Sequential TransArterial Chemoembolization and Stereotactic RadioTherapy Followed by ImmunoTherapy for Downstaging Hepatocellular Carcinoma for Hepatectomy (START-FIT)
Phase: PHASE2
Conditions: HCC
Sponsor: The University of Hong Kong

START-FIT v4 (Date: 27 Apr, 2021) 
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Sequential TransArterial chemoembolization 
and stereotactic RadioTherapy Followed by 
ImmunoTherapy 
for 
downstaging 
hepatocellular carcinoma for hepatectomy 
(START-FIT) 
 
Sponsor:  
 
 
 
The University of Hong Kong 
Funder:  
 
 
 
Merck Healthcare KGaA, Darmstadt, Germany 
ClinicalTrials.gov Identifier: 
NCT03817736 
Local Institutional Review Boards: UW 18-541 
 

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Protocol Title: 
Sequential 
TransArterial 
chemoembolization 
and 
stereotactic RadioTherapy Followed by ImmunoTherapy 
for downstaging hepatocellular carcinoma for hepatectomy 
(START-FIT)  
Principal Investigator: 
Dr. C.L. CHIANG 
Department of Clinical Oncology 
The University of Hong Kong  
Tel: +852-2255-4352 
E-mail: chiangcl@hku.hk 
Co-Investigators: 
Prof. Albert C.Y. CHAN 
Department of Surgery  
The University of Hong Kong  
Tel: +852-2255-3025 
E-mail: acchan@hku.hk 
 
Dr. T.C. LAM 
Department of Clinical Oncology  
The University of Hong Kong  
Tel: +852-2255-4352 
E-mail: lamtc03@hku.hk 
Consulting Statistician: 
Dr. Horace C.W. Choi, PhD 
Department of Clinical Oncology 
University of Hong Kong 
Tel: +852-2255-4352 
Email: hcchoi@hku.hk 
Funder: 
Sponsor: 
Merck KGaA (Monetary and drug support)  
The University of Hong Kong 
Protocol-specific Sponsor contact information can be found in the Investigator(s) Study 
File. 
Laboratory-related information can be found in the Investigator(s) Study File, Section 
named ‘Laboratory Documents

START-FIT v4 (Date: 27 Apr, 2021) 
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Investigator(s) Signatory  
I agree to conduct this Clinical Study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol. 
 
 
___________________________________________ 
_______________________ 
Typed Name: Dr. CHIANG Chi Leung 
Title: Clinical Assistant Professor 
Date 

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TABLE OF CONTENTS 
1. 
BACKGROUND .......................................................................................................... 7 
1.1 
SBRT ............................................................................................................................................................ 7 
1.2 
TACE Plus SBRT ........................................................................................................................................ 7 
1.3 
Immune Checkpoint Inhibitors (ICI) ........................................................................................................ 8 
2. 
STUDY OBJECTIVES .................................................................................................... 9 
2.1 
Primary Objective ....................................................................................................................................... 9 
2.2 
Secondary Objectives .................................................................................................................................. 9 
2.3 
Study Design .............................................................................................................................................. 10 
2.4 
Study Participants ..................................................................................................................................... 10 
3. 
ELIGIBILITY CRITERIA (CHECKLIST FORM A) .............................................................. 10 
3.1 
Inclusion Criteria ...................................................................................................................................... 10 
3.2 
Exclusion Criteria ..................................................................................................................................... 11 
4. 
STUDY SCHEMA ...................................................................................................... 13 
5. 
REGISTRATION PROCEDURE .................................................................................... 13 
5.1 
Clinical Evaluation / Management .......................................................................................................... 13 
5.2 
Radiological Evaluation ............................................................................................................................ 14 
5.3 
Quality-of-Life Evaluation ....................................................................................................................... 14 
5.4 
Informed Consent ..................................................................................................................................... 14 
5.5 
Registration Guidelines ............................................................................................................................ 15 
6. 
STUDY INTERVENTION ............................................................................................ 15 
6.1 
Investigational Product ............................................................................................................................. 15 
6.2 
Non-investigational Product ..................................................................................................................... 16 
6.3 
TACE ......................................................................................................................................................... 16 
6.3.1 
Procedure ........................................................................................................................................... 16 
6.3.2 
TACE adverse event .......................................................................................................................... 16 
6.3.3 
TACE Toxicity Assessment During Therapy .................................................................................... 16 

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6.4 
SBRT .......................................................................................................................................................... 17 
6.4.1 
Immobilization and Simulation ......................................................................................................... 17 
6.4.2 
Target volumes .................................................................................................................................. 17 
6.4.3 
Dose Specifications ........................................................................................................................... 17 
6.4.4 
Radiation Therapy Adverse Events ................................................................................................... 19 
6.4.5 
Radiotherapy Toxicity Assessment During Therapy ......................................................................... 20 
6.4.6 
Radiation Modification Table ............................................................................................................ 20 
6.5 
Checkpoint Inhibitor: Avelumab ............................................................................................................. 21 
6.5.1 
Avelumab Dosage Form and Packaging ............................................................................................ 21 
6.5.2 
Avelumab Preparation ....................................................................................................................... 21 
6.5.3 
Avelumab Administration ................................................................................................................. 22 
6.5.4 
Avelumab Adverse Event .................................................................................................................. 22 
6.5.5 
Dose Modifications for Avelumab as Single Agent .......................................................................... 22 
6.5.6 
Adverse Drug Reaction Requiring Avelumab Discontinuation or Delays ........................................ 23 
6.5.7 
Management of Avelumab Infusion-Related Reaction ...................................................................... 23 
6.5.8 
Avelumab: Immune-Related Adverse Events .................................................................................... 25 
6.6 
Record of Treatment Details and Acute Reactions (Form C) ............................................................... 34 
7. 
FOLLOW UP AND OUTCOME EVALUATION .............................................................. 34 
7.1 
Follow-Up Schedule .................................................................................................................................. 34 
7.2 
Decision on Resectability, Subsequent Treatment and Treatment Failure .......................................... 35 
7.3 
Outcome Measures .................................................................................................................................... 35 
7.3.1 
Primary Endpoint ............................................................................................................................... 35 
7.3.2 
Secondary Endpoints ......................................................................................................................... 36 
7.4 
Follow-Up and Record of Events (Form D) ............................................................................................ 37 
7.5 
Criteria for Removal From Protocol Treatment .................................................................................... 37 
7.6 
Exploratory Biomarkers ........................................................................................................................... 38 
7.7 
Safety Reporting ........................................................................................................................................ 38 

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7.7.1 
Adverse Events (AE) ......................................................................................................................... 38 
7.7.2 
Serious Adverse events (SAE)........................................................................................................... 39 
7.7.3 
Adverse Events of Special Interest (AESI) ........................................................................................ 39 
7.7.4 
Pregnancy Reports ............................................................................................................................. 40 
7.7.5 
Assessment of Causality of Adverse Events ...................................................................................... 40 
7.7.6 
Methods of Recording Adverse Events ............................................................................................. 40 
7.7.7 
Procedure of Reporting Serious Adverse Events ............................................................................... 41 
7.7.8 
Monitoring of subjects with Adverse Events ..................................................................................... 42 
8. 
STATISTICS .............................................................................................................. 42 
8.1 
Statistical Analysis .................................................................................................................................... 42 
8.2 
Sample Size Calculation ........................................................................................................................... 43 
8.3 
Early Stopping Rule .................................................................................................................................. 44 
9. 
ETHICAL, REGULATORY & STUDY OVERSIGHT CONSIDERATIONS .............................. 44 
9.1 
Responsibilities of the Investigator(s) ...................................................................................................... 44 
9.2 
Subject Information .................................................................................................................................. 45 
9.3 
Informed Consent (Form B) ..................................................................................................................... 45 
9.4 
Compensation to Subjects ........................................................................................................................ 45 
9.5 
Ethics Committee or Institutional Review Board................................................................................... 46 
9.6 
Role of Funding Source ............................................................................................................................ 46 
9.7 
Publication Policy ...................................................................................................................................... 46 
10. STUDY MANAGEMENT ............................................................................................ 46 
10.1 Data Quality Assurance ............................................................................................................................ 46 
10.2 Direct Access to Source Data/Documents ............................................................................................... 47 
10.3 Study File and Archiving .......................................................................................................................... 48 
11. REFERENCES ............................................................................................................ 49 
 
 
 

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1. 
BACKGROUND 
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and ranks the 
third on the incidence of cancer-related death. There are more than 500,000 new cases 
diagnosed annually worldwide. The incidence and prevalence of HCC are on rising trend with 
the majority of the disease burden is in Asia where viral hepatitis B is endemic. (1)  
Surgical resection, radiofrequency ablation (RFA) and liver transplantation (LT) represent the 
only chance of cure for HCC patients. Despite more aggressive surgical approach has been 
adopted in most Asian countries, yet curative interventions remain only amendable in 30% of 
patients. (2) Most patients are diagnosed with intermediate or advanced stage diseases; the 
long-term cure rate is only 0-10%. For those with inoperable disease, trans-arterial 
chemoembolization (TACE) is the most widely used local therapy and is the standard of care 
for intermediate stage HCC. (3-4) Our previous randomized trial is one of the landmark studies 
to demonstrate the survival benefit in these patients. (3) However, its efficacy is limited in 
those with large tumor burden and vascular involvement. Shim et al. reported the 2-year 
survival of HCC patients receiving TACE is 42% versus 0% for tumor sizes of 5-7cm and ≥ 
8cm, respectively. (5) Tumor response is even more rarely seen in patients receiving oral multi-
kinase inhibitors. (6-7) To date, there is no effective down-staging strategy in unresectable 
HCC due to limited response of various therapeutic approaches. There is a huge unmet need 
for more effective therapy for locally advanced HCC.  
1.1 
SBRT 
Until recently, external radiotherapy has a limited role in the management of HCC. Stereotactic 
body radiotherapy (SBRT) has been introduced to treat liver malignancy since l990s. (8) SBRT 
refers to the utilization of a few fractions of a potent dose of highly conformal radiation with 
excellent geometric precision, therefore able to deliver tumoricidal dose to the tumor while 
sparing the adjacent normal structures. Several prospective series have demonstrated that a 
local control rate of 87-100% at 1-year, overall survival of 60-69% at 2-year and limited 
toxicity. (9-12) Data from literature and our group suggested that SBRT might offer a better 
response rate and more durable control than TACE in locally advanced HCC patients. Large-
scale randomized phase III trial is ongoing in evaluating the combining SBRT and systemic 
therapy Sorafenib versus Sorafenib alone. (13) 
1.2 
TACE Plus SBRT 
Further, meta-analysis has demonstrated TACE plus radiotherapy (RT) are more 
therapeutically beneficial than TACE alone. (14) There are several reasons for the potential 
synergism between the two treatment modalities: RT can kill the residual cancer cells after 
TACE, especially those at the tumor periphery that remain viable through the blood supply 
from the collateral circulation (15); secondly, TACE damages large numbers of cancer cells, 
which promotes the residual cells from a non-proliferative phase into cell proliferation, and 
thus become more radiosensitive (16); thirdly, TACE also decreases the tumor volume, which 
in turn reduces the radiation field and adverse events (17); in addition, the retention of 
chemotherapeutic agents from embolization in liver tumor cells has a radio-sensitizing effect 

START-FIT v4 (Date: 27 Apr, 2021) 
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and accelerates tumor necrosis (18); finally, our group has reported the lipiodol enabled more 
accurate localization of HCC during SBRT. (19) 
Our team had reviewed 73 intermediate to advanced stage HCC patients who received a single 
dose of TACE followed by SBRT. The median size of the tumor is 11.2cm, and 25% of them 
have the vascular invasion. The objective response rate (ORR) was 68%, the 1-year local 
control (LC) rate was 93.6%, the median progression-free survival (PFS) was 7.2 months, and 
median overall survival (OS) was 19.8 months. Twelve (16.4%) patients had treatment 
response were amendable for subsequent surgical resection, median OS was not yet reached 
for those who have operated. There was no patient developed radiation-induced liver disease 
(RILD) (20). Further, we also retrospectively compared the outcomes of TACE plus SBRT 
versus TACE in patients with intermediate HCC using propensity score matching (1:2). There 
was a significant improvement in median OS after TACE+SBRT when compared to TACE 
alone (23.9 months vs. 10.4 months, p<0.001). Also, there was a significant improvement of 
3-year PFS (26.6% vs. 8.3%, p=0.03). (Unpublished data)  
In a recently published phase II randomized trial, 90 unresectable HCC patients with vascular 
invasion were randomized to receive TACE+RT versus Sorafenib; the TACE+RT was 
associated with significantly better 12-week PFS rate (77.8% vs. 26.7%; p<0.001), median 
time to disease progression (30 weeks vs. 8 weeks; p<0.001), and median OS (55 weeks vs. 43 
weeks; p=0.04) than Sorafenib alone. (21)  
Taken together, combined TACE and SBRT is a more powerful local treatment than TACE 
alone, yet distant control remains a key challenge for unresectable HCC patients. 
1.3 
Immune Checkpoint Inhibitors (ICI) 
Immune checkpoint inhibitors (ICI) represent another breakthrough in the management of 
advanced HCC patients. Preclinical data have shown that HCC’s tumor microenvironment is 
immunosuppressive; (22) the overexpression of inhibitory proteins PD-1 and CTLA-4 on the 
exhausted T-cells has rendered the checkpoint inhibitors a promising therapeutic option. (23)  
The first published report on checkpoint inhibition in HCC is a phase II trial using the CTLA-
4 inhibitory antibody tremelimumab. The trial enrolled 21 patients with hepatitis C–related 
cirrhosis. Among 17 evaluable patients, three (18.0%) had a partial response, and an additional 
10 (58.8%) had stable disease, with a median time to progression of 6.5 months. However, 
nearly half (45%) of all patients experienced grade 3 or higher toxicity, primarily transaminase 
elevations. Typical immune-related toxicities such as rash (65%) and diarrhea (30%) were 
common, but no patients required corticosteroid treatment for toxicity. (24) Later, the 
checkmate-040 phase I/II trial was recently published, among 214 of advanced HCC patients 
received anti-PD1 Nivolumab 3mg/Kg every 2 weeks, the objective response rate (ORR) was 
20%, the median duration of response was 9.9 months, and the toxicity profile was manageable. 
(25) The favorable ORR and durability of response have lead to FDA accelerated approval of 
Nivolumab in HCC patients who have previously been treated with Sorafenib.  
There is evidence of synergistic effect from the combination of immunotherapy regimes with 
SBRT. Radiation could induce immunogenic cell death and convert the irradiated tumor into 
an in-situ vaccine to prime the immune system for the checkpoint inhibition. (26) Pre-clinical 
data have demonstrated that the combination of SBRT and checkpoint inhibition resulted in 

START-FIT v4 (Date: 27 Apr, 2021) 
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better local tumor regression and abscopal (out-of-field) effect when compared with the use of 
either single modality treatment. (27-28) Early clinical reports in melanoma and lung cancer 
patients have provided further support for the efficacy and safety of this novel combination. 
(29-30). In the randomized phase III PACIFIC trial in stage III non-small cell lung cancer, 
patients were randomized to receive anti-PD-L1 Durvalumab or placebo after completion of 
chemo-radiation, the PFS was significantly longer in patients receiving checkpoint inhibitors 
(16.8 months versus 5.6 months, p<0.0001). (31)  
Based on our pilot work and the recent evidence, we propose a phase II trial to test the concept 
of combined TACE and SBRT followed by immune checkpoint inhibitor as a neo-adjuvant 
treatment in unresectable HCC patients.  
 
2. 
STUDY OBJECTIVES  
2.1 
Primary Objective  
1. To assess the number of patients amenable to curative surgical interventions in HCC 
patients treated with combined TACE and SBRT followed by Avelumab 
2.2 
Secondary Objectives 
1. To assess the number of patients amenable to curative surgical interventions and/or 
achieve radiological complete response in HCC patients treated with combined TACE 
and SBRT followed by Avelumab 
2. To assess the objective response rate in HCC patients per mRECIST treated with 
combined TACE and SBRT followed by Avelumab 
3. To evaluate the time-to-progression (TTP), progression-free survival (PFS) and 
overall survival (OS) in HCC patients treated with combined TACE and SBRT 
followed by Avelumab 
4. To measure the toxicities in HCC patients treated with combined TACE and SBRT 
followed by Avelumab 
5. To evaluate the patient-reported quality of life (QoL) treated with combined TACE 
and SBRT followed by Avelumab 
6. To describe the pathological response among HCC patients amenable to surgery after 
receiving combined TACE and SBRT followed by Avelumab 
7. To assess the disease control rate (DCR) in HCC patients treated with combined 
TACE and SBRT followed by Avelumab 
8. To assess the local control rate among HCC patients treated with combined TACE 
and SBRT followed by Avelumab  
9. To evaluate the duration of response among HCC patients responded to combined 
TACE and SBRT followed by Avelumab 
10. To describe the pattern of failure at the time of progression  

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11. To assess the objective response rate in HCC patients per RECIST 1.1 treated with 
combined TACE and SBRT followed by Avelumab 
12. Collection of bio-specimens for future correlative studies in patients treated with 
TACE and SBRT followed by Avelumab 
2.3 
Study Design  
This study is a prospective phase II, single arm clinical trial assessing the efficacy and safety 
of the sequential administration of trans-arterial chemo-embolization (TACE) and stereotactic 
body radiotherapy (SBRT) followed by Avelumab in intermediate to advanced hepatocellular 
carcinoma (HCC) patients.  
2.4 
Study Participants 
A total of 33 patients will be accrued to assess the potential benefit of combined TACE and 
SBRT followed by Avelumab. 
 
3. 
ELIGIBILITY CRITERIA (CHECKLIST FORM A)  
3.1 
Inclusion Criteria 
1. 
Diagnosis of unresectable HCC confirmed pathologically or made according to 
American Association for the Study of Liver Diseases (AASLD) practice guideline 
2010: patients with cirrhosis of any etiology and patients with chronic hepatitis B 
(HBV) who may not have fully developed cirrhosis, the presence of liver nodule 
>1cm and demonstrated in a single contrast-enhanced dynamic imaging [magnetic 
resonance imaging (MRI)] of intense arterial uptake and “washout” in portal venous 
and delayed phases.   
2. 
Male or female subjects with age: 18-80 years old 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 
4. 
Tumor size 5-25cm and number of lesions ≤3  
5. 
Portal vein involvement (Vp1-3) is allowed: Vp1, presence of a tumor thrombus 
distal to, but not within, the second-order branches of the portal vein; Vp2, presence 
of a tumor thrombus in the second-order branches of the portal vein; Vp3, presence 
of a tumor thrombus in the first-order branches of the portal vein. (32)   
6. 
Child-Pugh liver function class A-B7 
7. 
Liver volume minus intrahepatic GTV >700 cc. 
8. 
Minimal distance from GTV to stomach, duodenum, small or large bowel >1 cm. 
9. 
No prior systemic therapy nor immunotherapy 
10. 
No prior trans-arterial chemo-embolization (TACE)   
11. 
No prior radiotherapy to the liver or selective internal radiation (SIRT)  

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12. 
Written informed consent obtained for clinical trial participation and providing 
archival tumor tissue, if available. 
13. 
Subjects with confirmed concomitant HBV infection (defined as HBsAg positive 
or HBV DNA detectable) that are eligible for inclusion must be treated with 
antiviral therapy (per local institutional practice) prior to enrollment to ensure 
adequate viral suppression (HBV DNA <2000 IU/mL), must remain on antiviral 
therapy for the study duration, and continue therapy for 6 months after the last dose 
of investigational product(s) 
14. 
At least one measurable lesion according to RECIST v1.1. 
15. 
Adequate organ and marrow function, as defined below: 
 Hemoglobin ≥9 g/dL 
 Absolute neutrophil count ≥1,500/μL 
 Platelet count ≥75,000/μL 
 Total bilirubin ≤2.0 × ULN 
 ALT ≤3 × ULN 
 Albumin ≥2.8 g/dL 
 INR ≤1.6 
 Calculated creatinine clearance ≥45 mL/minute as determined by Cockcroft-
Gault (using actual body weight) or 24-hour urine creatinine clearance 
16. 
Females of childbearing potential or non-sterilized male who are sexually active 
must use a highly effective method of contraception  
17. 
Females of childbearing potential must have negative serum or urine pregnancy test  
3.2 
Exclusion Criteria  
1. 
Prior invasive malignancy within 2 years except for noninvasive malignancies such 
as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma 
of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically 
cured 
2. 
Contraindicated of SBRT: Any one hepatocellular carcinoma >25 cm; Total 
maximal sum of hepatocellular carcinoma >30 cm; More than 3 discrete hepatic 
nodule; Direct tumor extension into the stomach, duodenum, small bowel, large 
bowel, common or main branch of biliary tree 
3. 
Severe, active co-morbidity 
4. 
Presence of extra-hepatic metastases (M1)  
5. 
Vp4: presence of a tumor thrombus in the main trunk of the portal vein or a portal 
vein branch contralateral to the primarily involved lobe (or both) or inferior vena 
cava (IVC) thrombosis or involvement 
6. 
Presence of clinically meaningful ascites as ascites requiring non pharmacologic 
intervention (eg, paracentesis) or escalation in pharmacologic intervention to 
maintain symptomatic control 
7. 
Hepatic encephalopathy  
8. 
Active or untreated gastrointestinal varices 

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9. 
Untreated central nervous system (CNS) metastatic disease, lepto-meningeal 
disease, or cord compression 
10. 
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke ( <6 months prior to enrollment), myocardial infarction ( <6 months 
prior to enrollment), unstable angina, congestive heart failure (New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication. 
11. 
Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or 
PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other 
immuno-regulatory receptors or mechanisms 
12. 
Irritable bowel syndrome or other serious gastrointestinal chronic conditions 
associated with diarrhea within the past 3 years prior to the start of treatment 
13. 
Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
14. 
On chronic systemic steroid or any other forms of immunosuppressive medication 
within 14 days prior to the treatment. Except:  
(a) intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-
articular injection);  
(b) Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or 
equivalent;  
(c) Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication).  
15. 
Active or prior documented autoimmune or inflammatory disorders in the past 2 
years, except diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases 
not requiring immunosuppressive treatment 
16. 
History of primary immunodeficiency or solid organ transplantation 
17. 
Receipt of live, attenuated vaccine within 28 days prior to the study treatment 
18. 
Active infection requiring systemic therapy 
19. 
Severe hypersensitivity reaction to treatment with another monoclonal antibody 
(mAb)  
20. 
Females who are pregnant, lactating, or intend to become pregnant during their 
participation in the study 
21. 
Psychiatric disorders and substance (drug/alcohol) abuse 
 
 

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4. 
STUDY SCHEMA 
 
 
 
 
Protocol treatment must begin within 28 days after study registration  
 
Patient Population (See section 3 for eligibility) 
 Unsuitable for surgical resection or transplant or radiofrequency ablation (RFA)  
 Barcelona Clinic Liver Cancer Stage (BCLC) Intermediate (B) or Advanced (C)  
 No main portal vein thrombosis  
 No lymph node nor extra-hepatic metastases   
 
5. 
REGISTRATION PROCEDURE  
5.1 
Clinical Evaluation / Management  
 Document performance status 
 Documentation of liver disease etiology including cirrhosis, hepatitis history (hepatitis 
B and hepatitis C), alcohol, autoimmune disease, non-alcoholic steatohepatitis (NASH) 
 Documentation of prior HCC therapies 
 Initiation of treatment of viral hepatitis B (if untreated) prior to study therapy 
 Patients with known portal hypertension or known history of varices are encouraged to 
have an endoscopic assessment of and appropriate treatment of varices within 6 months 
of study entry  
 Blood tests including complete blood picture, liver function test, renal function test, 
free T4 and TSH, eGFR, clotting profile within 28 days prior to study entry  
 Alpha-fetoprotein (AFP) within 28 days prior to study entry  
4 weeks 
2 weeks 
 
TACE 
 
Avelumab  
every 2 week 
(+/- 3 days) 
Treatment 
end 
Progression 
Unacceptable 
toxicity 
Maximum of 2 years 
Or 
 Amendable to 
curative surgical 
interventions  
 
SBRT 
27.5-50Gy in 5 
fractions 

START-FIT v4 (Date: 27 Apr, 2021) 
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 Urine or serum pregnancy test every 4 weeks while on avelumab therapy 
 Free T4 and TSH must be performed at baseline and at least every 8 weeks during 
avelumab treatment and at end of treatment or 30 days post-treatment safety follow-up 
(if not performed in the previous 8 weeks) 
 20cc blood for bio-banking: Peripheral blood monocytic cells (PBMC) will be collected 
to analyze the peripheral T-cell response during treatment  
5.2 
Radiological Evaluation  
All HCC patients are required to have a dynamic imaging with contrast (MRI) to confirm the 
diagnosis of HCC and assessment of tumor status 
 Number of HCC nodule(s) 
 Sum of maximum diameter of tumor(s) 
 Degree of vascular involvement: inferior vena cava, main portal vein, right or left portal 
vein, peripheral portal branches, hepatic vein 
 Extra-hepatic disease status, number of sites and sum of maximum diameter of extra-
hepatic disease 
MRI 
MRI will be performed on 1.5T GE Signa system (GE Healthcare, Milwaukee, WI) or Philips 
3T MRI Achieva scanner (Philips Healthcare, Best, The Netherlands) with a 12/16-channel, 
phased-array body coil. The protocol, as recommended by LI-RADS v2017 includes axial free-
breathing fat-suppressed echo-planar imaging based DW-MRI, axial breath-hold fat-
suppressed 2-dimensional (2D) fast spin-echo T2W with short and long echo times, axial 
breath-hold 2D in- and opposed-phase T1W and axial 3D gradient-echo T1W before and after 
contrast injection (arterial, portovenous and delayed phases).  
The cross-sectional images will be reviewed by a multi-disciplinary team.  
5.3 
Quality-of-Life Evaluation  
Quality of life will be assessed by the previously validated EORTC-QLQ-C30 and FACT-Hep 
questionnaire. The EORTC QLQ-C30 incorporates 30 items comprising five functional scales 
(physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and 
nausea and vomiting), and a global health and QoL scale. The FACT-Hep is a 45-item self-
report instrument designed to measure health-related quality of life (HRQL) in patients. All 
forms will be self-administered surveys. A nurse or other health care provider will be available 
to help the patient with any questions regarding the QOL forms. 
5.4 
Informed Consent 
The Investigator(s) (according to applicable regulatory requirements), or a person designated 
by the Investigator(s), and under the Investigator(s)’s responsibility, should fully inform the 

START-FIT v4 (Date: 27 Apr, 2021) 
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patient of all pertinent aspects of the clinical study including the written information giving 
approval/favorable opinion by the Ethics Committee (IRB/EC). All participants shall be 
informed to the fullest extent possible about the study, in language and terms they are able to 
understand. 
Prior to a patients’ participation in the clinical study, the written Informed Consent Form (Form 
B) and any other local applicable documents in accordance with local laws and regulations, 
should be signed, name filled in and personally dated by the patient or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent discussion. 
A copy of the signed and dated written Informed Consent Form will be provided to the patient. 
The Informed Consent From used by the Investigator(s) for obtaining the patient’s informed 
consent must be reviewed and approved by the appropriate Ethics Committee (IRB/EC) for 
approval/favorable opinion. 
During a patient’s participation in the study, any updates to the consent form any updates to 
the written information will be provided to the patient. 
Further information about the informed consent is available in Section 9.2 and Section 9.3. 
5.5 
Registration Guidelines 
 All the patients must be registered with the Investigator(s) prior to initiation of treatment. 
 Forms A (registration) and B (consent) will be submitted. 
 The registration desk will confirm all eligibility criteria and obtain essential information 
(including patient number). 
 
6. 
STUDY INTERVENTION 
6.1 
Investigational Product 
An investigational product, also known as investigational medicinal product in some regions, 
is defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but 
used for an unauthorized indication, or when used to gain further information about the 
authorized form. 
The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the Investigator(s) to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations.  
In this protocol, the investigational products is Avelumab for injection. 

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6.2 
Non-investigational Product 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational product. 
6.3 
TACE  
6.3.1 Procedure  
Procedure of TACE will be standardized. A femoral artery puncture will be performed under 
local anesthesia. Celiac and superior mesenteric arterial and porto-venogram will be done to 
delineate arterial anatomy, to exclude main portal vein occlusion and to define size and number 
of tumor nodules. The right or left hepatic artery will then be super-selectively catheterized. 
An emulsion of a mixture of cisplatin (1mg/ml) with lipiodol in a volume ratio of 1 to 1 will 
be prepared. A maximum of 60ml (equivalent to 30mg of cisplatin) mixture will be injected 
slowly under fluoroscopic monitoring. The amount of mixture used will depend on tumor size, 
number and arterial blood flow. The aim is to deliver a sufficient amount of emulsion to tumor 
without retrograde flow. In case of bi-lobed HCC or super-selective cannulation is not possible, 
the emulsion will be injected to hepatic artery proper that distal to origin of gastro-duodenal 
artery. This will be followed by embolization with gelfoam pellets of 1mm diameter mixed 
with 40mg of gentamicin.  
6.3.2 TACE adverse event  
Common (60-80%) 
Post-embolization syndrome (RUQ pain, nausea, fatigue, fever, ileus and transient raised of 
liver enzymes), usually self-limiting and recover within 7-10 days 
Uncommon side effects (<5%) 
Hepatic decompensation, liver abscess, cholecystitis, bile duct injury, gastroduodenal 
ulceration and renal dysfunction 
6.3.3 TACE Toxicity Assessment During Therapy 
Patient should be seen at least once after TACE before initiation of SBRT. SBRT can be 
commenced if there is no grade 3 or 4 toxicity, bilirubin ≤3.0 mg/dL, Child Pugh score ≤7 and 
the treating physician recommends continuation. Otherwise, a delay in SBRT should occur 
until toxicities resolve.  

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6.4 
SBRT  
SBRT screening and planning will be performed by radiation therapists, medical physicists, 
and oncologists. Treatment will be delivered by a 6MV/10MV linear accelerator at 4 weeks (or 
within 21-35 days) after TACE  
6.4.1 Immobilization and Simulation 
Patients will be positioned supine in an Alpha Cradle or equivalent immobilization device will 
be custom made for each patient. Treatment planning CT scans will be required to define gross 
tumor volume (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). If oral contrast is used at simulation, similar timing and 
volume of oral contrast is to be used at the time of treatment. 
Breath-hold CT or average phase CT (from 4D-CT) may be used as the baseline CT for 
radiation therapy planning. 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 management is 
recommended if breathing motion is >5 mm. Motion management can be addressed using 
respiratory gating, active breathing control (ABC), or abdominal compression.   
 
6.4.2 Target volumes 
Gross tumor volume (GTV) is defined as HCC focus that is visualized on contrast imaging, 
usually best seen on arterial phase (as hyperintensity) or washout out at portovenous/ delayed 
phase. 
Clinical target volume (CTV) is defined as GTV with expansion to include the lipodol stained 
area.  
Planning target volume (PTV) will provide margin around each CTV to compensate for 
respiratory motions. Individualized margin will be added to CTV to form the planning target 
volume (PTV) to compensate for respiratory motions. The margin recipe depends on the 
motion management solution utilized. Typically, a minimum PTV of 4mm around each CTV 
is required and the maximum permitted PTV is 20mm.  
6.4.3 Dose Specifications 
Treatment Schedule: 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.  

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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 minimal planned prescription dose to PTVs is 27.5 Gy. 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. 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. 
Dose Specification: The prescription isodose should encompass 95% of PTV. 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.  
Vascular tumor thrombosis (e.g., portal vein thrombosis) dose should be the same as the HCC 
prescription dose. However, lower doses are acceptable if required to maintain normal tissue 
limits, since the cancer density may be lower than parenchymal HCC.  
Dose prescription based on mean liver dose (MLD)  
Prescription dose Liver – GTV mean dose 
Ideal 
Acceptable 
50Gy 
≤13Gy 
13-13.2Gy 
45Gy 
≤13Gy 
15-15.2Gy 
40Gy 
≤15Gy 
15-15.2Gy 
35Gy 
≤15.5Gy 
15.5-15.7Gy 
30Gy 
≤16Gy 
16-16.2Gy 
27.5Gy 
≤17Gy 
17-17.2Gy 
Organ-at-risk (OAR) dose constraints 
 
Compliance Criteria:  
Ideal 
Acceptable 
Priority 1: Mandatory dose constraints  
Stomach, small intestine, duodenum: 
Max (to 0.5cc) 
30Gy 
>30Gy but ≤32Gy 
Large bowel, oesophagus: 
Max (to 0.5cc) 
32Gy 
>32Gy but ≤34Gy 
Spinal cord + 5mm:  
Max (to 0.5cc) 
25Gy 
>25Gy but ≤28Gy 
Kidney: Bilateral mean dose 
≤10Gy 
>10Gy but ≤12Gy 

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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 
(a) PTV dosimetry  
 The intent is for prescription dose to cover 95% of each PTV 
 The PTV should be treated to as high a dose as possible, respecting normal tissue 
constraints (as above) 
 Modifying required PTVs due to close proximity of adjacent OARs is not permitted 
 
Dose to 95% PTV 
 
Per Protocol  
Prescription dose +/- 5% 
Variation acceptable  
90% - 110% of prescribed dose 
Derivation unacceptable  
<90% or >110% of prescribed dose,  
or <25Gy 
6.4.4 Radiation Therapy Adverse Events 
The criteria used for the grading of toxicities encountered in this study are Common Toxicity 
Criteria (CTC) version 4.0. 
Very likely (80-90%) 
 Fatigue 
 Skin irritation, itchiness, discomfort 
 Transient changes in blood work (decrease in blood counts, increase in liver 
enzymes), without symptoms 
Less likely (<30%) 
 Nausea, vomiting  
Priority 2: Non-mandatory dose constraints 
Heart: Max (to 30cc) 
<30Gy 
Gall bladder: Max (to 0.5cc)  
<55Gy 
Common bile duct: Max (to 0.5cc) 
<50Gy 
Central biliary structure (main portal 
vein + 1.5cm):  
V40 <21cc 
Skin: Max (to 0.5cc) (external + 5mm) 
<32Gy 
Great vessel: Max (to 0.5cc)  
<60Gy 

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 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 (<20%) 
 Radiation-induced liver disease (RILD) (<5%). Classic RILD is a clinical diagnosis of 
anicteric ascites, hepatomegaly and elevation of alkaline phosphatase 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 (~20%). RILD can lead to liver failure 
that could lead to death.  
 Permanent thrombocytopenia (<1%); this may lead to bleeding 
 Kidney injury (<1%); this may lead to changes on imaging  
6.4.5 Radiotherapy Toxicity Assessment During Therapy  
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 ≤3.0 mg/dL, Child 
Pugh score ≤7 and the treating physician recommends continuation. Otherwise, a delay in 
radiation therapy should occur with possible continuation of radiation after toxicities resolve. 
If the patient discontinues radiation therapy prematurely, the patient may be considered for 
study Avelumab, if the Child score is Child Pugh ≤7 and the treating physician recommends 
protocol treatment continuation.  
6.4.6 Radiation Modification Table 
TOXICITY 
MODIFICATION 
Hematological  
Grade 1 or 2 
Continue radiation  
Grade 3  
Hold radiation until ≤ grade 2, then continue 
Grade 4 
Hold radiation 1 week and until ≤ grade 2, then continue 
 
 
Gastrointestinal (nausea, vomiting and diarrhea)  
Grade 1 or 2 
Continue radiation  
Grade 3  
Hold radiation until ≤ grade 2, then continue 
Grade 4 
Discontinue radiation  
 
 
Hepatic dysfunction  
Grade 1 or 2 AST or ALT 
Continue radiation  
Grade 3 AST or ALT 
Hold radiation until ≤ grade 2, then continue 
Grade 4 AST or ALT 
Hold radiation 1 week and until ≤ grade 2, then continue 
Bilirubin ≤3.0 mg/dL 
Continue radiation  
Bilirubin >3.0 mg/dL 
Hold radiation until improved ≤3.0, then continue 

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Child-Pugh score >7 
Hold radiation until improves to CP score ≤7 
 
 
Other non-hematological  
Grade 1 or 2  
Continue radiation  
Grade 3  
Hold radiation until ≤ grade 2, then continue 
Grade 4 
Discontinue radiation  
6.5 
Checkpoint Inhibitor: Avelumab  
Avelumab will be started 14 days (or 14-18 days) upon completion of SBRT. 
6.5.1 Avelumab Dosage Form and Packaging 
Avelumab is a sterile, clear, and colorless solution intended for IV administration. Avelumab 
is formulated as a 20 mg/mL solution and will be supplied by the manufacurer in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-
off seal. 
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines. Avelumab will be packed as 
IMP in boxes each containing 8 vials. The information on the study treatment will be in 
accordance with approved submission documents. 
Avelumab will be shipped in transport cool containers (2oC to 8oC) that is monitored with 
temperature control devices. 
6.5.2 Avelumab Preparation 
The contents of the avelumab vials are sterile and non-pyrogenic, and do not contain 
bacteriostatic preservatives. Any spills that occur should be cleaned up using the facility’s 
standard clean-up procedures for biologic products. 
Avelumab must be diluted with 0.9% sodium chloride (normal saline solution). Detailed 
information on infusion bags and medical devices to be used for the preparation of the dilutions 
and subsequent administration will be provided. Must use tubing with in line, low protein 
binding 0.2 micron filter made of polyether sulfone (PES) during administration. 
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg). All patients should be weighed within 3 days prior to dosing 
for each dose to ensure they did not experience either a weight loss or gain of >10% from the 
weight used for the last dose calculation. For weight change less than 10% the decision to 
recalculate the avelumab dose can be in accordance with institutional practice. If the patient 
experienced either a weight loss or gain >10% compared to the weight used for the last dose 
calculation, the amount of study drug must be recalculated. 
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration. 

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6.5.3 Avelumab Administration 
Avelumab 10 mg/kg will be administered on Day 1 of each 2-week study cycle. Avelumab 
may be administered up to 3 days before or after the scheduled day of administration of each 
cycle due to administrative reasons. 
Pre-medication: Avelumab will be administered as a 1-hour IV infusion. In order to mitigate 
infusion-related reactions, a premedication regimen of diphenhydramine 25 to 50 mg IV or oral 
equivalent and paracetamol 500 mg IV or oral equivalent is mandatory approximately 30 to 60 
minutes prior to each dose of avelumab.  
Setting: Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures. Steroids (dexamethasone 
10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should beavailable for immediate access. 
Observation period: Following infusions, patients must be observed for 30 minutes post-
infusion for potential infusion-related reactions. 
Drug accountability including receipt and return, local discard and destruction, if appropriate, 
must be completed with appropriate documentation for all study sites. Lot number, and expiry 
date for Avelumab is recorded in the study site as per local guidelines unless otherwise 
instructed by the Sponsor. 
The investigator is responsible for taking steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution and usage of study treatments in accordance 
with the protocol and any applicable laws and regulations. 
6.5.4 Avelumab Adverse Event 
 Infusion related reaction 
 Fatigue 
 Immune-related 
adverse 
events 
include 
pneumonitis, 
colitis, 
hepatitis, 
endocrinopathies including thyroid disorders (hyperthyroidism, hypothyroidism, 
thyroiditis), adrenal 
insufficiency, hypophysitis, 
and diabetes mellitus 
or 
hyperglycemia, rash, nephritis and renal dysfunction, encephalitis, eye disorders 
(including uveitis, iritis), and other immune-mediated reactions including myositis and 
myocarditis. 
6.5.5 Dose Modifications for Avelumab as Single Agent 
For avelumab, no dose reductions are permitted in this study, but doses may be omitted based 
on persisting toxicity. Any adverse event suspected to be immune related should be managed 
according to the guidance for management of irAEs (see the following tables). 

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6.5.6 Adverse Drug Reaction Requiring Avelumab Discontinuation or Delays 
The following adverse reactions (ADRs) require permanent treatment discontinuation of 
avelumab: 
Any Grade 4 ADRs require avelumab treatment discontinuation except for single 
laboratory values out of normal range that are unlikely related to trial treatment as assessed by 
the Investigator(s), do not have any clinical correlate, and resolve within 7 days with adequate 
medical management. 
Any Grade 3 ADRs require avelumab treatment discontinuation except for any of the 
following: 
 Transient (≤6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management 
 Transient (≤24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to Grade ≤1 
 Single laboratory values out of normal range (excluding Grade ≥3 liver function test 
increase) that are unlikely related to trial treatment according to the Investigator(s), do 
not have any clinical correlate, and resolve to Grade ≤1 within 7 days with adequate 
medical management 
 Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor 
 Change in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to 3 
that resolve to ≤2 within 14 days (infusions should not be given on the following cycle, 
if the ECOG PS is 3 on the day of trial drug administration). 
Any Grade 2 ADR should be managed as follows: 
 If a Grade 2 ADR resolves to Grade ≤1 within 2 weeks treatment may continue. 
 If a Grade 2 ADR does not resolve to Grade ≤1 within 2 weeks, avelumab should be 
held. If after another 2 weeks the event has not resolved to Grade 1, the patient should 
permanently discontinue treatment with an avelumab (except for hormone 
insufficiencies, that can be managed by replacement therapy; for these hormone 
insufficiencies, up to 2 subsequent doses may be omitted). 
 Upon the second occurrence of the same Grade 2 ADR (except for hormone 
insufficiencies that can be managed by replacement therapy) in the same patient, 
treatment with avelumab has to be permanently discontinued. 
6.5.7 Management of Avelumab Infusion-Related Reaction 
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms such 
as fever, chills, rigors, diaphoresis, and headache). Treatment of the infusion-related reaction 

START-FIT v4 (Date: 27 Apr, 2021) 
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and modifications of avelumab infusion are mainly dependent upon severity, as indicated in 
Table. 
Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade 
Treatment Modification for 
Avelumab 
Grade 1 — mild  
Mild 
transient 
reaction; 
infusion 
interruption not indicated; intervention 
not indicated.  
Decrease the avelumab infusion rate by 
50% and monitor closely for any 
worsening.  
Grade 2 — moderate  
Therapy 
or 
infusion 
interruption 
indicated but responds promptly to 
symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 24 h.  
Temporarily 
discontinue 
avelumab 
infusion. Resume infusion at 50% of 
previous 
rate 
once 
infusion-related 
reaction has resolved or decreased to at 
least Grade 1 in severity, and monitor 
closely for any worsening.  
Grade 3 or Grade 4 — severe or  
life-threatening  
Grade 3: Prolonged (for example, not 
rapidly 
responsive 
to 
symptomatic 
medication and/or brief interruption of 
infusion); 
recurrence 
of 
symptoms 
following 
initial 
improvement; 
hospitalization indicated for clinical 
sequelae.  
Grade 4: Life-threatening consequences; 
urgent intervention indicated.  
Stop avelumab infusion immediately and  
disconnect infusion tubing from the 
subject.  
Subjects 
have 
to 
be 
withdrawn 
immediately from study avelumab and 
must not receive any further avelumab 
treatment. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion reaction, it must remain decreased for the next scheduled infusion. If no 
infusion reaction is observed in the next scheduled infusion, the infusion rate may be 
returned to baseline at the subsequent infusions based on Investigator(s)'s medical 
judgment.  
- If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = non-steroidal anti-inflammatory drugs. 
 
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions If, in the 
event of a Grade 2 infusion-related reaction that does not improve or worsens after 

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implementation of the modifications indicated in Table 6 (including reducing the infusion rate 
by 50%), the Investigator(s) may consider treatment with corticosteroids, and the infusion 
should not be resumed. At the next dose, the Investigator(s) may consider the addition of H2 
blocker antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the 
mandatory premedication. Prophylactic steroids are NOT permitted. 
Severe Hypersensitivity Reactions If hypersensitivity reaction occurs, the patient must be 
treated according to the best available medical practice. A complete guideline for the 
emergency treatment of anaphylactic reactions according to the Working Group of the 
Resuscitation 
Council 
(United 
Kingdom) 
can 
be 
found 
at 
https://www.resus.org.uk/pages/reaction.pdf. Patients should be instructed to report any 
delayed reactions to the Investigator(s) immediately. 
Symptoms include impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, 
hypotension, pale or clammy skin, and cyanosis. These symptoms can be managed with 
epinephrine injection and dexamethasone. Patients should be placed on monitor immediately, 
and the intensive care unit (ICU) should be alerted for possible transfer if required. 
 
6.5.8 Avelumab: Immune-Related Adverse Events 
Because inhibition of PD-L1 stimulates the immune system, avelumab may cause toxicity by 
increasing the immune response, leading to inflammatory reactions collectively referred to as 
immune-related adverse events (irAEs). 
Immune-related adverse events described with this class of drugs include drugs include 
dermatitis, pneumonitis, colitis, hepatitis, endocrinopathies including thyroid disorders 
(hyperthyroidism, hypothyroidism, thyroiditis), adrenal insufficiency, hypophysitis, and 
diabetes mellitus or hyperglycemia, rash, nephritis and renal dysfunction, encephalitis, eye 
disorders (including uveitis, iritis), and other immune-mediated reactions including myositis 
and myocarditis. 
Any adverse event which may have an underlying immune-mediated mechanism including 
those described above, and without other confirmed etiologies, should be considered immune-
related and managed according to guidelines described in this section. 
Treatment of irAEs is mainly dependent upon severity (NCI CTCAE grade): 
 Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring. 
 Grades 1 to 2 (persistent): manage similar to high grade AE (Grades 3 to 4). 
 Grades 3 to 4: treat with high dose corticosteroids. 
For patients receiving avelumab alone, any event suspected to be immune-related should be 
managed according to the guidance for management of irAEs in this section and Table.  
 
 

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Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1  
Diarrhea: <4 stools/day over 
Baseline  
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for 
worsening symptoms  
Educate subject to report 
worsening immediately  
If worsens:  
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids 
indicated <24 hours; not 
interfering with ADL Colitis: 
abdominal pain; blood in stool  
Withhold avelumab therapy  
Symptomatic treatment  
If improves to Grade I :  
Resume avelumab 
therapy  
If persists >5-7 days or 
recurs:  
Treat as Grade 3 or 4.  
Grade 3 to 4  
Diarrhea (Grade 3): 7 stools 
per day over Baseline; 
incontinence; IV fluids 24 h; 
interfering with ADL  
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs  
Grade 4: life-threatening, 
perforation  
Withhold avelumab for 
Grade 3.  
Permanently discontinue for 
Grade 4 or recurrent Grade 
3.  
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until 
Grade ≤ 1, then taper 
over at least 1 month; 
resume avelumab therapy 
following steroids taper 
(for initial Grade 3).  
If worsens, persists >3 to 
5 days, or recurs after 
improvement:  
Add infliximab 5mg/kg 
(if no contraindication). 
Note: infliximab should 
not be used in cases of 
perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering 30% body surface 
area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists >1 to 2 weeks 
or recurs:  
Withhold avelumab 
therapy 

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Consider skin biopsy  
Consider 0.5-1.0 
mg/kg/day prednisone or 
equivalent. Once 
improving, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for 
opportunistic infections, 
and resume avelumab 
therapy following 
steroids taper.  
If worsens: Treat as 
Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering >30% body 
surface area;  
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3.  
Permanently discontinue for 
Grade 4 or recurrent Grade 
3.  
Consider skin biopsy  
Dermatology consult 1.0 to 
2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade 1:  
Taper steroids over at 
least 1 month; resume 
avelumab therapy 
following steroids taper 
(for initial Grade 3).  
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1  
Radiographic changes only 
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 
weeks  
If worsens:  
Treat as Grade 2 or Grade 
3 to 4.  
Grade 2  
Mild to moderate new 
symptoms  
Withhold avelumab therapy  
Pulmonary and Infectious 
Disease consults  
Re-assess every 1 to 3 
days  
If improves:  
When symptoms return to 
Grade 1, taper steroids 

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Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
over at least 1 month, and 
then resume avelumab 
therapy following 
steroids taper  
If not improving after 2 
weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4  
Grade 3: Severe new 
symptoms; New/worsening 
hypoxia;  
Grade 4: Life-threatening  
Permanently discontinue 
avelumab therapy.  
Hospitalize.  
Pulmonary and Infectious 
Disease consults.  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
If improves to Grade 1:  
Taper steroids over at 
least 1 month  
If not improving after 48 
hours or worsening:  
Add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1  
Grade 1 AST or ALT >3.0 × 
ULN and/or Total bilirubin > 
ULN to 1.5 × ULN 
Continue avelumab therapy  
Continue liver function 
monitoring  
If worsens: 
Treat as Grade 2 to 3 or 
4. 
Grade 2  
AST or ALT >3.0 to 5 × ULN  
and/or Total bilirubin >1.5 to 3 
× ULN  
Withhold avelumab therapy  
Increase frequency of 
monitoring to every 3 days.  
If returns to Grade 1 :  
Resume routine 
monitoring; resume 
avelumab therapy.  
If elevation persists >5 to 
7 days or worsens:  
Treat as Grade 3 to 4.  

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Grade 3 to 4  
AST or ALT >5 × ULN and/or  
total bilirubin >3 × ULN  
Permanently discontinue 
therapy  
Increase frequency of 
monitoring to every 1 to 2 
days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/  
Consider obtaining MRI/CT 
scan of liver and liver 
biopsy if clinically 
warranted  
If returns to Grade 1:  
Taper steroids over at 
least 1 month  
If does not improve in >3 
to 5 days,  
worsens or rebounds:  
Add mycophenolate 
mofetil 1 gram (g) twice 
daily  
If no response within an 
additional 3 to 5 days, 
consider other 
immunosuppressants per 
local guidelines. 
Renal irAEs 
Grade of Creatinine 
Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1  
Creatinine increased > ULN to 
1.5 × ULN  
Continue avelumab therapy 
Continue renal function 
monitoring  
If worsens:  
Treat as Grade 2 to 3 or 
4.  
Grade 2 to 3  
Creatinine Increased >1.5 and 
6 × ULN  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.  
Add prophylactic antibiotics 
for opportunistic infections 
Consider renal biopsy  
If returns to Grade 1:  
Taper steroids over at 
least 1 month, and 
resume avelumab therapy 
following steroids taper.  
If worsens:  
Treat as Grade 4.  
Grade 4  
Creatinine increased >6 × ULN  
Permanently discontinue 
avelumab therapy  
Monitor creatinine daily  
If returns to Grade 1:  
Taper steroids over at 
least 1 month.  

START-FIT v4 (Date: 27 Apr, 2021) 
Page 30 of 51 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.  
Add prophylactic antibiotics 
for opportunistic infections  
Consider renal biopsy  
Nephrology consult  
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy.  
Hospitalize.  
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced 
heart failure and arrhythmia 
management.  
Cardiology consult to 
establish etiology and rule-
out immune-mediated 
myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult*. 
Consider myocardial biopsy 
if recommended per 
cardiology consult.  
If symptoms improve and 
immune-mediated 
etiology is ruled out, re-
start avelumab therapy.  
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, 
and immune-mediated 
etiology is suspected or 
confirmed following 
cardiology consult, 
manage as immune-
mediated myocarditis.  
Immune-mediated myocarditis  
Permanently discontinue 
avelumab.  
Guideline based supportive 
treatment as appropriate as 
per cardiology consult*.  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections.  
Once improving, taper 
steroids over at least 1 
month.  
If no improvement or 
worsening, consider 
additional 
immunosuppressants (e.g. 
azathioprine, 
cyclosporine A).  

START-FIT v4 (Date: 27 Apr, 2021) 
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*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines  
AHA guidelines website:  
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t
=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2  
(hypothyroidism,  
hyperthyroidism, adrenal  
insufficiency, type I diabetes  
mellitus)  
Continue avelumab therapy  
Endocrinology consult if 
needed  
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-
thyroid treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
hypophysitis)  
Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)  
Withhold avelumab therapy  
Consider hospitalization  
Endocrinology consult  
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-
thyroid treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
hypophysitis)  
Resume avelumab once 
symptoms and/or 
laboratory tests improve 
to Grade 1 (with or 
without hormone 
replacement/suppression)
.  
Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate.  

START-FIT v4 (Date: 27 Apr, 2021) 
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Hypopituitarism/Hypophysiti
s (secondary 
endocrinopathies)  
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol 
with inappropriately low 
ACTH):  
 
Refer to 
endocrinologist for 
dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women)  
 
Hormone 
replacement/suppressiv
e therapy as appropriate  
 
Perform pituitary MRI 
and visual field 
examination as 
indicated  
If hypophysitis confirmed:  
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month  
Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during 
at least 1 month.  
Add prophylactic antibiotics 
for opportunistic infections.  
Resume avelumab once 
symptoms and hormone 
tests improve to Grade 1 
(with or without hormone 
replacement).  
In addition, for 
hypophysitis with 
abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.  
Continue hormone 
replacement/suppression 
therapy as appropriate.  
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 

START-FIT v4 (Date: 27 Apr, 2021) 
Page 33 of 51 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Withhold avelumab therapy 
pending clinical 
investigation  
If irAE is ruled out, 
manage as appropriate 
according to the 
diagnosis and consider 
re-starting avelumab 
therapy  
If irAE is confirmed, treat 
as Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3  
Withhold avelumab therapy  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult as 
appropriate  
If improves to Grade 1:  
Taper steroids over at 
least 1 month and resume 
avelumab therapy 
following steroids taper. 
Recurrence of same Grade 3 
Permanently discontinue 
avelumab therapy  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult as 
appropriate  
If improves to Grade 1:  
Taper steroids over at 
least 1 month.  
Grade 4 
Permanently discontinue 
avelumab therapy  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed  
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult.  
If improves to Grade 1:  
Taper steroids over at 
least 1 month  
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency  
Permanently discontinue 
avelumab therapy  
Specialty consult  
 

START-FIT v4 (Date: 27 Apr, 2021) 
Page 34 of 51 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer  
6.6 
Record of Treatment Details and Acute Reactions (Form C) 
The treatment details of TACE, SBRT and Avelumab will be documented. The incidence of 
acute toxicities > grade 3 by Common Toxicity Criteria for Adverse Events version 4.0 
(CTCAE-v4) will also be recorded. 
 
7. 
FOLLOW UP AND OUTCOME EVALUATION 
7.1 
Follow-Up Schedule  
All participants will be followed every 2 weeks during the intervention. At each visit, patient’s 
performance status and toxicity of treatment will be monitored, and blood test will be checked 
for complete blood picture, liver function, renal function, clotting profile and alpha-fetoprotein 
(AFP). A urine or serum pregnancy test needs to be performed at least every month while the 
subject is on avelumab therapy. Free T4 and TSH must be performed at least every 8 weeks 
during avelumab treatment and at end of treatment or 30 days post-treatment safety follow-up 
(if not performed in the previous 8 weeks). Upon completion of intervention, patients will be 
seen at least every 4 months in the first two years, and then every 6 months. 
Blood-borne immune markers will be checked every 4 weeks for the first 24 weeks.  
Extended safety follow-up: 
 Given the potential risk for delayed immune-related toxicities, safety follow-up must 
be performed up to 90 days after the last dose of avelumab administration. 
 The extended safety follow-up beyond 30 days after last avelumab administration 
may be performed either via a site visit or via a telephone call with subsequent site 
visit requested in case any concerns noted during the telephone call. 
Treatment response and operability will be evaluated by contrast CT or MRI every 3 months 
during treatment, every 4 months in the first and second year after treatment, then every 6 
months. All CT or MRI reporting will be according to Modified Response Evaluation Criteria 
for Solid Tumours (mRECIST) criteria.  
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
Core-30 (QLQ-C30) and Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-
Hep) questionnaires will be used for assessment of quality of life every 3 months in the first 
two years, then every 6 months.  

START-FIT v4 (Date: 27 Apr, 2021) 
Page 35 of 51 
7.2 
Decision on Resectability, Subsequent Treatment and Treatment 
Failure 
A multidisciplinary meeting consists of surgeons, oncologists, and radiologists will be held 
every 3 months to evaluate treatment response/failure, to decide on subsequent treatment. 
Successful downstage and disease control (as defined by complete response, partial response 
and stable disease) will be evaluated for resection or transplantation of HCC 
 UCSF Criteria will be used to determine the suitability of transplantation  
 Single tumor ≤6.5cm 
 Or up to 3 tumors ≤4.5cm, and total sum is 8cm  
 No vascular invasion  
Treatment failure can be due to either poor liver function or tumor progression  
Poor liver function is defined as  
 Hepatic encephalopathy, 
 Diuretic refractory ascites,  
 Variceal bleeding,  
 Bilirubin >50umol/L,  
 Prothrombin time >4sec, or 
 Child Pugh C status.  
Tumor progression is defined as  
 Extra-hepatic disease,  
 New onset major vascular invasion (portal vein or hepatic vein invasion),  
 Progressive disease according to mRECIST,  
In patients who have treatment failure, unacceptable toxicity, or they have reached the end of 
treatment. Subsequent treatment will be decided in multidisciplinary panel based on best 
interests of patients. There is no restriction on choice of subsequent treatment.  
7.3 
Outcome Measures 
7.3.1 Primary Endpoint 
 Number of patients amenable to curative surgical interventions is defined as number of 
patients receiving curative surgical resection or transplantation after successful down-
sizing of tumor(s) by intervention  

START-FIT v4 (Date: 27 Apr, 2021) 
Page 36 of 51 
7.3.2 Secondary Endpoints 
 Response rate measured by mRECIST criteria: 
Complete response (CR): Disappearance of any intra-tumoral arterial enhancement in 
all target lesions  
Partial response (PR): At least a 30% decrease in the sum of diameters of viable 
(enhancement in the arterial phase) target lesions, taking as reference the baseline sum 
of the diameters of target lesions  
Stable disease (SD): Any cases that do not qualify for either partial response or 
progressive disease  
Progressive disease (PD): An increase of at least 20% in the sum of the diameters of 
viable (enhancing) target lesions, taking as reference the smallest sum of the diameters 
of viable (enhancing) target lesions recorded since treatment started  
 Number of patients amenale to curative surgical interventions and/or achieve 
radiological complete response: defined as number of patients receiving curative 
surgical intervention or transplantation after successful downstaging (i.e. equivalent to 
primary endpoint) plus number of patients achieveing radiological CR per mRECIST 
criteria. This endpoint is to reflect the number of patients achieve complete tumor 
clearance and potentially cure. 
 Time to progression (TTP): measured from the date of first study treatment to 
radiographically documented progression according to mRECIST 1.1. This does not 
include death from any cause. 
 Progression-free survival (PFS): measured from the date of first study treatment to 
radiographically documented progression according to mRECIST 1.1 or death from any 
cause (whichever occurs first). Participants alive and without disease progression or 
lost to follow-up will be censored at the date of their last radiographic assessment. 
 Overall survival (OS): measured from date of first study treatment to the date of death 
from any cause. Participants alive or lost to follow-up will be censored at the date of 
their last visit. 
 Quality of life (QoL): as assessed by the European Organization for Research and 
Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) and the 
Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) questionnaires 
 Safety outcome measures: Incidence, nature, and severity of adverse events graded 
according to the United States National Cancer Institute The Common Terminology 
Criteria for Adverse Events (NCI CTCAE 4.0) 
 Pathological response: assessed as the percentage of surface with non-viable cancer 
cells (represented by necrosis or fibrosis, the ultimate stage of necrosis) in relation to 
the total tumor area and will be equal to: 100% – viable cancer cells (%). If there are 

START-FIT v4 (Date: 27 Apr, 2021) 
Page 37 of 51 
multiple tumors, the mean percentage will be used. Pathological complete response 
(pCR) is defined by the absence of viable tumor cells in any nodule. 
 Disease control rate: Percentage of patients that had a CR, PR, or stable disease (SD) ≥ 
6 months per mRECIST 
 Local control: defined as absence of recurrence within the high-dose region (80% 
isodose volume), demonstrated by new enhancement or mRECIST progressive disease 
 Duration of response: time from first documented evidence of CR or PR until the first 
documented sign of disease progression (PD) or death from any caus 
 Pattern of failure:  
(1) In-field failure: defined as recurrence within the high-dose region (80% iso-dose 
volume), demonstrated by new enhancement or mRECIST progressive disease. 
(2) Out-field (intra-hepatic): defined as new or mRECIST progressive disease within 
liver parenchyma, but outside the SBRT treated volume 
(3) New vascular invasion: defined as new portal or hepatic vein invasion 
(4) Distant failure: defined as new disease outside liver parenchyma 
 Radiological response per RECIST 1.1 
7.4 
Follow-Up and Record of Events (Form D) 
 The patient should be followed-up until death. 
 
 The dates of diagnosis of in-field, out-of-field (intra-hepatic), and distant failure should 
be recorded. 
 In-field failure: defined as recurrence within the high-dose region (80% iso-
dose volume), demonstrated by new enhancement or mRECIST progressive 
disease. 
 Out-field (intra-hepatic): defined as new or mRECIST progressive disease 
within liver parenchyma, but outside the SBRT treated volume 
 Distant failure: defined as new disease outside liver parenchyma 
 The incidence of late toxicities > grade 3 by Common Toxicity Criteria for Adverse 
Events version 4.0 (CTCAE-v4) should be recorded.  
 All causes of death (if occur) will be recorded. Deaths due to unknown cause are 
counted as deaths due to HCC if disease is still present at last assessment. 
7.5 
Criteria for Removal From Protocol Treatment 
 Disease progression 
 Inter-current disease that would affect assessments of clinical status to a significant 
degree, require discontinuation of drug, or both 
 Unacceptable toxicity  
 The patient may withdraw from treatment at any time for any reason. The reason should 
be recorded. Follow-up will be continued for all consenting patients per standard 
clinical procedures, including regular follow-up visits, clinical and laboratory 
assessments for up to 5 years 

START-FIT v4 (Date: 27 Apr, 2021) 
Page 38 of 51 
 Avelumab treatment for maximum of 2 years 
7.6 
Exploratory Biomarkers 
 Blood Borne Immune Panel Exploratory Analysis 
Peripheral blood monocytic cells (PBMC) will be collected at baseline, then every 4 
weeks after initiation of treatment for 20 weeks.  
Procedure: after collection of patients’ blood, the sample will be centrifuged for 15 min 
at 3000 rpm. After removal of the plasma, PBMC will be isolated either by Ficoll-paque 
or red cell lysis buffer. The isolated PBMC will be washed twice with PBS for 
immediate analysis or frozen for further investigation. For the phenotyping of the 
immune cells, PBMC will be stained with different antibodies and examined by flow 
cytometry. The identification of CD8+ and CD4+ T cells are defined as CD8+ CCR7+ 
CD45RA+ and CD4+ CCR7+ CD45RA+, respectively. For the T-reg cell, we define 
as positive for CD4 and Foxp3. We will also examine the expression of Ki-67 and TIM-
3 in the T-cells to demonstrate the possible cell proliferation and functions. We will 
also examine the expression of PD-1 and PD-L1 expression on each subset of cell to 
correlate the pathological response and clinical outcome.  
 Tumor samples (immune-related markers in surgical specimens) 
The expression and spatial distribution of immune-related or response-related markers 
by immunohistochemistry may also include, but may not be limited to, PD-L1, CTLA-
4, CD3, CD4, CD8, CD45RO, forkhead box P3, granzyme B, OX40, PD1, cleaved 
caspase 3 and Ki67. 
7.7 
Safety Reporting 
7.7.1 Adverse Events (AE) 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An adverse event can therefore be any of the following: 
 Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
 Any new disease or exacerbation of an existing disease (a worsening in the   character, 
frequency, or severity of a known condition)  
 Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
 Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 

START-FIT v4 (Date: 27 Apr, 2021) 
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 Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
7.7.2 Serious Adverse events (SAE) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 Is fatal (i.e., the adverse event actually causes or leads to death) 
 Is life threatening (i.e., the adverse event, in the view of the Investigator(s), places the 
patient at immediate risk of death) 
 This does not include any adverse event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death. 
 Requires or prolongs inpatient hospitalization 
 Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions) 
 Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 Is a significant medical event in the Investigator(s)'s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]; the event itself may be of 
relatively minor medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded in 
the clinical database. 
7.7.3 Adverse Events of Special Interest (AESI) 
AESIs (serious or non-serious) are a subset of Events to Monitor of scientific and medical 
concern specific to the Merck Drugs in this protocol for which ongoing monitoring and rapid 
communication by the Investigator(s) to Merck Drug Safety is required. Such an event might 
require further investigation in order to characterize and understand it.  
Infusion related reactions including study intervention hypersensitivity reactions and immune-
mediated adverse reactions (immune-related pneumonitis, immune-related colitis, immune-
related hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, 
new onset type I diabetes mellitus, pituitary disorders), immune-related nephritis and renal 
dysfunction and other immune-related AEs (myositis, myocarditis, Guillain-Barré syndrome, 
uveitis) have been identified as adverse events of special interest for avelumab. 
Any AE that is suspicious to be a potential immune-mediated adverse reaction or infusion 
related reaction will be considered an AESI. AESIs do not require expedited reporting unless 

START-FIT v4 (Date: 27 Apr, 2021) 
Page 40 of 51 
they are serious. Should the AESI be serious, a SAE form should be filled instead and the 
reporting process for SAEs should be followed. 
7.7.4 Pregnancy Reports 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator(s) if they become pregnant during the study. 
7.7.5 Assessment of Causality of Adverse Events 
Investigator(s) should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an adverse 
event is considered to be related to the study drug, indicating “Yes” or “No” accordingly. The 
following guidance should be taken into consideration: 
 Temporal relationship of event onset to the initiation of study drug 
 Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 Known association of the event with the study drug or with similar treatments 
 Known association of the event with the disease under study 
 Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
7.7.6 Methods of Recording Adverse Events 
All AEs must be documented in the appropriate section of the CRF. An SAE report form 
(initial or follow up) must be completed in addition. 
The following aspects must be recorded for each event in the CRF: 
A description of the AE in medical terms, not as reported by the subject; 
 The date of onset (start date) 
 The time of onset (start time) 
 The date of recovery (stop date) 
 The time of recovery (stop time) 
 The severity of the sign and/or symptom or clinically significant abnormal laboratory 
value according to NCI-CTC, Version 4.0. If no toxicity grade is described for a given 
sign, symptom or abnormal laboratory value, the Investigator(s) will grade the severity 
as mid (grade 1), moderate (grade 2), severe (grade 3), or life-threatening or disabling 
(grade 4). 

START-FIT v4 (Date: 27 Apr, 2021) 
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 Death (grade 5) as defined by NCI-CTCAE v.4.0 is mainly regarded as an outcome and 
will be documented accordingly (see below). 
 The causal relationship to Avelumab, TACE and radiotherapy as assessed by the 
Investigator(s); the decisive factor in the documentation is the temporal relation 
between the AE and the study drug. The following judgments of the causality to study 
drug or study procedures are to be used:  
 Not Related = not suspected to be reasonably related to the investigational product. 
AE could not medically (pharmacologically/ clinically) be attributed to the 
investigational product under study in this protocol 
 Related = suspected to be reasonably related to the investigational product. AE 
could medically (pharmacologically/ clinically) be attributed to the investigational 
product under study in this protocol 
 Action taken on Avelumab (none, medication discontinued, dose reduction, medication 
delayed, reduction of infusion rate). 
 Other action (none, concomitant medication given, new or prolonged hospitalization, 
procedural surgery).  
 The outcome according to the following definitions: 
 Recovered without sequelae (AE disappeared) 
 Recovered with sequelae (AE has resulted in permanent disability/incapacity)  
 Not yet recovered 
 Not recovered at death 
 Change in toxicity grade/severity or seriousness (e.g., an AE with no change of 
toxicity grade but newly classified as an SAE due to hospitalization. 
 Fatal (AE resulted in death) 
 Concomitant medication given: Yes or No (Note: If this question is answered “Yes” 
the corresponding serious criteria must be ticked) 
 Subject died 
 Life-threatening 
 New or prolonged hospitalization 
 Persistent/significant disability 
 Congenital abnormality 
 Important medical event 
 Seriousness: Yes or No 
If in any one patient the same AE occurs on several occasions, then the AE in question must 
be documented and assessed anew each time. 
7.7.7 Procedure of Reporting Serious Adverse Events 
The Sponsor-Investigator(s) primary responsibilities for safety reporting are to identify and 
follow-up on Serious Adverse Events (SAEs) experienced by participants in the study and to 
forward the information to the local regulatory authorities and Merck, as required by local 
regulations (for regulatory reporting) and as required by the ISS agreement (for reporting to 
Merck). 

START-FIT v4 (Date: 27 Apr, 2021) 
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The following reportable events must be submitted to Merck within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. The 
Principal Investigator(s) will assume responsibility for submitting the reportable event(s) to 
Merck as well as ensuring that any local reporting requirements are completed in parallel.  
 Serious Adverse Events (see section 7.4.2)  
 Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event)  
 Occupational exposure (even if not associated with an adverse event)  
 Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs.  
Contact information for submission of reportable events to Merck: 
Fax: +49 6151 72 6914 or  
E-mail: ICSR_CT_GPS @merckgroup.com 
Specifying: 
 PROTOCOL Number and/or Title 
 Funder’s Study Identifier 
 SUBJECT Number 
 Principal Investigator Name 
 Sponsor Name 
 SAE/ONSET DATE 
7.7.8 Monitoring of subjects with Adverse Events 
Any AE that occurs in the course of a clinical study must be monitored and followed up until 
the last study visit. It is the responsibility of the Investigator(s) that any necessary additional 
therapeutic measures and follow-up procedures are performed. 
 
8. 
STATISTICS 
8.1 
Statistical Analysis  
 Patients who complete TACE will be considered as the study population for primary 
and secondary endpoints. 
 The primary endpoint - the rate of patients amendable to curative surgical intervention 
will be estimated based on exact binomial distribution.  

START-FIT v4 (Date: 27 Apr, 2021) 
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 Objective response rate (ORR), pathological response rate, and number of patients 
amendable to curative interventions and / or radiological CR will be expressed based 
on exact binomial distribution.  
 Survival outcomes, including TTP, PFS and OS and their corresponding 95% 
confidence interval, will be estimated using Kaplan-Meier method.  
 Patient reported QoL scores will be estimated at baseline, during and following therapy. 
Scores at each time point will be summarized with descriptive statistics including 
means, standard deviations, median and range. The changes from baseline during 
therapy and after therapy will be calculated for each patient and also summarized with 
means and standard deviations/95% CI. Linear mixed-effect model will be used to 
study the longitudinal changes of QoL scores. 
 All of the tests and reported P values will be 2-tailed, and P<0.05 will be considered 
statistically significant. The analyses will be performed using statistical software 
packages SPSS and R. 
Procedures for Handling Missing, Unused, and Spurious Data: All available data will be 
included in the data listings and tabulations. Where appropriate, imputations of values for 
missing data for primary and secondary efficacy analyses will be performed as specified in the 
Statistical Analysis Plan. All data recorded on the CRF will be included in the data listings that 
will accompany the clinical study report. 
If, after the study has begun, but prior to the conduct of any analysis, changes made to primary 
and / or key secondary endpoints, or the statistical methods related to those hypotheses, then 
the protocol will be amended. Changes to exploratory analyses made after the protocol 
finalized will be documented and referenced in the final report. Post hoc exploratory analyses 
will also be identified in the final report.  
 
8.2 
Sample Size Calculation  
H0: The null hypotheses of no difference in the number of patients who can undergo surgery: 
similar to the historical result of QMH, 5% of patients can undergo surgical intervention after 
TACE.  
H1: The alternative hypotheses of treatment efficacy: the experimental treatment would result 
in 20% of study population who can undergo surgical resection after treatment response. 
To detect 15% of differences from 5% to 20% in the number of patients proceeding to surgery, 
with Type I error of 0.05 and 80% power, assume 10% patients who have withdrawnmay 
withdraw consent and patients who cannot be contacted during survival follow-up period, 
withdrawn subjects are only tobefore starting their protocol treatment. Patients will not be 
replaced once their protocol treatment started. The target accrual is 33 patients. Simon’s two-
stage optimal design will be used. In the first stage ten patients will be enrolled. If at least one 
is amenable to curative surgical intervention, the study can proceed to the second stage and an 

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additional 19 patients could be recruited. If at least 4 of the total 29 patients are amenable to 
curative surgical intervention, the treatment will be considered worthy of further investigation.  
8.3 
Early Stopping Rule  
Excessive toxicity will be monitored, which includes: (a) grade 4 or 5 hepatic; (b) grade 4 or 5 
gastrointestinal; (c) grade 4 thrombocytopenia associated with any bleeding or grade 5 
thrombocytopenia; (d) any grade 5 treatment-related adverse event. Assuming no more than a 
10% rate of the above AEs on TACE, SBRT, or Avelumab alone, the increase to a rate of 30% 
or greater in the studied treatment will be considered unacceptable, and the study will be 
stopped prematurely. Upon the recruitment of these 33 patients, if 14 or more patients had 
treatment-related SAE, the study will be stopped. The corresponding lower bound of exact one-
sided 90% confidence interval is 30.5%. The table below shows the stopping guideline 
scenarios for the first 8, 16 and 24 patients. For example, the study will be stopped when 11 of 
the first 24 patients develop an acute toxicity. The upper bound for the confidence intervals is 
100%. 
 
Number of patients with 
serious adverse event 
Number of patients 
enrolled 
Lower bound of exact 
one-sided 90% 
confidence interval 
5 
8 
11 
8 
16 
24 
34.46% 
31.78% 
31.48% 
 
9. 
ETHICAL, REGULATORY & STUDY OVERSIGHT 
CONSIDERATIONS 
9.1 
Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) to perform the clinical study in accordance with this clinical 
study protocol, ICH guideline for Good Clinical Practice (GCP) (ICH E6 R2 Step 4) approved 
on November 9, 2016) and applicable regulatory requirements in Hong Kong. These 
documents state that the informed consent of the subjects is an essential precondition for 
participation in the clinical study. 

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9.2 
Subject Information 
An unconditional prerequisite for a patient participating in the study is his/her written informed 
consent. Adequate information must therefore be given to the subject by the Investigator(s) 
before informed consent is obtained. A person designated by the Investigator(s) may give the 
information, if permitted by local regulations. A subject information sheet in the local language 
and prepared in accordance with Good Clinical Practice will be provided by the Investigator(s) 
for the purpose of obtaining informed consent. In addition to this written information, the 
Investigator(s) or his/her/their designate will inform the subject verbally. In doing so, the 
wording used will be chosen so that the information can be fully and readily understood by 
laypersons. 
The patient information sheet will be revised whenever important new information becomes 
available that may be relevant to the consent of patients. 
9.3 
Informed Consent (Form B) 
The consent of the patient to participate in the clinical study has to be given in writing before 
any study-related activities are carried out. It must be signed and personally dated by the patient 
and by the Investigator(s)/person designated by the Investigator(s) to conduct the informed 
consent discussion. 
Provision of consent will be confirmed in the case report form (CRF) by the Investigator(s). 
The signed and dated declaration of informed consent will remain at the Investigator(s)'s site 
and must be safely archived by the Investigator(s) so that the forms can be retrieved at any time 
for monitoring, auditing and inspection purposes. A copy of the signed and dated information 
and consent should be provided to the patient prior to participation. 
If the patient or legally acceptable representative is unable to read, a reliable, independent and 
impartial witness should be present during the entire informed consent discussion. The choice 
of the witness must not breach the subject’s right to confidentiality. A reliable independent 
witness is defined as one not affiliated with the institution or engaged in the investigation. A 
family member or acquaintance is an appropriate independent witness. After the subject or 
legally acceptable representative verbally consents and has signed, if capable, the witness 
should sign and personally date the consent form attesting that the information is accurate and 
that the subject or legally acceptable representative has fully understood the content of the 
informed consent agreement and is giving true informed consent. 
9.4 
Compensation to Subjects 
The patients do not receive payment for taking part in the study. Patients who are entitled to 
discounted or free health care, e.g. civil servants, will receive their entitled free treatment as 
normal. The study is covered by an insurance policy from the Clinical Trial Center of the 

START-FIT v4 (Date: 27 Apr, 2021) 
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University of Hong Kong, in which to cover claim by, or compensation for, patients treated in 
study, e.g. those who developed AEs or SAEs, and this will be covered by the existing hospital 
insurance. 
9.5 
Ethics Committee or Institutional Review Board 
Prior to commencement of the study, the study protocol will be submitted together with its 
associated documents (patient information, consent form, IB) to the IRB/EC for their 
favourable opinion. The favourable opinion/approval of the IRB/EC will be filed in the study 
file. The study will only commence following provision of a written favourable opinion.  
Any amendments to the protocol will be submitted to the IRB/EC and they will be informed 
about SAEs in accordance with national and/or local requirements. 
9.6 
Role of Funding Source 
The study drug and partial funding will be provided by Merck KGaA, Darmstadt, Germany. 
The Funder otherwise has no role in study design, data collection, data analysis, data 
interpretation, or in the writing of the study report. The Funder will be review the manuscript 
before submission for publication. 
9.7 
Publication Policy 
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results in accordance with standard 
editorial and ethical practice.  
The Sponsor agrees to submit all manuscripts or abstracts to the Funder for review before 
submission for publication. This allows the Funder to protect proprietary information and to 
provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 
10. STUDY MANAGEMENT 
10.1 Data Quality Assurance 
The main objective is to obtain those data required by the study protocol in a complete, 
accurate, legible and timely fashion. The data in the eCRF should be consistent with the 
relevant source documents.  

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The CRFs must be filled in completely and legibly (with either black or blue ballpoint pen, 
acceptable for use on official documents). Any amendments and corrections necessary must be 
undertaken and countersigned by the Investigator(s), stating the date of the 
amendment/correction. Errors must remain legible and may not be deleted with correction aids 
(e.g., Tipp-Ex). The Investigator(s) must state his/her reasons for the correction of important 
data. In the case of missing data/remarks, the entry spaces provided in the case report form 
should be cancelled out so as to avoid unnecessary follow-up inquiries.  
CRF entries will be done by the study team and checked against source documents, except for 
the pre-identified source data directly recorded in the CRF. The Informed Consent Form will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
Ethics Committee (IRB/EC), and the regulatory authorities to have direct access to source data 
which support the data on the CRF. Such personnel, bound by professional secrecy, must keep 
confidential all personal identity or personal medical information (according to confidentiality 
rules). 
10.2 Direct Access to Source Data/Documents 
For the purpose of ensuring compliance with the clinical study protocol, Good Clinical Practice 
and applicable regulatory requirements, the Investigator(s) shall permit auditing by the 
Sponsor, the Funder, and inspection by applicable regulatory authority. 
The Investigator(s) agree(s) to allow the auditors/inspectors to have direct access to the study 
records for review, being understood that these personnel is bound by professional secrecy, 
and as such will not disclose personal identity or personal medical information. 
The Investigator(s) will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents.  
As soon as the Investigator(s) is/are notified of a future inspection by the authority, he will 
inform the Sponsor.  
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authority will be 
communicated by the Investigator(s) to the Sponsor and the Funder as per timeframe stipulated 
in the ISS agreement. 
The Investigator(s) shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections.  

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10.3 Study File and Archiving 
The Investigator(s) shall maintain a Study File for the study purpose. This file contains all 
relevant documents necessary for the conduct of the study. This file must be safely archived 
after termination of the study in accordance with the local relevant regulations. 
 
 

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