medications, should be obtained, and 
alcohol use should be ruled out. See Section 5.2 for drugs which may interfere with hepatic 
function.  
 For all of these cases, subjects 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 subject is off pembrolizumab therapy for 


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infection, obstruction, or drug/alcohol-related toxicity for more than 3 weeks, or if they have 
esophageal bleeding, or become Child-Pugh C at any point. 
 
6.3 
Rescue Medications & Treatment of Pembrolizumab-Related Toxicities 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of oral 
or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below). Refer to Section 6.1 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.  
 
 Hepatic: 
Guidance for Diagnosis and Management of hepatic dysfunction can be found in Section 6.2 
 
 Pneumonitis:  
o 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. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/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 diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 


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 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 Hypophysitis: 
o 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. 
o 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 less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients 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. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 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. 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
 
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 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with pembrolizumab. 
 


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Table 8: Management of Infusion Reactions 
 
NCI CTCAE Grade 
Management 
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 hours 
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 investigator. 
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. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued 
from further trial treatment administration. 
Subject may be premedicated 
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 subject is deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
6.4 
Radiation Therapy Toxicity Assessment During Therapy 
 
Expected toxicities from SBRT are listed in Section 7.1.1.2. Patients will be assessed at least once 
during radiation therapy for toxicity. Radiation therapy will continue as planned as long as there is no 
grade 3 or 4 toxicity, bilirubin is <51 mmol/L, Child score is A5-6 and the treating physician 
recommends continuation. Otherwise, a delay in radiation therapy should occur with possible 


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continuation of radiation if it resolves. If there is evidence of rapid changes in liver function suggestive 
of developing toxicity, or if the investigator has concerns regarding the clinical status of the subject, a 
delay in radiation therapy should be considered even if the criteria below are not met. 
 
If the patient discontinues radiation therapy prematurely, the patient may be considered for further 
pembrolizumab, if criteria for treatment (see Section 6.1) are met within the allowed time window, and 
at the discretion of the treating Investigator. 
 
Table 9: Radiation Therapy Toxicity and Suggested Modification 
 
Toxicity 
Modification 
Hematologic Toxicities 
Grade 1-2 
Continue radiation 
Grade 3 
Hold radiation until ≤ grade 2, then resume 
Grade 4 
Hold radiation 1 week and until ≤ grade 2, then resume 
Gastrointestinal Toxicities 
Grade 1-2 
Continue radiation 
Grade 3-4 diarrhea 
Hold radiation until ≤ grade 2, then resume 
Grade 1-2 nausea or vomiting 
Initiate anti-emetics prior to radiation and as needed and 
continue radiation 
Grade 3 nausea or vomiting 
Hold radiation until ≤ grade 2, then resume with anti-
emetics prior to radiation and as needed 
Hepatic Dysfunction 
Bilirubin 22-51 umol/L 
Continue radiation 
Bilirubin > 51 umol/L 
Hold radiation until bilirubin improves to ≤ 51 mmol/L; 
treat as per hepatic ECI (Section 6.2) Consider resuming 
radiation only if rapid improvement. 
Grade 1-2 AST/ALT 
Continue radiation 
Among subjects with baseline 
ALT <2×ULN: ALT ≥5×ULN 
 
Among subjects with baseline 
ALT ≥2×ULN: ALT >3× the 
baseline level 
Hold radiation until bilirubin improves to ≤ grade 2; treat 
as per hepatic ECI (Section 6.2). Consider resuming 
radiation only if rapid improvement 
Child-Pugh Score > 7 
Hold radiation until improves to Child-Pugh Score ≤ 7 
Other non-hematologic toxicities 
Grade 1-2 
Continue radiation 
Grade 3 
Hold radiation until improves to ≤ grade 2, then resume 
Grade 4 
Discontinue radiation 
 
 
 
 


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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
7.1 
List of Adverse Events and Reporting Requirements 
 
This study will utilize the CTCAE v4.0 for toxicity and Adverse Event reporting. A copy of the 
CTCAE v4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE v4.0.   
 
7.1.1 Expected Adverse Events and Protocol-Specific Expedited Adverse Event Reporting for 
Investigational Agent(s) 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list 
of AEs and the characteristics of an observed AE will determine whether the event requires expedited 
reporting as an SAE in addition to routine reporting. 
 
In addition, hospitalizations for routine procedures, protocol treatment, blood sampling, investigations 
and tissue biopsies are NOT considered SAE in this protocol. 
 
7.1.1.1 
Expected Adverse Events for Pembrolizumab 
 
Refer to the current Pembrolizumab Investigator’s Brochure for detailed information on adverse 
events. 
 
Most Frequently Reported (Incidence ≥ 5%) Adverse Events Presented by decreasing Frequency 
and Considered Drug-Related by the Investigator in Participants Treated with Pembrolizumab  
 
Likely (10-30%) 
 Fatigue  
 Pruritis 
 Arthralgia 
 Nausea 
 Diarrhea  
 Rash or itch 
 
Less likely (<10%) 
 Decreased appetite 
 Asthenia 
 Vitiligo 
 Fever 
 Hypothyroidism  
 Myalgia 
 Infusion reaction 
 Hyperthyroidism 
 
Rare (1% or less) 


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 Pituitary disorders  
 Autoimmune hepatitis  
 Myositis  
 Autoimmune nephritis  
 Pericarditis  
 Pancreatitis  
 Diabetes Mellitus  
 Uveitis  
 Hypoadrenalism  
 Myocarditis  
 Myasthenia  
 Sarcoidosis  
 Encephalitis  
 Stepven-Johnson Syndrome and Toxic Epidermal Necrolysis 
 Myelitis 
 
Most Frequently Reported (Incidence ≥ 0.2%) Serious Adverse Events Presented by Decreasing 
Frequency and Considered Drug-Related by the Investigator in Participants Treated with 
Pembrolizumab 
 
 Pneumonitis 
 Colitis 
 Diarrhea 
 Pyrexia 
 Hypopituitarism 
 Pneumonia 
 Adrenal insufficiency 
 Hyponatraemia 
 Dyspnoea 
 Hyperthyroidism 
 Type I Diabetes Mellitus  
 Hypopituitarism 
 Hypothyroidism 
 Vomiting 
 Aspartate aminotransferase increased 
 Pericardial effusion 
 Pleural effusion 
 Alanine Aminotransferase increased 
 Interstitial lung disease 
 Autoimmune Hepatitis 
 
7.1.1.2 
Expected Adverse Events for SBRT 
 
Very likely (80-90%) 


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 Fatigue (which generally resolves after radiation therapy is completed) 
 Skin irritation, redness, itchiness, discomfort 
 Temporary changes in blood work, without symptoms 
 
Less likely (30%) 
 Nausea, vomiting (during therapy) – more common if stomach or GI tract irradiated 
 Diarrhea or sensitivity to food – more common if GI tract irradiated 
 Gastritis, esophagitis, duodenitis, colitis – more common if relevant portion of the GI tract 
is irradiated 
 Gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, 
obstruction or changes in motility following therapy (may require medications or surgery) 
(<10% permanent changes) 
 Chest wall pain, rib fracture (< 10%) 
 
Less likely, but serious (<1-25%) 
 Radiation-induced liver disease (RILD) (<5%). Classic RILD is a clinical diagnosis of 
anicteric ascites, hepatomegaly and elevation of ALP relative to other transaminases that 
may occur 2 weeks to 3 months following radiation to the liver. 
 Non-classic RILD includes elevation of liver enzymes and/or any decline in liver function 
within 12 weeks from start of therapy (~25%). RILD can lead to liver failure that could lead 
to death. There is an increased risk of liver toxicity in patients with large tumors and in 
patients with pre-existing liver disease. 
 Permanent thrombocytopenia (<1%); this may lead to bleeding 
 Kidney injury (<1%); this may lead to changes on imaging and more rarely the need for 
medication. 
 
7.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE v4.0.  A copy of the CTCAE v4.0 can be downloaded from the CTEP web site: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Associated with the use of the treatment: There is a reasonable possibility that the experience may 
have been caused by the drug/biologic. 
 
Life threatening adverse treatment experience: Any adverse drug/biologic experience that places 
the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred. 


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Serious adverse treatment experience: Any event is an AE occurring at any dose that results in any 
of the following outcomes: 
 
Death 
 
A life-threatening AE (The subject was, in the view of the Investigator, at immediate risk of death 
from the event as it occurred. It does not mean that the event, had it occurred in a more severe form, 
might have caused death). 
 
Hospitalization or prolongation of existing hospitalization (Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization   or   fulfills   any   other   serious   
criteria, the   event   is   serious. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered to be an AE). 
 
A persistent or significant disability/incapacity (A substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
accidental trauma (i.e., sprained ankle) that may interfere or prevent everyday life functions but do 
not constitute a substantial disruption). 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition  (Examples include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization 
or the development of drug dependency or drug abuse). 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported as an 
SAE. A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). 
 
Events not considered to be serious adverse events are:  
 hospitalizations for the routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition,  
 treatment, which was elective or pre-planned, for a pre-existing condition that is unrelated to the 
indication under study and did not worsen,  
 admission to a hospital or other institution for general care, not associated with any deterioration in 
condition, or  
 treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious given above and not resulting in hospital admission.  
 
Any SAE occurring after the subject has provided informed consent and until 4 weeks after the subject 
has stopped study participation must be reported. This includes the phase in which the study protocol 
interferes with the standard medical treatment given to a subject (e.g. treatment withdrawal during 
screening phase, change in treatment to a fixed dose of concomitant medication). Serious adverse events 
occurring more than 4 after study discontinuation need only be reported if a relationship to 
pembrolizumab or SBRT is suspected.  
 


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Unexpected adverse treatment experience: Any adverse drug/biologic experience, the nature, 
frequency, or severity of which is not consistent with the product monograph, or not consistent with the 
risk information described above as a protocol-specific expected adverse event (see “Expected Adverse 
Events and Protocol-Specific Expedited Adverse Event Reporting Exclusions”, above). 
 
Pembrolizumab Overdose: 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 subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is attributed to the overdose of a Merck product, the adverse event(s) is reported 
as a serious adverse event, even if no other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.” 
 
7.3 
Serious Adverse Event Reporting 
 
7.3.1 Sponsor Notification 
 
Any serious adverse event or event of clinical interest must be reported to the Central Office within 24 
hours of the Investigator at the site learning of the event by a completed SAE form. The adverse event 
must be completely described in the case report form. 
 
The Central Office will provide expedited reports of on-study SAEs to Health Canada and Merck for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are BOTH 
serious AND unexpected (as determined by reference to the Investigator Brochure), AND which are 
thought to be related to protocol treatment (or for which a causal relationship with protocol treatment 
cannot be ruled out).  
 
All adverse signs and symptoms which occur during or following the course of drug administration must 
be reported in detail on the subject’s case report form. This description is to include the nature of the 
sign or symptom, time of onset in relation to drug application, duration, severity, and possible 
relationship to drug, required therapy, and outcome. The subject should be followed until the adverse 
reaction is resolved, or until in the opinion of the Principal Investigator, reversal of the reaction is not 
likely to occur.  
 
7.3.2 SAE Follow-up 
 
Follow-up SAE reports is subject to the same timelines as the initial report, and is sent to the same 
parties to whom the original Serious Adverse Event Form was sent. A new serious adverse event form 
is completed for the follow-up, stating that this is a follow-up to the previously reported serious adverse 
event and giving the date of the original report. Each re-occurrence, complication or progression of the 


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original event should be reported as a follow-up to that event. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the subject continued 
or discontinued study participation.  
 
The Sponsor-Investigator and Institution will assist Merck in investigating any SAE and will provide 
any follow-up information reasonably requested by Merck. 
 
7.3.3 REB Notification of SAEs 
 
Investigators must notify their Research Ethics Boards (according to their local REB policies) and file 
the report in their study files. Documentation as outlined below must be maintained for reportable SAEs.  
Documentation that serious adverse events (SAEs) have been reported to REB must be forwarded to the 
Central Office and kept on file at the Centre. Documentation can be any of the following:  
 letter or email from the REB acknowledging receipt  
 stamp from the REB, signed and dated by REB chair, acknowledging receipt 
 letter or email demonstrating the SAE was sent to the REB 
 
7.3.4 Health Canada SAE Reporting 
 
All serious, unexpected adverse drug reactions must also be reported by the Central Office to Health 
Canada within 15 days if the reaction is neither fatal nor life threatening, and within 7 days if the reaction 
is fatal or life threatening. 
 
As Princess Margaret Cancer Centre is the sponsor delegate of this study in Canada, the Central Office 
of this study will be responsible for reporting all serious unexpected adverse events to Health Canada.   
 
7.3.5 SAE Reporting to Merck 
 
To ensure subject safety, each serious adverse event or hepatic event of clinical interest must also be 
reported by the Central Office to Merck Global Safety (in English) within 24 hours of learning of its 
occurrence, even if it is not felt to be treatment-related (Attn: Worldwide Product Safety; FAX 215 993-
1220).  Follow-up information about a previously reported serious adverse event must also be reported 
within 24 hours of the Investigator-sponsor receiving it. The SAE Report Form must indicate the 
relationship to study treatment and be signed by the investigator. All reports of overdose with and 
without an adverse event must be reported within 24 hours to the Central Office, and within 2 working 
days by the Central Office to Merck Global Safety.  
 
7.4 
Routine Adverse Event Reporting 
 
For abnormal laboratory values, it is the responsibility of the Principal Investigator to assess the clinical 
significance of each abnormality. Only abnormal laboratory values that can be assessed for grade using 
CTCAE v4.0 will be documented. The Investigator will determine whether abnormal laboratory values 
are considered clinically significant and represent AEs based on their medical judgment.  
 
Data on all adverse experiences/toxicities regardless of seriousness must be collected for documentation 
purposes only.   


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Clinical Laboratory Abnormalities: 
 
All abnormal laboratory values should be captured on source documentation and assessed for clinical 
significance by the Investigator at the site. Only abnormal laboratory values deemed clinically 
significant should be listed as AEs in the CRFs. All clinically significant abnormal laboratory results 
will be followed up until the related AE resolves, returns to < grade 1 or baseline value in the follow-up 
period. Clinically significant laboratory abnormalities will be dictated in the clinic notes. Additionally, 
laboratory abnormalities resulting in an intervention are considered to be clinically significant. 
 
7.5 
Documentation of Adverse Events 
 
All AEs must be captured in the source documents, as well as reported in electronic document capture 
(EDC) system. AEs reported using SAE forms must also be reported in EDC system. 
 
All serious and non-serious AEs occurring from the start of study medication administration to the end 
of study drug administration visit must be recorded as AEs on the CRF. The Investigator should review 
all documentation (e.g., hospital progress notes, laboratory, or diagnostic reports) relative to the event 
being reported.  
 
7.6 
Follow-Up of AEs and SAEs 
 
All SAEs and AEs should be followed until 4 weeks after the last dosing of study drug/biologic or 
until they are resolved (return to normal or baseline values), stabilized, improve to < Grade 2, or the 
subject is lost to follow-up and cannot be contacted.  Additional investigations (e.g., laboratory tests, 
diagnostic procedures, or consultation with other healthcare professionals) may be required to 
completely investigate the nature and/or causality of an AE or SAE.  If the subject dies during the 
study or within 4 weeks following the last dose of study medication, any postmortem findings 
(including histopathology) should be provided to the Sponsor.   
 
After the Off Treatment Visit, only AEs considered related to study drug are to be followed until 
resolution (return to normal or baseline values), stabilized, improve to < Grade 2, patient starts another 
treatment, or the subject is lost to follow-up and cannot be contacted. 
 
CRF data should be updated with any new information as appropriate. 
 
7.7 
Pregnancy 
 
If the study subject is the father, then two forms should be completed, one for the father and the other 
for the mother and neonate. To ensure subject safety each pregnancy must also be reported to Merck 
within 15 days of learning of its occurrence.  
Pregnancies and lactations that occur in a study subject or in a study subject’s partner from the time of 
treatment allocation through 120 days following cessation of study treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator to the Central Office within 24 hours or learning of the event. Central Office 
will report pregnancy to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
within 2 working days. All reported pregnancies must be followed up to determine outcome, including 


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spontaneous or voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications.  
 
7.8 
Investigator Notifications 
 
The Sponsor-Investigator will receive Investigator Notifications (INs) issued by Merck for suspect, 
unexpected SAEs which have occurred in Merck-sponsored studies with the study drug. The Sponsor-
Investigator is responsible for forwarding these INs to all sub-investigators participating in the study, as 
well as to the Research Ethics Boards, according to local practice. 
 
7.9 
Data Safety and Monitoring Board 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the data from 
this research throughout the study to see if there are unexpected or more serious side effects than 
described in the consent. For this study, the Drug Development Program DSMB will be fulfilling this 
role. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents administered 
in this study can be found in Section 7.1. 
 
8.1 
Investigational Agent - Pembrolizumab 
 
Pembrolizumab will be provided by Merck as a liquid solution (100 mg/4mL vial) in Type I glass vials 
intended for single use only. The drug product is stored under refrigerated conditions (2 to 8°C).  
 
The liquid drug product can be further diluted with normal saline or 5% dextrose in the concentration 
range of 1 to 10 mg/mL in intravenous (IV) containers made of polyvinyl chloride (PVC) or non-PVC 
material. Diluted pembrolizumab solutions may be stored at room temperature for a cumulative time of 
up to 4 hours. In addition, IV bags can be stored at 2 to 8°C for up to a cumulative time of 20 hours. 
Refer to pharmacy manual for more information. 
 
Pembrolizumab Manufacturing 
 
Merck manufactures Pembrolizumab for clinical use. 
 
Pembrolizumab Packaging and Labeling 
 
Clinical supplies of pembrolizumab will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
Pembrolizumab Handling and Storage 
 
Investigational agent will be stored under secure (with limited access), and temperature-controlled 
conditions specified on the label for the duration of the study. Receipt and dispensing of trial medication 


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must be recorded by an authorized person at the trial site. 
 
Pembrolizumab Ordering and Shipping 
 
Pembrolizumab will be supplied by Merck to the study site. The Principal Investigator, or authorized 
study personnel, upon receipt of the study medication supplies, will conduct an inventory and 
acknowledge receipt to Merck, or designee. 
 
Study medication should only be dispensed once a subject has (1) signed an informed consent form 
(ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and continuing 
eligibility requirements, and (4) been assigned a subject identification number. 
 
Agent Accountability 
The Investigator is responsible for study medication accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or designated 
study personnel must maintain study medication accountability records throughout the study.   
 
The accountability records maintained during the study will be used to support subject dosing data.  Site 
personnel are responsible for reconciling and resolving discrepancies in study medication accountability.   
 
Missing study medication must be recorded along with an explanation of the discrepancy. At the 
conclusion of the study, all unused study medication and all medication containers will be destroyed 
locally as per UHN destruction policy. 
 
Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a careful record 
of the inventory and disposition of all agents received using their site-specific Drug Accountability 
Record Form (DARF). 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Biomarker analyses in this study will be exploratory. 
 
9.1 
Tumor Biopsies 
 
A pre-treatment biopsy will be performed in all patients enrolled. The biopsy should be performed at 
any time during the screening period before cycle 1, day 1 once informed consent has been signed. 
The biopsy will be conducted according to institutional guidelines using standard surgical techniques. 
4 cores will be obtained. 
 
Tumor material will be prioritized as follows: 
 
1. Whole exome sequencing 
2. Whole transcriptome sequencing 
3. PD-L1 expression and TIL analysis 
4. Methylation profiling 


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*In the event that a patient has not had a biopsy to determine clinical diagnosis prior to study entry the 
first core must be prioritized for this. This will require a review by a pathologist of collected samples. 
 
An optional post treatment biopsy will take place between weeks 3-6 and tissue will be banked.  
 
9.1.1 MOLECULAR ANALYSES AND DATA EVALUATION 
 
9.1.1.1 
WES of Tumor DNA 
 
WES of tumor DNA and germline DNA will be performed in OICR with already established protocol 
using next generation DNA sequencing. Data generated will be analyzed using established 
bioinformatics pipelines to study somatic mutations and derive potential mutational signatures. These 
results should be available within 8 weeks of baseline fresh tumor biopsy.  
 
Germline mutations detected in study subjects will be reported to the co-investigator (treating physician) 
to facilitate clinical confirmation of mutation(s). Participants with pathogenic germ line mutations 
identified through the study and who have consented to be informed of genetic information will be 
approached by the study genetic counselor (Canadian and American board certified). The research 
results disclosure session will consist of genetic counseling about the research finding and need for 
confirmation testing. The session will also summarize gene specific risks and inheritance pattern. The 
study genetic counselor will offer confirmation testing of the research finding through a clinically 
accredited laboratory. When clinical confirmation results are available, these will be disclosed to the 
participant and their treating physician by the genetic counselor. Clinical results disclosure session will 
summarize gene specific cancer risks, inheritance, surveillance for early detection and/or surgical 
interventions for prevention, and procedures for testing family members.  
 
9.1.1.2 
RNAseq of Tumor  
 
Whole transcriptome sequencing of tumor RNA will be performed using next generation sequencing in 
OICR with established protocols (see Lab Manual). RNAseq data will be used to perform exploratory 
analysis. Planned analyses include evaluation of differences in gene expression levels between 
responders and non-responders to study treatment. Further exploratory analyses will include 
interrogation of inflammatory signatures. In patients consenting for a second optional biopsy, immune 
signatures will be compared pre and post treatment. 
 
9.1.2 PD-L1 and Immunoscore 
 
Tumor samples from this study will be analyzed for percentage PD-L1 expression. PD-L1 protein level, 
as assessed by IHC in tumor sections, has been shown to correlate with response to pembrolizumab in 
subjects with NSCLC, and a PD-L1 IHC diagnostic is marketed for use with pembrolizumab in NSCLC. 
Preliminary data indicates that this association may also be true in additional cancer types (i.e., triple-
negative breast cancer, head and neck, and gastric). The burden of tumor-infiltrating lymphocytes (TILs) 
may also predict response to ICIs and provide an ‘immunoscore’ which can prognosticate in HCC; 
densities of CD8, CD3, CD45R0 and PD-1 will also be assessed.65,66  This will be performed by QualTek 
Molecular Laboratories, Pennsylvania. 


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9.1.3 Methylation Profiling 
 
DNA extracted from tumor biopsies will be delivered to the DeCarvalho laboratory at the Princess 
Margaret Cancer Centre for DNA methylation mapping. Tumor methylation profiling will be 
correlated with that seen in cfDNA. (Section 9.2.1) 
 
9.1.4 Handling of specimens 
 
See lab manual. 
 
9.2 
Blood withdrawal and biomarker studies 
 
9.2.1 ctDNA  
 
There is evidence that ctDNA obtained from blood specimens of advanced cancer patients may be 
representative of the mutational status of DNA from tumor cells and may identify the emergence of 
treatment resistance prior to radiographic progression.67 2 X 10 ml EDTA will be drawn on days 1, cycle 
1 day 10+/- 2 days and cycle 5, day 1 (day 85) +/- 7days. A further sample will be collected at 
progression. Whole blood samples should be processed (double spun) within 4 hours of collection to 
separate cells from plasma. Plasma Serum samples will be stored at -80°C until batched transfer to 
biospecimens program. Cell free DNA will be analyzed for circulating tumour DNA quantitative 
analysis.  This testing will be performed by the Pugh lab at OICR. 
 
9.2.2 Germline analysis 
 
Blood draw at C1D1 will also be used to obtain a buffy coat for DNA extraction and germline analysis. 
Sample should be transferred to OICR and stored at -80oC for further processing. 
 
9.2.3 Methylation profiling 
 
Plasma separated from samples at time-points in 9.2.1 will also be used for DNA methylation profiling. 
1ml of plasma will be delivered to the DeCarvalho laboratory. Methods to be described in laboratory 
manual.  
 
9.2.4 Cytokine analysis 
 
1 x 10ml EDTA sample will be collected Cycle 1, Day 1, Cycle 1 Day 5, Cycle 1 Day 10+/-2, Cycle 3 
Day 1, Cycle 5 Day 1 and at progression (+/- 7 days). Whole blood samples should be processed (double 
spun) within 4 hours of collection to separate cells from plasma. Plasma Serum samples will be stored 
at -80◦C until batched transfer to biospecimens program. Expression of clinically relevant cytokines will 
be measured using a multiplexed electrochemiluminesce (ECL) immunoassay manufactured by Meso 
Scale Diagnostics, and performed at the Liu lab at the University Health Network. We will specifically 
look for cytokines reflective of an abscopal effect. 
 
 


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10. STUDY CALENDAR 
 
Baseline (pre-study) evaluations are to be conducted within 14 days prior to start of protocol therapy, 
unless specified differently in the study calendar. Scans (including tumor measurements) x-rays, 
informed consent, tumor biopsy, and hepatitis testing must be done ≤ 28 days prior to the start of therapy. 
In the event that the subject’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. Some visits might be conducted remotely and / 
or some assessments might be deferred as per physician discretion. Some of the safety lab assessments 
may also be done at external or community laboratories as applicable. In such cases, sites should provide 
Normal reference ranges of such lab and lab licenses to the Central Office.  
 
The following schedule of assessments applies to all subjects. More frequent assessments should be 
obtained if clinically indicated. If pre-study laboratory and clinical assessments were done within 5 days 
prior to treatment initiation, they do not need to be repeated for cycle 1 day 1. For subsequent cycles 2+, 
day 1 assessments can be completed up to 4 days prior to day 1. A cycle is 21 days long for the purposes 
of this protocol. 
 
 
 
Cycle 1 
Cycle 2  
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 
6+ 
 
 
 
Pre- 
Study 
Day 
1 
Day 
2 
Day 
5 
Day 
10 
Day 
1 
Day 
1 
Day 
1 
Day 
1 
Day 
1 
Off 
Treatment 
Visitc 
Survival 
Follow-
Upc 
Pembrolizumab 
 
A 
 
 
 
A 
A 
A 
A 
A 
 
 
SBRT  
 
 
B------------------B 
 
 
 
 
 
 
 
Informed consent (Main and 
Optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
TNM Staging, BCLC Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
Vascular Thrombosis Stagingf 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
 
Physical exam 
X 
X 
 
Xe 
 
X 
X 
X 
X 
X 
X 
 
Vital signsd 
X 
X 
X 
Xe 
 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Performance status 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Child-Pugh Score 
X 
X 
 
Xe 
 
X 
X 
X 
X 
X 
X 
 
ALBI Score 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, PT/INR 
X 
X 
 
Xe 
 
X 
X 
X 
X 
X 
X 
 
Neutrophil-Lymphocyte Ratio 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Serum chemistrya 
X 
X 
 
Xe 
 
X 
X 
X 
X 
X 
X 
 
T3 and TSH 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
Hepatitis B Testingg 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C Testingh 
X 
 
 
 
 
 
 
 
 
 
 
 


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Anti-HDV Testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
ECHO 
X 
 
As clinically indicated 
 
EKG  
X 
 
As clinically indicated 
 
Adverse event evaluation 
 
 
X---------------------------------------------------------------------------X 
X 
 
Tumor measurements 
X 
 
Xm 
Documentation (radiologic) must be provided for subjects removed from 
treatment for progressive disease. 
X i 
 
Radiologic evaluation 
X 
 
Xm  
Xi 
 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
AFP 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Biopsy for correlative studies 
X 
 
 
 
 
 
 
 
 
 
 
 
Optional biopsy for correlative 
studies 
 
 
 
 
 
Xk 
 
 
 
 
 
 
Blood for ctDNA/methylationl 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
Blood for cytokine analysisl 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
 All assessments may be performed up to 2 working days prior to scheduled day. 
A: 
Pembrolizumab 200 mg IV Q3W 
B: 
SBRT as per Section 5.1.2, commencing Cycle 1 Day 2, consisting of 5 fractions over 5-15 days 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, AST, ALT, 
sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
See Section 5.4 for post-treatment follow-up requirements.   
d: 
Blood pressure, temperature, pulse, O2 saturation, and respiratory rate. 
e: 
Day of assessment while on SBRT may vary due to weekends, but should be as close to day 3 as possible. 
f: 
See Appendix 4 for vascular thrombosis staging chart. 
g: 
All patients should have baseline Hepatitis B screening which should include: HbsAg, Anti-Hbs and Anti-Hbc (total+IgM). For patients with known 
hepatitis B, or if they have been deemed infected through baseline screening, additional test should include: HBV viral load (DNA), HbeAg and Anti-Hbe. 
If HBV viral load has been performed within previous 3 months a repeat test is not required. If Hepatitis B Testing has been performed for eligibility less 
than 28 days prior to start of therapy it is not required to be repeated again as a part of Baseline (Pre-study) evaluations. 
h: 
All patients should have baseline Hepatitis C screening which should include: Anti-HCV. For patients with known hepatitis C, or if they have been deemed 
infected through baseline screening, HCV viral load (RNA) should be performed. If HCV viral load has been performed within previous 3 months a repeat 
test is not required. If Hepatitis C Testing has been performed for eligibility less than 28 days prior to start of therapy it is not required to be repeated again 
as a part of Baseline (Pre-study) evaluations. 
i: 
Patients who come off study treatment for reasons other than radiological progression are to have tumor measurements and disease response evaluated ever 
3mo ± 14 days until documented progression per iRECIST or start of new therapy. 
j:      Only required if the patient has a known history of Hepatitis B and the testing has not been completed previously. If testing has been done previously, a 
repeat test is not required. If Anti-HDV Testing is required, this must be done ≤ 28 days prior to the start of therapy. 
k:     Optional biopsy to be done between 3-6 weeks on study for patients that have consented to procedure 
l:      Research bloods to be drawn prior to Pembrolizumab administration. Research blood must be collected on-site at Princess Margaret Cancer Centre. 
m:    Radiologic evaluation and tumor measurements should be performed at 12 weeks on treatment and then repeated every 10 weeks thereafter (± 2 weeks).  
CT scans should be performed at planned time points regardless of any dose delays. 
 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, subjects should be re-evaluated for response every 12 weeks. In addition 
to a baseline scan, confirmatory scans should also be obtained 4-8 weeks following initial documentation 
of objective response. 
 
Note, response in the irradiated volume is challenging to assess before 3 months post radiation therapy 
due to radiation change in the surrounding liver. Even at 3 months, changes in the surrounding liver 
around the HCC may represent radiation treatment change, rather than tumor progression. Thus, review 
of images by experienced radiologists is required, as is importance of relaying radiation information to 
the radiologists, to avoid inaccurate labeling of progression when liver changes are due to radiation 
effect on the liver. 
 
Response and progression will be evaluated in this study using both RECIST 1.1 and the new criteria 
proposed by immune modified Response Evaluation Criteria in Solid Tumors (iRECIST) guideline 
(Seymor 2017). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the iRECIST criteria. Overall 
response will be assessed, as well as response in lesions outside the SBRT treatment field. These criteria 
keep the uni-dimensional measurement of RECIST, but incorporate the concept of unconfirmed 
progression (iUPD) noted with the use of immunotherapy. In the case of new lesions, assessments 
continue as per RECIST 1.1 but are recorded in a separate case report form. Contrasting to RECIST 1.1 
new lesions may results in iUPD but immune confirmed progression (iCPD) is only assigned on the 
basis of this category if at next assessment additional new lesions appear or an increase in size of new 
lesions is seen (≥5 mm for sum of new lesion target or any increase in new lesion non-target); the 
appearance of new lesions when none have previously been recorded, can also confirm iCPD. iUPD 
may occur before iPR, iCR or iSD, in contrast to RECIST 1.1 where progression could not occur. 
Notable in this study, radiated lesions will be counted as part of the response criteria, an exception to 
the rules of RECIST 1.1. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their first treatment 
with pembrolizumab. 
 
Evaluable for objective response.  Only those subjects who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. These subjects will have their response classified according to the definitions 
stated below. (Note: Subjects who exhibit objective definitive disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Subjects who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The 
response assessment is based on the presence, absence, or unequivocal progression of the lesions. For 


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iUPD, iCPD will need to be confirmed by repeat imaging 4-8 weeks after iUPD was identified, as per 
iRECIST. 
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, 
MRI, or calipers by clinical exam. For nodal lesions, see criteria below. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Tumor lesions treated with SBRT as part of the study protocol will be considered measurable for the 
primary analysis. Other previously irradiated lesions will not be considered measurable. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must 
be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitic involvement of skin or lung, inflammatory breast disease, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.  
 
Vascular thrombosis will be considered non-measurable disease, unless vascular HCC is the only HCC 
present. In this case, vascular response guidelines in 11.1.4.3 should be used. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same subject, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured 
at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Vascular thrombi will not be selected as target lesions, unless 
vascular HCC is the only HCC present. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  
If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in the 


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measurable dimension of the disease. Radiated lesions can be counted as target lesions provided there 
has been demonstrated progression in the lesion. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. The same 
method of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up.  
 
Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and  10 mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by colour photography including a ruler to estimate 
the size of the lesion is recommended. When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end 
of the study. 
 
Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
 
CT & MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. CT should be performed with slice thickness of 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised.   
 
Cytology, Histology:  These techniques can be used to differentiate between PR and CR in rare cases. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumour has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease.  
 
11.1.4 RECIST/ iRECIST Assessment of Disease 
 
Response 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment 
classified as outlined below: 


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Complete Response (CR): disappearance of target and non-target lesions and normalization of tumour 
markers. Pathological lymph nodes must have short axis reduction to < 10mm (Note: continue to record 
the measurement even if < 10mm and considered CR). Residual lesions (other than nodes < 10mm) 
thought to be non-malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases [ref RECIST 1.1]) before CR can be accepted. 
Confirmation of response is required 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. Patients with CR/iCR or PR/iPR should have scans 
repeated after 4 weeks, but no more than 8 weeks, to confirm response. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD taking as reference the smallest sum of diameters on study 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking as 
references the smallest sum of diameters recorded on study (including baseline) AND an absolute 
increase of ≥ 5mm. Appearance of new lesions will also constitute progressive disease (including lesions 
in previously unassessed areas). When the patient has only non-measurable disease, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the overall 
tumour burden has increased sufficiently to merit discontinuation of treatment or where the tumour 
burden appears to have increased by at least 73% in volume. Modest increases in the size of one or more 
non-target lesions are NOT considered unequivocal progression. If the evidence of PD is equivocal 
(target or non-target), treatment may continue until the next assessment, but if confirmed, the earlier 
date must be used. 
 
Patients that are clinically well may continue on therapy following RECIST progression with new 
lesions or increase in target lesions if the increase in disease burden does not meet the definition of PD 
by immune response criteria [Seymour 2017]. In this situation, patients do not have unequivocal progression 
until immune response criteria are met (see Table 10 below). 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 10: Integration of Target, non-Target and New Lesions into Response Assessment 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions* 
Overall 
Response 
Best Response for this 
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes <10mm 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once ≥ 4 wks. 
from baseline 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes* 
PD 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-CR / 
non-PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yes* 
PD 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. This is a reason for stopping therapy, but is NOT objective PD. Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
* 
Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may 
be continued pending further assessments – see New Lesion section below.  


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Immune-Related Response Assessment (iRECIST) 
Overall response will also be assessed using iRECIST [Seymour 2017]. Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in many 
respects but have been adapted to account for instances where an increase in tumour burden, or the 
appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-points and best overall responses will be recorded separately. 
 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
- 
Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
- 
Continued unequivocal progression in non-target disease with an increase in tumour 
burden 
- 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions. 
 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in Table 11, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. Patients who have iUPD 
and are not clinically stable should be designated as not clinically stable in the case report form. 
 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per organ, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 


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measurements of NLT should not be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case 
record form.
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD, confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional new 
lesions. 
 
Table 11: Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirm iCPD if NLs were previously identified and have 
increased in size (≥5 mm in SOM for NLT or any increase for 
NLNT) or number. If no change in NLs (size or number) from last 
TP, remains iUPD 
iSD, iPR, 
iCR 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further increase in 
size of NT disease (need not meet RECIST 1.1 criteria for 
unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD or iCR 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
- further increase in SOM by at least 5 mm, otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase 
in: 
- previously identified target lesion iUPD SOM ≥5 mm and / or 
- NT lesion iUPD (prior assessment need not be unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase 
in: 
- previously identified T lesion iUPD ≥5 mm and / or 
- previously identified NT lesion iUPD (need not be unequivocal) 
and /or 
- size or number of new lesions previously identified 
Non- 
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
- increase in size or number of new lesions previously identified 
* 
Using RECIST 1.1 principles. If no pseudoprogression (PSPD) occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. 
**    In any lesion category. 
***  Previously identified in assessment immediately prior to this time point. 


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Vascular Thrombosis Response Evaluation 
 
There are no validated guidelines to monitor and report vascular thrombosis response. Consistent 
with RECIST1.1, thrombosis will be considered non-measurable disease. Vascular thrombosis 
response should be recorded using the following guidelines: 
 
    
iCR thrombosis:  
Complete resolution of thrombosis, with recanalization of vessel. 
 
      
iPR thrombosis: any of 
 
a) Partial recanalization of thrombosis (if prior complete blockage) 
 
b) Unequivocal reduction in the maximal girth of thrombosis 
c) Unequivocal reduction in the volume, or elimination, of arterial enhancing portion of 
thrombosis 
 
iPD thrombosis: any unequivocal, unambiguous increase in the volume of new or 
existing enhancing thrombosis 
 
Note that for “unequivocal progression” of thrombosis (non-measurable disease), the 
increase in overall tumor burden (enhancing thrombosis) must be comparable to the 
increase required for iRECIST definition of PD of measurable disease. 
 
 iSD thrombosis: any of 
a) No change or small changes that do not meet the above criteria for iPR or iPD, taking 
as reference the smallest sum diameters while on study. 
 b) Increase in the volume of non-enhancing thrombosis 
 c) New bland non-enhancing thrombosis 
 
11.1.5 Progression-Free Survival 
 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.   
 
11.1.6 Response Review 
 
All iCR and iPR responses will be reviewed by an expert(s) independent of the study at the 
subject’s completion of the study by simultaneous review of subject files and radiologic images. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 above 
(Adverse Events: List and Reporting Requirements). 
 
 
 


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12.1 
Data Collection and Reporting 
 
All data obtained in the clinical trial described in this protocol will be reported on eCRFs in the 
Medidata Electronic Document Capture system (Medidata). Data reported on eCRFs should be 
consistent with the source documents and verifiable.  All data for the primary and secondary 
endpoints will source verified prior to publication. The Investigator will review the data and 
electronically sign the eCRFs to acknowledge agreement with the data entered. Data will be 
entered into Medidata will be used for developing tables and listings for the final study report. 
 
Prior to the start of the study, the Investigator will complete a Site Participants Log showing the 
signatures and handwritten initials of all individuals who are authorized to make or change entries 
on source documents and eCRFs. 
 
12.2 
Source Documents 
 
Source documents refer to the original documents, data, and records where the first recording of a 
data point occurred. Examples of source documentation include, but are not limited to:  
 
Hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 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) 
 
Please ensure that source document entries are attributable, legible, contemporaneous, original, 
and accurate. Note that sign-off of source documents should be attributable to a single record and 
“bracketing” multiple entries on source document pages for a single signature is not allowed.  
Corrections to source document entries should only be completed by drawing a single line through 
the previous entry and then recording the corrected data, initialing the change, and dating the 
change.  Only the individual that initially recorded the data should make any corrections.    
 
12.3 
Retention of Subject Records and Study Files 
 
The ICH guidance document, Good Clinical Practice: Consolidated Guidelines (ICH Guidance 
Document E6) (1997) states that the investigator and sponsor shall retain study records relating to 
the study until at least 2 years after the last approval of a marketing application and until there are 
no pending or contemplated marketing applications, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. In the event of a trial 
discontinuation, sponsor records should also be kept for a minimum of 2 years. Per Health Canada, 
all original records should be maintained for 25 years after the above requirements are satisfied 
and the final report has been issued. Records contained in the Clinical Trial Application should be 
maintained on file for at least 25 years. We will comply with these regulations. The Sponsor will 
notify sites when documents are to be destroyed. 
 
 


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12.4 
Site and Study Closure 
 
Upon completion of the study, the following activities, when applicable, will be completed by the 
Central Office in conjunction with the Investigator, as appropriate: 
 Collection of study materials (i.e., specimen collection kits, drug shippers, etc.) 
 Data clarifications and/or resolutions 
 Accounting, reconciliation, and final disposition of used and unused study medication 
 Review of site study records for completeness 
If the Sponsor or Investigator or appropriate regulatory officials identify conditions arising during 
the study that indicate that the study should be halted or that the study center should be terminated, 
this action may be taken after appropriate consultation among the Sponsor and Investigator. 
Conditions that may warrant termination of the study include, but are not limited to, the following: 
 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product  
 Failure of the Investigator to enroll subjects into the study at an acceptable rate  
 Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
 Submission of knowingly false information to the Sponsor, or appropriate regulatory 
authority  
 Insufficient adherence to protocol requirements 
 Refusal of the Investigator to supply source documentation of work performed in this 
clinical trial 
 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonisation (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, ICH E6 4.12, ICH E6 4.13, ICH E6 5.20, and ICH E6 5.21. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a single-arm, non-comparative, open-label phase II study of combination treatment with 
pembrolizumab and SBRT in patients with advanced HCC who have experienced disease 
progression after treatment with sorafenib/lenvatinib. 
 
Study objectives are stated in Section 1.1 to 1.3. 
 
The primary endpoint of the study is overall response rate, defined as the proportion of the subjects 
in the study population who have a complete response (iCR) or partial response (iPR), as defined 
by iRECIST, at any time on study treatment. Of note this may follow a period of iUPD. 
 


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13.2 
Sample Size/Accrual Rate 
 
Given the preliminary results with nivolumab, we would expect that pembrolizumab alone would 
produce responses in 15% of patients.24 We hypothesize that combining pembrolizumab with 
SBRT will increase the ORR to 40%, a clinically meaningful increase in systemic response rate 
and indicative of significant activity (Note: ORR is a composite sum of irradiated local tumor and 
other measurable metastatic disease - local radiotherapy response, systemic pembrolizumab 
response and potential abscopal effect on all measurable disease).  
 
With 90% power, we would need to accrue 22 evaluable patients in a two-stage study design, with 
a one-sided significance level of 10%. If 2 or more patients show response from the first 10 
evaluable patients, we will continue to accrue to a total of 22 evaluable patients. We expect to 
accrue up to 27 patients as some patients may not be evaluable for the primary endpoint. A total 
number of 6 or more responders in 22 evaluable patients would be considered to reject the null 
hypothesis. We expect to accrue 2-3 patients per month, leading to complete accrual in 12 months 
following study activation. 
 
13.3 
Analysis of Primary Endpoint 
 
Overall Response Rate (ORR) 
ORR is defined as the proportion of the subjects in the study population who have a complete 
response (iCR) or partial response (iPR), as defined by iRECIST, at any time on study treatment. 
This is noting that radiated lesions will count as target lesions provided there has been 
demonstrated progression in the lesion. 
 
The point estimate and 95% confidence interval for ORR will be provided using the Clopper and 
Pearson exact binomial method. An interim analysis for futility will be undertaken when response 
data are available on the first 10 evaluable subjects enrolled. If ≤1 responses are documented, the 
trial will be stopped. If 2 or more responses (iCR or iPR) are documented, the study will continue 
to full accrual. Subjects who are inevaluable for the primary endpoint will be replaced. 
  
13.4 
Analysis of Secondary Endpoints 
 
Response in non-irradiated lesions 
Response in non-irradiated lesions is defined as the proportion of subjects in the study population 
who demonstrate iCR or iPR, by iRECIST 1.1, when tumors within the radiotherapy treatment 
field are excluded from analysis. Subjects will be ineligible for this analysis if no RECIST-
measurable lesions exist outside the radiotherapy treatment field. 
 
The point estimate and 95% confidence interval for ORR will be provided using the Clopper and 
Pearson exact binomial method. 
 
Duration of Response (DOR) 
For subjects who demonstrate iCR or iPR, by iRECIST, DOR is defined as the time from first 
documented evidence of iCR or iPR until disease progression or death due to any cause, whichever 
occurs first. 


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DOR will be estimated by the Kaplan-Meier method, and the Cox proportional hazard regression 
model will be used to analyze the effects of factors, in addition to treatment, that may be associated 
with DOR. 
 
Progression-Free Survival (PFS) 
PFS is defined as the time from enrollment until the date of objective disease progression, by 
iRECIST, or death (by any cause in the absence of progression). 
 
PFS will be estimated by the Kaplan-Meier method, and the Cox proportional hazard regression 
model will be used to analyze the effects of factors, in addition to treatment, that may be associated 
with PFS. 
 
Overall Survival (OS) 
OS is defined as the time from study enrollment to death due to any cause. 
OS will be estimated by the Kaplan-Meier method, and the Cox proportional hazard regression 
model will be used to analyze the effects of factors, in addition to treatment, that may be associated 
with OS. 
 
13.5 
Analysis of Exploratory Endpoints 
 
Genomic signatures that may predict responses to Pembrolizumab and radiation will be explored 
using logistic regression. Descriptive statistics such as mean, standard deviation, median and 
range, will be reported for the levels of circulation tumor DNA and immunologic correlatives. 
Comparison between different time points can be made by t-test or Wilcoxon test where 
appropriate. Logistic regression will be carried out to examine their association with response to  
pembrolizumab and SBRT.  
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All subjects will be evaluable for toxicity from the time of their first treatment with 
pembrolizumab. Toxicities will be evaluated and graded according to CTCAE v4.0, and will be 
assigned an attribution as per Section 7.2. Safety and tolerability will be assessed by clinical review 
of all relevant parameters including AEs, laboratory tests and vital signs. 
 
Toxicity tables will be constructed to summarize the observed incidence of adverse events by 
toxicity and grade. The relative frequency of each type of toxicity will be quantified as the number 
of toxicity-evaluable cycles in which the adverse event was noted as grade 3 or higher considered 
by the treating physician to be possibly, probably or definitely related to one of the agents in the 
regimen, divided by the number of toxicity-evaluable cycles administered to patients enrolled on 
the trial. 
 


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13.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible.  Each subject will be assigned one of the 
following categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 8) unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, 
category 8 usually designates the “unknown” status of any type of data in a clinical database.]  
 
All of the subjects who met the eligibility criteria (with the exception of those who received no 
study medication) will be included in the primary analysis of the response rate.  Subjects in 
response categories 4-7 will be considered to have a treatment failure (disease progression).  Thus, 
an incorrect treatment schedule or drug administration will not result in exclusion from the analysis 
of the response rate. For analysis of the primary endpoint, subjects with missing data will be 
considered non-responders. If data are missing for survival endpoints, subjects will be censored at 
last assessment. 
 
The analysis population for response in non-irradiated lesions consists of subjects with RECIST-
measurable disease outside the radiotherapy treatment field. The analysis population for DOR 
consists of responders (iPR and iCR). 
 
All conclusions will be based on all eligible subjects. Subanalyses may then be performed on the 
basis of a subset of subjects, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these subanalyses will not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding subjects from the analysis will be 
clearly reported. The 95% confidence intervals will also be provided.  
 
 
 
 


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APPENDIX 1 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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APPENDIX 2 
CHILD-PUGH SCORE 
 
The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly cirrhosis. 
Although originally designed to predict mortality after surgery, it is now used to determine 
prognosis and eligibility for treatment as well as the need for future liver transplantation. 
 
The score employs five clinical measures of liver disease. Each measure is scored between 1 and 
3, with 3 indicating most severe derangement. The scores are then added to form a total. 
 
Measure 
1 point 
2 points 
3 points 
Bilirubin (umol/L) 
<34 
34-51 
>51 
Albumin (g/L) 
>35 
28-35 
<28 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
None 
Easily controlled 
Poorly controlled 
Hepatic 
encephalopathy1 
None 
Grade I-II (mild or 
moderate) 
Grade III-IV (severe or 
coma) 
 
Points 
Class 
One year 
survival 
Two year 
survival 
5-6 
A 
100% 
85% 
7-9 
B 
81% 
57% 
10-15 
C 
45% 
35% 
 
1 Hepatic encephalopathy graded according to West Haven Criteria for Semi-quantitative 
Grading of Mental Status: Adapted from: Conn H, Lieberthal M. The hepatic coma 
syndromes and lactulose. Baltimore: Williams & Wilkins; 1979. 
 Grade I: Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired 
performance of addition or subtraction 
 Grade II: Lethargy or Lethargy or apathy; minimal disorientation for time or place; subtle 
personality change; inappropriate behavior 
 Grade III: Somnolence to semi-stupor, but responsive to verbal stimuli 
Confusion; Gross disorientation 
 Grade IV: Coma (unresponsive to verbal or noxious stimuli) 
 
 


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APPENDIX 3 
HEPATITIS B DEFINITIONS AND TREATMENT 
CONSIDERATIONS 
 
The following table describes the various definitions for hepatitis B and the treatment conditions 
for subjects with hepatitis B. 
 
Hepatitis B Definitions and Treatment Considerations 
Test 
Patient Status 
Eligible for 
trial? 
HBV treatment indicated? 
HBsAg (-) 
Total anti-HBc (+) 
HBsAb (+) 
Immune after infection 
Yes 
No 
HBsAg (-) 
Total anti-HBc (-) 
HBsAb (+) 
Immune after vaccination 
Yes 
No 
HBsAg (+) 
Total anti-HBc (+) 
IgM anti-HBc (+) 
HBsAb (-) 
Acute Infection 
No 
N/A 
HBsAg (+) 
Total anti-HBc (+) 
IgM anti-HBc (-) 
HBsAb (-) 
Chronic Infection 
Yes 
Yes, need HBV treatment for ≥ 
2 weeks prior to start of 
pembrolizumab 
Exclude if: 
(a) <2 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 (-) 
Unclear. Could be: 
(1) Resolved infection 
(2) False positive anti-HBc 
(3) Low level infection 
(4) Resolving acute infection 
Yes 
No 
HBsAg (-) 
Total anti-HBc (+) 
IgM anti-HBc (-) 
HBsAb (-) 
HBV viral load (+) 
(1) Low level infection 
(2) Resolving acute infection 
Yes 
Yes (as for acute infection) 
 
 
 
 


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APPENDIX 4 
VASCULAR THROMBOSIS STAGING 
 
The three categories for staging vascular tumor thrombus are: 
 
1. Tumor thrombosis involving the IVC, the main portal vein or the right or left main branch 
portal vein. This includes any thrombi involving these vascular structures at least partially, 
defined as involving any of the IVC, main portal vein or the right or left main branches of 
the portal vein. The right and left main branches of the portal vein are the first branches off 
the main portal vein, up to the first bifurcation of the right and left portal veins, as shown 
in the diagram below. 
 
2. Any other thrombosis (e.g. involving the more distal portal veins or hepatic veins). 
 
3. No vascular thrombosis. 
 
 


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APPENDIX 5 
DATA MANAGEMENT GUIDELINES 
 
Data Management Guidelines 
 
Case Report Form Submission Schedule 
 
The Registration Checklist will be a paper form that will be provided by the Drug Development 
Central Office. All other data required for the study will be collected in eCRFs in Medidata.  The 
form submission schedule is outlined below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline Form 
Within 4 weeks of on study date 
On Treatment Form 
Within 4 weeks of the end of each cycle of 
treatment 
Off Treatment Form 
Within 4 weeks of the subject coming off-study 
Short Follow-up Form 
Within 4 weeks of the subject coming to clinic.  
Required every 3 months until death.  
Final Report Form 
Within 3 months of the subject's death being 
known to the investigator unless this constitutes a 
reportable adverse event when it should be 
reported according to expedited guidelines  
 
Case Report Form Completion 
 
The paper Registration Checklist must be completed using black or blue ink. Any errors must be 
crossed out so that the original entry is still visible, the correction clearly indicated and then 
initialed and dated by the individual making the correction. eCRFs will be completed according 
to the schedule noted above.  
 
All subject names or other identifying information will be removed prior to being sent to the 
Central Office and the documents labeled with subject initials, study number and the protocol 
number if applicable.  
 
Monitoring 
 
This is an investigator initiated study and study monitoring will be performed by the Drug 
Development Program Central Office or its designate. 
 
Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance 
measures will be performed.  Electronic data queries as well as paper query letters may be issued 
to the site. 
 
Regulatory Requirements 
 
 Please submit all required documents to the DDP Central Office. 
 Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. The signed original is to be sent to the DDP Central Office. 


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 All investigators must have an up-to-date CV (signed within 2 years) on file with the 
DDP Central Office. 
 Laboratory certification/accreditation and normal ranges are required 
 Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
 Consent forms must be reviewed by the Central Office before submission to the local 
ethics regulatory board (REB/IRB) and must include a statement that 1) information will 
be sent to and 2) medical records will be reviewed by the DDP Central Office. 
 A Membership list of the local ethics board is required. 
 A copy of the initial approval letter from the ethics board must be submitted to the DDP 
Central Office. 
 A completed Site Participant List/Training Log is required and must be submitted to DDP 
Central Office 
 Continuing approval will be obtained at least yearly until follow-up on subjects is 
completed and no further data is being obtained for research purposes