Leveraging Immunotherapy For Tumor Downstaging to Milan Criteria in Patients With Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Hepato Cellular Carcinoma
Sponsor: Ju Dong Yang

 
 
 
 
RESEARCH PROTOCOL 
 
Leveraging Immunotherapy For Tumor 
downstaging to Milan Criteria in patients with 
Hepatocellular Carcinoma 
 
Protocol Number: IIT2025-03-YANG-LIFT-HCC  
 
 
 
Principal Investigator:  
Ju Dong Yang, MD, MS 
 
 
Sub-Investigators  
Department/Division 
Emily Kaymen, MD 
Medical Oncology, Cedars-Sinai Cancer Beverly Hills 
Nicholas Nissen, MD 
Transplant Surgery 
Ekaterina Koltsova, MD, PhD 
Vascular Immunology 
Stephen Shiao, MD, PhD 
Radiation Oncology, Biomedical Sciences 
Manaf Alsudaney, MD 
Karsh Division of Gastroenterology and Hepatology 
 
Biostatistician: 
Shaowli Kabir, PhD 
FDA Status:  
 
 
IND Exempt 
Funding Source:  
Cedars-Sinai Medical Center 
NCT Number:   
 
Pending 
Current Version: 
 
Version 1.0 dated 19 JUN 2025 
 
 
 

 
 
 
 
 
IIT2025-03-YANG-LIFT-HCC 
Protocol Version 1.0: Dated 19 JUN 2025 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
______________________________________________ 
 
 
_________________ 
Principal Investigator (PI) Signature    
 
 
 
 
Date

IIT2025-03-YANG-LIFT-HCC 
________________________________________________________________________ 
 
 
Contents 
LIST OF ABBREVIATIONS 
1 
STUDY SCHEMA 
2 
STUDY SUMMARY 
4 
1.0 
BACKGROUND AND RATIONALE 
5 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
8 
3.0 
STUDY DESIGN 
9 
4.0 
PATIENT ELIGIBILITY 
11 
5.0 
TREATMENT PLAN 
13 
6.0 
STUDY PROCEDURES 
17 
7.0 
ADVERSE EVENTS (AE), SERIOUS ADVERSE EVENTS (SAE), 
UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR 
OTHERS (UPIRSO), AND SUSPECTED UNEXPECTED SERIOUS ADVERSE 
REACTIONS (SUSAR) 
23 
8.0 
CORRELATIVES/SPECIAL STUDIES 
27 
9.0 
STATISTICAL CONSIDERATIONS 
28 
10.0 
STUDY MANAGEMENT 
31 
11.0 
APPENDICES 
37 
12.0 
REFERENCES 
47 

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LIST OF ABBREVIATIONS 
 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BCLC 
Barcelona Clinic Liver Cancer stage 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
DSUR 
Development Safety Update Report 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
Electrocardigram 
EOS 
End Of Study 
EOT 
End of Treatment 
FACS 
Fluorescence-activated cell sorting 
FU 
Follow Up 
GEE 
Generalized Estimating Equations 
H&P 
History & Physical Exam 
HCC 
Hepatocellular Carcinoma 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
ICI 
Immune Checkpoint Inhibitor 
imAE 
Immune-mediated Adverse Event 
INR 
International Normalized Ratio 
IV (or iv) 
Intravenously 
LMM 
Linear Mixed-effects Model 
LRT 
Locoregional Treatment 
LT 
Liver Transplantation 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
QMC 
Quality Management Core 
RETREAT 
Risk Estimation of Tumor Recurrence After Transplant 
score 
RFA 
Radiofrequency Ablation 
RFS 
Recurrence-Free Survival 
SAE 
Serious Adverse Event 
scRNAseq 
Single-cell RNA sequencing 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SOC 
Standard of Care 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TACE 
Transarterial Chemoembolization 
TARE or Y90 
Transarterial Radioembolization 
TTP 
Time to Progression 
UCSF 
University of California, San Francisco (transplant 
criteria) 
WBC 
White Blood Cells 
 
 
 
 

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STUDY SCHEMA  
 
Figure 1. Study schematic diagram of the study design 
Abbreviations and Notes: Immune checkpoint inhibitor, EOS: End of study (Day 90 after last research-related ICI dose), EOT: End of Treatment (marks the patient’s last ICI dose given under 
study authority. If the treating physician later continues durvalumab or another ICI as standard of care, that therapy is documented as concomitant medication and does not reopen or extend 
the study calendar for that participant. LRT: (TACE, TARE-Y90, or RFA) Locoregional therapy, TACE: Transarterial Chemoembolization, Y90: (also referred as TARE) Transarterial 
Radioembolization,  RFA: Radiofrequency Ablation, LT: Liver transplantation, mRECIST: Modified Response Evaluation Criteria In Solid Tumors, RETREAT score: se section 11.6, SOC: 

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Standard of care, Start STRIDE regimen: Tremelimumab 300mg IV once + Durvalumab 1500mg IV on C1D1, followed by Durvalumab 1500mg IV once every 4 weeks, UCSF: University of 
California, San Francisco.  

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STUDY SUMMARY 
 
 
Study Title 
Leveraging Immunotherapy For Tumor downstaging to Milan Criteria 
in patients with Hepatocellular Carcinoma (LIFT-HCC) 
Short Title 
LIFT-HCC 
Protocol Number 
IIT2025-03-Yang-LIFT-HCC 
Study Phase 
II  
Study Design and 
Methods 
Phase II, single-cohort, open-label, clinical trial designed to assess the 
success of combining Immune Checkpoint Inhibitor (ICI) and 
Locoregional Therapy (LRT) in intermediate to advanced stage HCC 
for tumor downstaging to Milan Criteria. 
Study Duration 
Approximately 4 years (36 months accrual + 12 months 
treatment/downstaging window + 3 months safety follow-up and data 
lock) 
Study Site 
Cedars-Sinai Medical Center and other Cedars-Sinai participating 
locations 
Primary Objective 
Assess the success rate of combining ICIs and LRT (as neoadjuvant 
treatment) in tumor downstaging to Milan Criteria within 12 months of 
baseline STRIDE dose in patients with HCC exceeding the UCSF 
criteria. 
Number of Subjects 
41 
Study Population 
Age ≥ 18 Patients with HCC beyond UCSF criteria, ECOG 
performance status ≤ 2, and Child-Pugh A or B7. 
Study Intervention 
STRIDE Regimen (Tremelimumab 300 mg AND Durvalumab 1500 
mg) combined with LRT (TACE, TARE, or RFA) 
Statistical 
Methodology 
Simon two-stage design 
 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
In 2022, liver cancer was diagnosed in more than 860,000 individuals, making it the sixth most common 
type of cancer, and caused nearly 760,000 deaths, ranking third in cancer-related mortality (7.8% of all 
cancer deaths). Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for 75-
85% of these cases [1, 2] Liver transplantation (LT) is the standard treatment for patients at risk of liver-
related death, including those with HCC, providing a curative option that enhances overall survival (OS) 
and recurrence-free survival (RFS) [3]. It offers the potential to eliminate both HCC tumors and the 
underlying diseased liver. However, it is generally reserved for patients with early-stage HCC. The 
increased likelihood of recurrence in patients with more advanced disease, combined with the limited 
availability of donor organs, makes LT primarily suitable for those in the early stages. For patients with 
HCC exceeding the Milan criteria, locoregional treatments (LRTs) can help reduce tumor size, enabling 
them to qualify for LT, with successful downstaging rates reported between 30-70% depending on the 
initial tumor burden [4-6].  Among those with a larger tumor burden at initial presentation, successful 
downstaging rate decreases to less than 30%, highlighting the unmet need for a robust, successful 
downstaging strategy. 
Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy both as an adjuvant treatment 
for surgically treated HCC and as a first-line therapy for advanced-stage cases. Due to their success in 
advanced HCC, there is growing interest in exploring their use in earlier stages of the disease. TACE, 
TARE, and ablation are key types of LRTs used for early and intermediate-stage HCC, serving as 
essential treatments for downstaging or reducing the risk of waitlist dropout in patients awaiting live LT. 
Recent studies of using ICI in HCC treatment have sparked interest in utilizing immunotherapy as a pre-
transplant downstaging strategy. The growing body of evidence supports the use of ICIs in reducing tumor 
burden and increasing eligibility for LT, offering hope for curative treatment in patients with advanced 
HCC.  
However, integrating ICIs into the tumor downstaging and LT pathway demand thoughtful safety planning. 
While these agents boost anti-tumor immunity, they can also heighten the chance of allograft rejection, so 
clinical teams must balance efficacy with graft protection [7]. Early reports from case series to small 
cohort studies suggest rejection rates may not differ markedly from non-ICI recipients[8], yet the lack of 
large-scale, controlled studies limits definitive conclusions.  
Practical safety strategies are emerging. Extending the washout interval between the final ICI dose and 
transplantation appears to lower rejection risk, offering a workable buffer[9]. Ongoing questions include 
how factors such as patient age, total ICI exposure, and concurrent therapies interact with this washout 
period. Well-designed prospective trials are still needed, but these evolving precautions provide a 
foundation for safer ICI use for tumor downstaging and potential curative transplantation.  
 

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1.2 
Study Agent(s) Background and Associated Known Toxicities 
Several ICI combination therapies have been tested in clinical trials, such as atezolizumab plus 
bevacizumab in the IMbrave150 trial [10], and durvalumab with tremelimumab (STRIDE regimen) in the 
HIMALAYA trial, see details below [11]. Both have shown promising results in treating advanced HCC. 
Additionally, camrelizumab combined with rivoceranib which was evaluated in in CARES- trial [12] is 
currently under FDA review, while atezolizumab-bevacizumab and durvalumab-tremelimumab 
combinations have been approved for advanced-stage HCC treatment. In addition to retrospective cohort 
studies reporting the safety and effectiveness of combining ICIs and LRTs [13], two Phase 3 randomized 
controlled trials have evaluated the combination of ICIs, LRTs, and tyrosine kinase inhibitors (TKIs) for 
intermediate-stage HCC. The EMERALD-1 trial [14] assessed TACE combined with durvalumab ± 
bevacizumab for unresectable HCC patients eligible for embolization. Similarly, the LEAP-012 trial [15] 
explored the combination of lenvatinib, pembrolizumab, and TACE for intermediate-stage HCC. Both trials 
have shown promising results with HR of 0.77 (95% CI:0.61–0.98; P = 0.032), grade 3–4 treatment-
related adverse events occurred in 45 % of patients receiving durvalumab + bevacizumab, most 
commonly hypertension and anemia for EMERALD-1 trial. HR of 0.66 (95% CI:0.51–0.84; P < 0.01) for 
LEAP-012 trial in progression-free survival, with Grade 3–4 treatment-related adverse events were 
reported in 71 % of patients in the combination arm vs 31 % with TACE alone; hypertension, proteinuria 
and elevated liver enzymes were the most frequent events. Taken together, these data demonstrate that 
ICI-based combinations can down-stage intermediate-stage HCC with manageable toxicity, as grade 3–4 
AE rates in the 45–70 % range are considered acceptable for contemporary HCC treatments. Further 
supporting the potential of these combination therapies in treating intermediate-stage HCC and 
successful downstaging. 
 
Phase III HIMALAYA trial 
The STRIDE regimen—comprising a single priming dose of tremelimumab (300 mg) combined with 
durvalumab (1,500 mg every 4 weeks)—was evaluated in the Phase III HIMALAYA trial as a first-line 
treatment for patients with unresectable hepatocellular carcinoma (HCC)[16]. Trial outcomes shown 
below: 
Table 1.1: Summary of Phase III HIMALAYA Trial Outcomes 
Efficacy Outcomes 
Overall Survival (OS) 
Median OS with STRIDE was 16.4 months, compared to 13.8 
months with sorafenib. Hazard Ratio (HR) for death was 0.78 
(95% CI: 0.66–0.92; p = 0.0035), indicating a statistically 
significant improvement. At 4 years, 25.2% of patients treated 
with STRIDE were alive, versus 15.1% in the sorafenib group. 
Objective Response Rate (ORR) 
STRIDE achieved an ORR of 20.1%, compared to 5.1% with 
sorafenib. 

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Duration of Response 
Median duration of response was 22.3 months for STRIDE, 
versus 18.4 months for sorafenib. 
Progression-Free Survival (PFS) 
Median PFS was similar between the two groups: 3.8 months 
for STRIDE and 4.0 months for sorafenib. 
Safety and Toxicity 
Adverse Events (AEs) 
Grade 3 or 4 AEs occurred in 50.5% of patients receiving 
STRIDE, compared to 52.4% with sorafenib. Treatment 
discontinuation due to AEs was less frequent with STRIDE 
(13.7%) than with sorafenib (16.8%). 
Immune-Mediated Adverse Events 
(imAEs): 
imAEs requiring high-dose corticosteroids occurred in 20.1% 
of patients on STRIDE. Only 5.7% discontinued treatment due 
to imAEs. Common imAEs included hypothyroidism, hepatic 
events, diarrhea/colitis, and rash. 
Correlation with Outcomes 
Patients experiencing imAEs had a median OS of 23.2 
months, compared to 14.1 months in those without imAEs, 
suggesting a potential association between immune activation 
and improved survival. 
 
These findings support the STRIDE regimen as an effective and tolerable first-line treatment option for 
patients with unresectable HCC, offering improved survival outcomes with a manageable safety profile. 
 
1.3 
Study Rationale 
ICI therapy has demonstrated high efficacy in treating locally advanced HCC; however, their value in 
earlier stage disease to downstage tumors to Milan criteria remains untested in prospective trials. The 
present Phase II study therefore focuses on determining the proportion of patients who achieve 
successful radiologic downstaging to Milan criteria within 12 months of initiating the combined therapy 
and evaluate the regimen’s safety and effectiveness in this earlier stage population, tracking immune-
related adverse events, and treatment tolerability during the 12-month and the 3-month post treatment 
windows. 
Data on LT listing, wait-list progression, and post-transplant graft outcomes will be collected, but these 
endpoints will be exploratory status; they will not gate primary study completion. 
By anchoring the trial on a near-term, clinically actionable milestone (downstaging within one year) and 
rigorous safety monitoring, the study will generate the first prospective evidence for using ICI-based 
combination therapy to expand curative options in intermediate-stage HCC. Exploratory transplant-related 
outcomes and planned biospecimen analyses will supply additional insights for future precision-medicine 
strategies but will not extend the primary timeline or influence stopping decisions. 

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The study will incorporate standard-of-care (SOC) safety monitoring parameters and direct investigator 
oversight throughout the treatment and post-treatment follow up. Furthermore, the longitudinal collection 
of biospecimens will support translational research aimed at identifying novel biomarkers predictive of 
treatment response and long-term outcomes. This integrative approach will not only enhance clinical 
understanding but also advance the development of precision strategies in managing HCC patients 
eligible for transplantation. 
 
1.4 
Correlative Measures 
We will conduct paired liver tumor biopsy during the lead-in phase of the clinical trial, and blood and stool 
will be collected at baseline and every 6-8 weeks after starting STRIDE treatment to understand 
predictors of response to ICI. We will aim to characterize the microenvironment to determine responders 
vs. non-responders for downstaging; recurrence risk stratification after ICI successful downstaging and 
liver transplantation.  
We will test checkpoint molecules (Tim3, CTLA4, PD1, PDL1), IFNg, IL27 in circulation/serum, in 
tumor/liver, CD8 cytotoxic cells (cell numbers, markers of exhaustion, markers of cytotoxicity (Granzymes, 
Perforin), IFNg, markers of activation Innate cytotoxic cells (NK, ILC1; cell numbers, markers of 
exhaustion, markers of cytotoxicity (Granzymes, Perforin), neutrophils (long-lived= tumor promoting 
neutrophils), tumor associated macrophages/DC  (pro-inflammatory (former M1) vs anti-inflammatory 
(former M2); cDC1 vs cDC2 B cells (Bregs (IL10+)-poor prognosis; B cells -good prognosis), Tregs 
(numbers, suppressor functions, conversion to effect cells (by scRNAseq trajectory analyses), microbiota 
analysis (if we go this way). Proposed correlative studies will involve 1) scRNA seq of biopsies vs. PBMC; 
2) spatial analyses (biopsies); 3) multi-color FACS; 4) cytokine multiplex; and 5) microbiota 16s seq -> 
metabolomics.    
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• 
To assess the success rate of combining ICIs and LRT (as neoadjuvant treatment) in tumor 
downstaging to Milan Criteria within 12 months of baseline STRIDE treatment in patients with 
HCC exceeding the University of California San Francisco (UCSF) criteria. 
2.2 
Primary Endpoint 
• 
Proportion of evaluable patients whose tumor burden meets Milan criteria on contrast CT/MRI 
within 12 months of baseline STRIDE treatment, confirmed by using mRECIST assessment. 
2.3 
Secondary Objectives  
• 
To assess the safety and tolerability of combining ICIs and LRT during the 12-month downstaging 
window. 
• 
To determine the ORR per mRECIST at months 3, 6 and 12. 
• 
To determine PFS within the 12-month period. 

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2.4 
Secondary Endpoints 
• 
Incidence, severity and relatedness of adverse events, graded by NCI CTCAE v5.0. 
• 
ORR which includes the complete response (CR) and partial response (PR) rate assessed using 
mRECIST criteria at months 3, 6 and 12. 
• 
PFS assessed by measurement of time from first dose to radiologic progression or death, 
censored at 12 months. 
2.5 
Exploratory Objectives 
• 
Describe rates of LT listing, receipt of LT, and post-LT outcomes (graft survival, rejection, 
RETREAT score, recurrence-free survival), correlate washout interval between last ICI dose and 
LT with graft rejection and recurrence. 
• 
Explore associations between novel biomarkers (tumor immune microenvironment, circulating 
immune cells, cytokines, microbiome) and clinical outcomes (downstaging success, PFS, post-LT 
outcomes. 
 
2.6 
Exploratory Endpoints 
• 
LT listing rate and proportion undergoing LT within study follow-up, allograft rejection rate and 
time to rejection, RETREAT score distribution and post-LT recurrence-free survival. 
• 
Correlative biomarker changes (immune profiling, microbiome shifts) versus clinical outcomes. 
 
 
3.0 
STUDY DESIGN 
This is a Phase II prospective, single-cohort, open label clinical trial designed to evaluate the efficacy and 
safety of combining ICI and LRT in intermediate to advanced stage HCC (tumor burden beyond the 
UCSF) for tumor downstaging to Milan Criteria. 
The study will enroll 41 evaluable adult participants (≥18 years old) with histologically, cytologically, or 
radiologically confirmed HCC and a life expectancy of at least 12 months. All participants must be beyond 
UCSF criteria for LT at the time of study entry. 
The study is structured into three sequential periods: 
• 
Screening Period: Patients will undergo eligibility assessments including imaging, laboratory 
testing, and medical history evaluation. 
• 
Treatment Period: Eligible patients will receive combination therapy beginning with the 
administration of immune checkpoint inhibition using the STRIDE regimen (durvalumab plus 
tremelimumab) in conjunction with clinician-selected LRT (e.g., TARE, TACE or ablation). 
Administration of Durvalumab therapy will continue every 4 weeks until either successful 
downstaging to within Milan criteria or a maximum of 12 treatment cycles, whichever occurs first. 

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• 
Post-Treatment Follow-up Period: All patients will be followed for 3 months after completion of 
treatment period for post treatment safety monitoring. For participants who receive LT after the 
study, exploratory Post-LT Surveillance follow up for up to 365 days Post LT.  
Throughout the study, standard-of-care (SOC) safety monitoring parameters and direct investigator 
oversight will be implemented to minimize treatment-related adverse events. See study schema 
(Figure 1) and Time and Events (Section 6.7) for reference. 
 
3.1    Rationale for Study Design 
The design of this trial reflects an urgent clinical need to explore effective downstaging strategies in 
patients with intermediate to advanced HCC who are beyond current transplant eligibility criteria. ICIs 
have demonstrated robust efficacy in advanced-stage HCC, and recent RCT studies suggest that their 
combination with LRTs may yield synergistic effects in tumor control. However, no prospective studies to 
date have systematically evaluated this combination specifically for the purpose of downstaging to Milan 
criteria. 
Patients whose HCC exceeds Milan/UCSF transplant criteria yet remains confined to the liver currently 
lack effective treatment options. LRT alone rarely yields durable control, and existing systemic regimens 
have not been prospectively tested as neoadjuvant downstaging strategies. Preclinical and clinical signals 
indicate that ICI can potentiate LRT-induced tumor antigen release, creating a synergistic “in situ vaccine” 
effect [17]. Yet no prospective trial has quantified how often this combination can downstage tumors to 
Milan criteria within a clinically actionable timeframe. 
Eligible local therapies include TACE, ablation, or resection. Radiotherapy were not included because 
they are not part of the standard downstaging practice at our institution and are not routinely offered in 
our transplant program [18]. 
To address this gap, we chose a Phase II, open-label design with an interim efficacy/futility stopping rule 
(Simon optimal two-stage). The trial’s primary endpoint provides a clear, near-term measure of 
therapeutic success and aligns with real-world transplant-listing practices. Focusing follow-up on the first 
year (active treatment period) also limits calendar time and directly answers the question most relevant to 
multidisciplinary tumor boards: Can this regimen create new surgical or transplant options, and is it 
tolerable while doing so? 
Published series suggest that downstaging success rates with SOC LRT alone are approximately 25–
40% [19]. While it is not possible to fully disentangle the contributions of local therapy versus ICI, 
exploratory analyses will collect detailed response and outcome data to aid interpretation. 
Although all patients will be monitored for listing, transplantation, and post-LT outcomes, these events are 
exploratory, ensuring they do not delay primary analysis. Given variability in transplant wait times and 
post treatment safety measures, data completeness may be limited; these analyses will therefore be 
exploratory and hypothesis-generating. This will allow the study to first, quantify efficacy and safety of the 
regimen in intermediate advanced -stage HCC without waiting years for graft outcomes, second, generate 

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the first prospective benchmark for down-staging success, progression-free survival, and immune-related 
toxicity in this setting. And third, provide correlative biospecimens to interrogate immune and microbiome 
predictors of response. 
 
3.2 
Rationale for Study Population 
The total number of subjects involved in the study will be 41. Of those, we estimate that approximately 
30% will be cisgender women. The estimated racial/ethnic breakdown of the study may approximately be 
that 10% may be Black or African American, 20% may be Asian, and 5% may be Native Hawaiian-Pacific 
Islander. Approximately 40% of the subjects may be Hispanic. While this provides only an estimated 
breakdown of the study population, efforts should be made to ensure equitable recruitment of individuals 
who meet the above eligibility requirements. 
 
 
4.0 
PATIENT ELIGIBILITY  
Patients must meet all the following inclusion criteria to be enrolled in the study: 
4.1 
 Inclusion Criteria  
1- Age ≥ 18 at the time of signing the Informed Consent Form. 
2- Beyond UCSF criteria HCC with diagnosis confirmed histologically/cytologically, radiologically, or 
clinically per AASLD criteria, with life expectancy of at least 12 months. 
3- Histologically confirmed HCC via liver biopsy obtained within 3 months prior to initiation of study 
treatment as part of SOC. If no historical biopsy is available, a biopsy must be performed at 
screening for confirmation. Screening liver biopsy may be conducted as part of research activities 
if not performed per SOC practice. 
4- ECOG performance status ≤ 2 within 7 days prior to initiation of study treatment. 
Child-Pugh A or B7 (5 to 7 points) at screening and within 7 days prior to study treatment. D1 
ECOG/CTP may not repeat if screening ECOG/CTP collected within 7 days prior to D1. 
5- HCC with Measurable disease by mRECIST (see Appendix 11.2) (at least one ≥10mm target 
lesion) that is not suitable for resection per standard clinical practice and beyond UCSF criteria 
(see section 11.5) confirmed with most recent imaging obtained within 3 months prior to 
screening. 
6- For subjects of childbearing potential (SOCBP), negative serum or urine pregnancy test and 
agreement to use adequate contraception or abstinence from the time of screening until 3 months 
following the last dose of Durvalumab. 
7- Written informed consent obtained from subject and ability for subject to comply with the 
requirements of the study. 
 

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4.2 
Exclusion Criteria 
1- Known fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma 
and HCC. 
2- Extrahepatic spread with organ involvement other than liver. 
3- Portal vein tumor thrombus (VP3-4) or any viable hepatic vein tumor thrombus at screening. 
4- History of immune therapy exposure (and-PD-1, and PDL-1, and anti-CTLA-4) treatment. 
5- Is pregnant or breastfeeding or expecting to conceive or impregnate someone during the study 
period. 
6- Active or history of autoimmune diseases, including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis. 
7- Patient lacks interest or inadequate psychosocial support for organ transplantation. 
8- Patients who have a known concurrent malignancy that is progressing or requires active treatment, 
who have not completely recovered from prior treatment, or who have a significant malignancy 
history that, in the opinion of the investigator, should preclude participation. 
9- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-
induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest computed tomography (CT) scan. 
10- Active tuberculosis (TB), as documented by a positive purified protein derivative (PPD) skin test or 
TB blood test and confirmed by a positive chest X-ray within 3 months prior to initiation of study 
treatment. 
11- Active co-infection with HBV and HCV. Participants with a history of HCV infection but who are 
negative for HCV RNA by PCR will be considered non-infected with HCV. 
12- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active 
infection that, in the opinion of the investigator, could impact participant safety. 
13- Treatment with investigational therapy within 28 days prior to initiation of study treatment. 
14- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-
2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study 
treatment. 
15- Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor [TNF] agents) within 2 weeks prior to initiation of study treatment, or anticipation of 
need for systemic immunosuppressive medication during study treatment, with the following 
exceptions: 

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• 
Participants who received acute, low-dose systemic immunosuppressant medication or a one-
time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for 
a contrast allergy) are eligible. 
• 
Participants who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study. 
16- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or 
anticipation of need for such a vaccine during study treatment, within 5 months after the final dose 
of ICI. 
17- Radiotherapy within 28 days, or abdominal/pelvic radiotherapy within 60 days, prior to initiation of 
study treatment. 
18- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
initiation of study treatment; or abdominal surgery, abdominal interventions, or significant abdominal 
traumatic injury within 60 days prior to initiation of study treatment; anticipation of need for major 
surgical procedure during the course of the study; or non-recovery from side effects of any such 
procedure. 
19- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding 
that contraindicates the use of the study drugs, may affect the interpretation of the results, or may 
render the participant at high risk from treatment complications 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Table 5.1: Study Drug Dosage and Administration 
Drug 
Dose 
Route 
Frequency 
Duration 
Tremelimumab 
300 mg 
I.V. 
Once 
N/A 
Durvalumab 
1500 mg 
I.V. 
Once every 4 weeks 
Up to12 treatment cycles 
 
Study treatment (Tremelimumab and Durvalumab) will be administered under standard of care (SOC) 
clinical practice guidelines within the institution, and dosing will align with FDA-approved regimens for the 
STRIDE protocol.. Tremelimumab and Durvalumab are commercially available and will be obtained 
locally. Study agents will be provided under institutional SOC access. All treatments will occur under 
direct supervision of qualified investigators during the up to 12 months study treatment duration. 
However, if clinically indicated per SOC practice, Durvalumab administration may be extended after 
month 12 strictly under treating physician management, research related assessments at this point will be 
limited to follow up on medical record review and survival status check. If a patient continues ICI beyond 
12 months under SOC, further AEs/irAEs are not research assessments but may be captured 

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retrospectively by medical record review as part of exploratory objectives (e.g., incidence and severity 
comparisons between those who stop at 12 vs. those who continue SOC). 
Locoregional treatment (LRT), including Transarterial Chemoembolization (TACE), Transarterial 
Radioembolization (TARE/Y90), or Radiofrequency Ablation (RFA), will be administered within 6 weeks of 
initiating immunotherapy, per SOC and multidisciplinary clinical evaluation. Treatment planning and 
sequencing will be individualized per tumor burden and patient-specific factors. 
 
5.2 
Rationale for Dose and Treatment Schedule  
The selected dose and schedule for Tremelimumab and Durvalumab are based on the STRIDE regimen 
validated in the HIMALAYA trial for advanced HCC. This combination has shown a favorable safety 
profile and anti-tumor activity. Monthly Durvalumab dosing post-initial Tremelimumab bolus provides 
sustained checkpoint inhibition. Integration of LRT within the first 6 weeks complements immunologic 
priming, aiming to increase likelihood of tumor necrosis and immune cell infiltration to enhance 
downstaging. 
This schedule allows flexibility for clinical judgment in tailoring LRT modality, accommodating variable 
tumor responses while maintaining immune pressure throughout the downstaging period. 
 
5.3 
Toxicities and Dosing Delays/Dose Modifications  
STRIDE administration may be delayed at the investigator’s discretion for any reason. Dose modifications 
per SOC guidelines are permitted. Refer to Section 5.5 for dose holding or discontinuation criteria. Refer 
to the respective package insert for detailed toxicity information. 
 
5.4 
Evaluable for toxicity  
Any patient who receives at least one dose of study treatment is evaluable for toxicity and will be included 
in the safety analysis. 
 
5.5 
Dosing and Toxicity Safety Plan 
This study includes enhanced vigilance for ICI and LRT-associated toxicities and complications through 
the 12-month down-staging window, and (exploratorily) for participants who later undergo LT. The safety 
plan includes: 
 
• 
Adverse Event Monitoring: Special focus will be placed on identifying and grading immune-
related adverse events (irAEs) commonly associated with ICI therapy, including but not limited to 
colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic reactions. LRT-specific 
complications (bleeding, post embolization syndrome, biliary injury) will be monitored with 
targeted labs/imaging. AEs and SAEs will be documented and reported per institutional and 
regulatory guidelines (see section 7). 

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• 
 On Treatment Additional Safety Monitoring:  
 
Table 5.2: On-Treatment Additional Safety Monitoring Plan 
Time point 
(Toxicity-triggered) Safety assessments 
Baseline 
H&P; ECOG; CBC, CMP, INR, albumin, bilirubin; TFT; cortisol ± ACTH; 
viral hepatitis serologies; pregnancy test (if applicable); contrast CT/MRI. 
Day 1 of each ICI cycle 
(q 4 w) 
Interval H&P; vitals; CBC, CMP, bilirubin, creatinine; TFT (q 8 w); random 
glucose. 
Weeks 2 & 3 of Cycle 1 
Focused visit or tele-check; CBC, CMP to catch early irAEs. 
Within 7 days pre-LRT 
CBC, CMP, coagulation panel; crossmatch if indicated. 
Post-LRT (24 h- 7 days 
after LRT) 
Clinical exam; labs for hemoglobin, AST/ALT, bilirubin; Doppler US if 
concern for vascular injury. 
every 8 weeks through 
Month 12 
Imaging safety/efficacy (Triphasic CT or MRI) 
Day 1 and each On 
treatment study visits 
Concomitant meds/ AEs, review for corticosteroid bursts, antibiotics, 
immunosuppressants, Any Grade ≥ 2 irAE triggers repeat labs every 48–
72 h until improving to ≤ Grade 1. 
 
On Treatment additional safety assessments are conditional and conducted as unscheduled visit, 
assessment may be triggered at the investigator’s discretion after certain conditions like 
suspected treatment-related toxicity or dosing delay, time points of those conditional 
assessments may overlap and incorporated within the main study schedule of events, 
overlapping assessments do not need to be repeated. 
Even though all grade 3–5 AEs will be captured, the Bayesian toxicity monitor applies only to the 
composite severe irAE endpoint defined above (see section 9.4). The composite of (severe-irAE) 
include any treatment-related grade 4–5 AE, Or grade 3 irAE that requires hospitalization, IV 
steroids, or leads to permanent ICI discontinuation. While isolated lab abnormalities (e.g., 
AST/ALT) that are grade 3 but managed as outpatient and resolve in ≤ 14 days, will not qualify 
under this category of severe irAE. 
• 
Dose Holding or Discontinuation Criteria: Administration of study drugs will be withheld or 
discontinued in participants who develop Grade 2 irAE persisting > 5 days or Grade ≥3 irAEs or 
show signs of organ dysfunction suspected to be immune-mediated. Management of irAEs will 
follow FDA-approved US labeling, as well as ASCO/NCCN guidelines and may include 
corticosteroids or other immunosuppressants. Grade 4 irAE (except endocrinopathy controlled on 
hormone replacement) will permanently discontinue ICIs. 
• 
Grade 3 or 4 LRT complication: delaying resumption of systemic therapy at least 6 weeks, treat 
per local standard; resume when ≤ Grade 1 and medically stable, or discontinue if not recovered. 
• 
For participants who receive LT after the study: Pre-LT washout: Minimum 4 half-lives (6 
weeks) between last durvalumab dose and LT is recommended; shorter intervals are captured for 
exploratory analysis. Early post-LT period (Day 0–90): graft function tests, RETREAT score, liver 

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Doppler, and biopsy on clinical indication per transplant unit SOP; data abstracted to study CRFs. 
Late post-LT (Day 91–365): rejection episodes, and recurrence-free survival recorded at routine 
transplant clinic visits (exploratory endpoints only; they do not delay primary analysis). As an 
exploratory safety objective, the study will assess immunologic and molecular markers (e.g., PD-
1/PD-L1 expression, T-cell subsets, cytokine profiles, and autoantibody panels) from pre- and 
post-treatment biopsies to identify predictors of treatment response. Patients who proceed to 
transplant will be flagged to routine clinical practice for intensified SOC immunologic monitoring 
post-operatively. 
• 
Safety Oversight and Escalation: Refer to Section 7 for safety reporting requirements.  
 
5.6 
Concomitant Medications/Treatments 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription (primarily corticosteroid bursts, antibiotics, immunosuppressants) over 
the counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during 
the trial period, documentation of drug dosage, frequency, route, and date will also be included on 
the CRF.  
No other anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, surgery, 
biologic therapy) or investigational agent may be used from 28 days prior to registration and until 
the end-of-treatment visit. 
 
5.7 
Duration of Study Participation 
The anticipated duration of participation for each subject is approximately 16 months, structured 
as follows: 
• 
Screening Period (up to 28 days): Eligibility assessments including history, labs, imaging, and 
biopsy review. 
• 
Treatment Period (up to 12 months): Begins Day 1 of STRIDE regimen. Durvalumab continues 
until patient is successfully down staged to Milan criteria or reaches 12 months post-treatment 
(ICI) initiation. Patients with successfully down staged tumor may continue ICI treatment per SOC 
routine practice until receiving LT under the discretion of the treating physician. 
• 
Post-Treatment Follow-up Period (3 months after EOT): Begins at end of treatment and 
continues for safety monitoring 90 days after last dose. 
 
Additionally, for participants who receive LT after the study, we will review medical records for 
Post-LT exploratory surveillance, which includes the following timepoints: Pre-LT washout (6 
weeks) between last durvalumab dose and LT. Early post-LT period (Day 90) reviewing SOC 

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graft function tests, RETREAT score, liver Doppler, and biopsy on clinical indication per 
transplant-unit SOP. Lastly Late post-LT (Day 365) for rejection episodes, and recurrence-free 
survival recorded at routine transplant clinic visits (exploratory endpoints only; they do not delay 
primary analysis). 
 
5.8 
Removal of Patients from Protocol  
Patients will be removed from the study when any of the criteria listed in Section 6.8 apply. Notify 
the Principal Investigator, and document the reason for study removal and the date the patient 
was removed on the Case Report Form. The patient should be followed-up per protocol.  
 
5.9 
Evaluability and Subject Replacement 
Subjects who withdraw from the study treatment prior to starting study intervention will be 
replaced. We expect up to enroll up to 45 eligible patients to achieve 41 evaluable subjects.  
 
5.10 Assessment of Response 
Participants will undergo tumor assessments (Pathology and mRECIST v1.1) at screening and 
throughout the study until loss of clinical benefit as determined by the investigator. At the 
investigator's discretion, tumor assessments may be repeated at any time if progressive disease 
is suspected. All measurable and/or evaluable lesions identified at baseline should be re-
assessed at subsequent tumor evaluations. A baseline liver biopsy must be obtained during the 
screening period; a historical liver biopsy performed within 3 months prior to enrollment is 
acceptable and does not need to be repeated. A second liver biopsy must be conducted under 
the research protocol concurrently when receiving LRT therapy. At the investigator's discretion, 
other methods of assessment of disease as per mRECIST v1.1 (see Appendix 11.2) may be 
used. The same radiographic procedures used to assess disease sites at screening should be 
used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). 
 
6.0 
STUDY PROCEDURES 
6.1 
Screening Visit  
Assessments performed exclusively to determine eligibility for this study will be done only after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values even if the studies were done before informed consent was 
obtained. All screening procedures must be performed within 28 days prior to the Enrollment Visit, unless 
otherwise stated.  
The screening procedures include: 
• 
Informed Consent 
• 
Review subject eligibility criteria 

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• 
Medical History review: Relevant medical history, including history of current disease, and 
information regarding underlying diseases will be recorded at screening. 
• 
Concomitant Medications review 
• 
Demographics: Age, Sex, Race, Ethnicity, Patients may be offered the Inclusive Demographics 
Questionnaire, which is a standard, non-study-specific document, available on the CS-Link’s 
selection for demographics. Study team to record responses in the subject’s OnCore record. 
Completion is voluntary; patients may decline to complete the Inclusive Demographics 
Questionnaire. 
• 
Physical exam 
• 
ECOG Performance Status 
• 
Height and Weight 
• 
Vital signs: Temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure 
will be assessed. 
• 
EKG will be obtained. In cases of clinical suspicion for myocarditis, EKG and cardiac biomarkers 
(e.g., troponin) will be repeated as clinically indicated. 
• 
Imaging for Tumor Measurements: Participants will undergo tumor assessments at screening. 
Tumor assessments performed as standard of care prior to obtaining informed consent and within 
28 days prior to initiation of study treatment do not have to be repeated at screening. Screening 
assessments must include triphasic CT scans (with IV contrast: with or without oral contrast) or 
magnetic resonance imaging (MRI) scans (with IV contrast) of the chest, abdomen, and pelvis. 
• 
Clinical Laboratory Evaluations: Complete Blood Count (CBC), International Normalized Ratio 
(INR), Liver Function Test (LFT), Thyroid Function Test (TFT), Urinalysis (UA), Hepatocellular 
Carcinoma Risk Panel (HCC panel), Amylase and lipase will be obtained at baseline and per 
SOC practice; repeat if clinically indicated for symptoms of pancreatitis, cardiac biomarkers (e.g., 
troponin) will be repeated as clinically indicated. Urine or Serum Pregnancy Test for SOCBP. 
• 
Liver Biopsy: A baseline liver biopsy must be obtained during the screening period; a historical 
liver biopsy performed within 3 months prior to initiation of study treatment is acceptable and does 
not need to be repeated. 
• 
Research Lab collection 
• 
Stool Sample Collection kits, giving participants the kit at screening lets them collect at home 
within 7 days pre-Day 1 visit. 
 
6.2 
Enrollment Visit / Lead-In (Day 1) 
• 
Medical Record Review: To record interval changes in medical history and concomitant 
medications.  
• 
Review and Confirm Eligibility Criteria 
• 
Physical Examination 

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• 
ECOG Performance Status  
• 
Weight 
• 
Vital Signs 
• 
Adverse event assessment: Baseline adverse events will be assessed. See section 7.0 for 
Adverse Event monitoring and reporting. Duration (start and stop dates and times), 
severity/grade, outcome, treatment and relation to study drug will be recorded on the case report 
form (CRF). 
• 
Clinical Laboratory Evaluations: As per screening visit assessment (If any assessment test at 
Screening was completed within 7 days prior to the Enrollment Visit, it does not need to be 
repeated). Additional (conditional) safety assessments might be performed (see section 5.5) 
• 
Research Lab Kit required only If the screening blood sample is older than 48 hours from Day 1 
visit. 
• 
Baseline Stool Sample Collection and kit for Week 6-8 collection. 
• 
Tremelimumab Administration 
• 
Durvalumab Administration 
 
6.3 
Week 3 Visit (LRT) (within 6 weeks after Day 1) 
• 
Medical Record Review 
• 
Physical Exam 
• 
ECOG Performance Status  
• 
Weight 
• 
Vital Signs 
• 
Adverse event assessment 
• 
Imaging and Tumor Measurements (at SOC timepoints). 
• 
Clinical Laboratory Evaluations: CBC, INR, LFT, TFT, UA, HCC panel. 
• 
Locoregional Treatment: Locoregional treatment consisting of either TACE, TARE(Y90), and/or 
local ablation to take place within 6 weeks after initiation of ICI, (LRT may be repeated during the 
study treatment period per PI discretion). 
• 
Liver Biopsy: Liver biopsy must be performed at date of (or within 7 days after) receiving LRT. 
 
6.4 
Each Cycle Day 1 (cycle=28 days), (+/- 7 days from the preceding cycle) 
• 
Medical Record Review 
• 
Physical Exam 
• 
ECOG Performance Status  
• 
Weight 
• 
Vital Signs 

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• 
Adverse event assessment 
• 
Imaging and Tumor Measurements (at SOC timepoints) 
• 
Urine or Serum Pregnancy Test for SOCBP 
• 
Clinical Laboratory Evaluations: CBC, INR, LFT, TFT, UA, HCC panel. 
• 
Research Lab Kit (every 6-8 weeks during STRIDE treatment) 
• 
Stool Sample Collection (every 6-8 weeks during STRIDE treatment) 
• 
Durvalumab Administration:  Durvalumab treatment cycles will continue until successful 
downstaging, or up to 12 cycles of treatment; or until any of the criteria in Section 6.8 is met. 
Subjects who have successful downstaging may continue treatment per treating physician 
discretion.  
 
6.5 
End-of-Treatment (EOT) Visit (+/- 7 days from the end of the preceding cycle) 
The end-of-treatment (EOT) visit is to be conducted once the subject reaches Milan criteria or completes 
12 cycles of treatment, or at the time when any other criteria in Section 6.8 is met, whichever occurs first. 
• 
Medical Record Review 
• 
Physical Exam 
• 
ECOG Performance Status  
• 
Weight 
• 
Vital Signs 
• 
Adverse event assessment: Following the AE assessment at the EOT visit, adverse events 
should be re-assessed at 90 days following the last durvalumab administration, via medical 
record review, in-clinic visit, or phone call to the patient. 
• 
Imaging and Tumor Measurements (at SOC timepoints) 
• 
Clinical Laboratory Evaluations: CBC, INR, LFT, TFT, UA, HCC panel. 
• 
Research Lab Kit 
• 
Stool Sample Collection 
 
6.6 
Post Treatment Follow-up safety assessments, 90 days post-last study dose (+/- 28 days). 
• 
Day 90 after EOT Medical Record Review for AEs and safety assessments review per SOC, 
including survival status (may be assessed by medical record review, phone call, or public 
records). 
• 
Exploratory Post LT assessments time points (for participant received LT) at Day 90 and Day 365 
Post LT time points, Medical Record Review for safety assessments review per SOC, including 
survival status (may be assessed by medical record review, phone call, or public records). 
 
 
 

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6.7 
Time and Events 
 
Table 6.1: Schedule of Events 
1. Treatment continues until subject reaches Milan criteria, or 1 year, or at the time when any other criteria in Section 6.8 is met, whichever occurs first. For subjects who achieve 
successful downstaging, Durvalumab treatment may continue per treating physician discretion.  
2. Once subject reaches Milan criteria, they proceed to the end of treatment (EOT) visit. 
3. CBC, INR, LFT, TFT, UA, and HCC panel. Additional safety labs include Thyroid panel including TSH will be obtained at baseline and every 8 weeks (or more frequently as clinically 
indicated), Cortisol ± ACTH at baseline; repeat if clinically indicated, Amylase and lipase will be obtained at baseline; repeat if clinically indicated for symptoms of pancreatitis, cardiac 
biomarkers (e.g., troponin) will be collected/repeated as clinically indicated.  
4. Baseline Liver Biopsy: Historical liver biopsy conducted within 3 months prior to C1D1 may be used. 
5. Liver biopsy must be performed at date of or within 7 days after receiving LRT. 
6. Every 6-8 weeks during STRIDE treatment 
 
 
Screening 
visit 
Enrollment 
Visit / Lead-In 
LRT 
Visit9 
Each Cycle Day 1 
EOT visit2 
EOS11 
Day 90 Follow-up 
Study Windows (Days): 
Within 28 days 
prior to D1 
Day 1 
3 to 6 weeks 
after Day 1 
Every 28 days (+/- 7days 
from the preceding cycle)1 
28 days following last study dose    
(+/- 7 days from the preceding cycle) 
Post last study Treatment dose 
(+/- 28 days)  
Informed Consent 
X 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
Medical History Review 
X 
 
 
 
 
 
Concomitant Medications Review 
X 
X 
 
X 
 
 
Medical Record Review 
X 
X 
X 
X 
X 
X 
Demographics Questionnaire 
X 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
 
Performance Status (ECOG) and 
Child-Pugh score (CTP) 
X 
X15 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
Adverse Events Assessment16 
 
X 
X 
X 
X 
X 
EKG14 
X 
 
 
 
 
 
Imaging for Tumor Measurements7 
X7 
 
 
X7 
Clinical Laboratory Evaluations3 
X 
X17 
X17 
X17 
X17 
 
Pregnancy Test (urine or serum) 
X 
X10 
 
X 
 
 
Liver biopsy 
X4 
X5 
 
 
 
Research Labs 
X 
X12 
 
X6 
X 
 
Stool Collection13 
 
X 
 
X6 
X 
 
Tremelimumab 
 
X 
 
 
 
 
Durvalumab 
 
X 
 
X1 
 
 
Locoregional Treatment (LRT) 
 
 
X8 
 
 
 
Survival Status 
 
 
 
 
 
X 

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7. Tumor assessment imaging will include contrast CT or MRI abdomen and pelvis, CT chest every 8 weeks (±1 w) as per SOC practice, Screening imaging is baseline Pre Treatment 
imaging. Imaging for tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be 
repeated at screening. 
8. Locoregional therapy may be repeated per PI’s discretion. 
9. Locoregional therapy occurs 3 weeks or up to 6 weeks following the Enrollment/Lead-In Visit.  
10. If pregnancy test at Screening was completed within 7 days prior to the Enrollment/Lead-In Visit, it does not need to be repeated. 
11. If participant receives LT, additional Exploratory Observational Post LT assessments time points at minus 6 weeks’ time point prior to LT, Day 90 and Day 365 Post LT time points, 
Medical Record Review for safety assessments review per SOC, including survival status (may be assessed by medical record review, phone call, or public records). (see section 
5.5) 
12. Research blood collection required only If the screening blood sample is older than 48 hours from Day 1 visit. 
13. Giving participants the Stool Sample Collection kit at screening lets them collect at home within 7 days pre-Day 1 visit. 
14. Baseline ECG will be obtained. In cases of clinical suspicion for myocarditis, ECG and cardiac biomarkers (e.g., troponin) will be repeated as clinically indicated. 
15. D1 ECOG/CTP may not repeat if screening ECOG/CTP collected within 7 days prior to D1. 
16. Any Grade ≥ 2 irAE triggers repeat labs every 48–72 h until improving to ≤ Grade 1. 
17. Additional (conditional) safety assessments might be performed (see section 5.5) 
 

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6.8 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own request, or they may 
be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation will be documented and may include:  
• 
Patient voluntarily withdraws (follow-up permitted). 
• 
Patient withdraws consent (termination of treatment and follow-up). 
• 
Patient is unable to comply with protocol requirements. 
• 
Patient demonstrates disease progression (unless continued treatment with study drug is deemed 
appropriate at the discretion of the investigator). 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe. 
• 
Treating physician determines continuation on the study would not be in the patient’s best 
interest. 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious adverse 
event). 
• 
Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma 
of the skin) that requires treatment, which would interfere with this study. 
• 
Lost to follow-up. If a research subject cannot be located to document survival after a period of 2 
years, the subject may be considered “lost to follow-up.” All attempts to contact the subject during 
the two years must be documented. This will be reviewed during an interim data monitoring visit. 
 
7.0 
ADVERSE EVENTS (AE), SERIOUS ADVERSE EVENTS (SAE), UNANTICIPATED 
PROBLEMS INVOLVING RISK TO SUBJECTS OR OTHERS (UPIRSO), AND SUSPECTED 
UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSAR)  
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
Laboratory test abnormalities 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, result in a delay or 
dose modification of study treatment, or judged relevant by the investigator), is considered an 
adverse event.   
 
7.1.2 
Serious Adverse Event (SAE) 
An adverse event is considered “serious” if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• 
Death 

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• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
7.1.3 
 Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO) 
UPIRSOs include any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied. 
• 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized 
7.1.4 
Immune-related adverse events (irAEs) 
• 
Immune-related adverse events (irAEs) commonly associated with ICI therapy, including 
but not limited to colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic reactions, 
isolated lab abnormalities (e.g., AST/ALT) that are grade 3 but managed as outpatient and 
resolve ≤ 14 days. 
• 
The composite of (severe-irAE) include any treatment-related grade 4–5 AE, Or grade 3 
irAE that requires hospitalization, IV steroids, or leads to permanent ICI discontinuation. 
 
7.2 
Principal Investigator Responsibilities for Safety Monitoring 
7.2.1 
 AE Reporting Period  
The investigator or designee is responsible for ensuring that all AEs (both serious and non-
serious) observed by the clinical team or reported by the subject which after the first dose of and 
until 90 days following the last dose of the study drug, are fully recorded in the subject’s medical 
records. 

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7.2.2 
 AE/SAE Documentation  
The investigator, sub-investigator (treating physician if applicable), or study team (according to 
the responsibilities delegated per the DOA) will document the following for all AEs (both serious 
and non-serious): 
• 
Event term, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5. The CTCAE current version is available at https://dctd.cancer.gov/research/ctep-
trials/for-sites/adverse-events  
• 
Description of the event 
• 
Date of onset and resolution 
• 
Expectedness of the toxicity 
Expected events are those that have been previously identified as resulting from administration of 
the agent. An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in: 
▪ 
the current known adverse events listed in this protocol. 
▪ 
the drug package insert; and/or 
▪ 
the current Investigator’s Brochure 
• 
Grade of toxicity, as per CTCAE v5.0 criteria 
• 
Attribution of relatedness to the investigational agent- (this must be assigned by an 
Investigator, sub-investigator, or treating physician) 
• 
Attribution categories are as follows: 
▪ 
Definite: The AE is clearly related to the study treatment. 
▪ 
Probable: The AE is likely related to the study treatment. 
▪ 
Possible:  The AE may be related to the study treatment. 
▪ 
Unlikely: The AE is doubtfully related to the study treatment. 
▪ 
Unrelated: The AE is clearly NOT related to the study treatment. 
• 
Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no action, 
received concomitant med or other intervention, etc. For the severe-irAE, PI and the DSMC 
will review context and recommend whether to modify or resume the trial. 
• 
Outcome of event 
Source documentation must be available to support all AEs.  
 
7.2.3 
Duration of AE monitoring  
All patients experiencing an AE of any grade, regardless of its relationship to study drug, will be 
monitored until:  
• 
the AE resolves or the symptoms or signs that constitute the AE return to baseline 
• 
any abnormal laboratory values deemed an AE has returned to baseline 

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• 
there is a satisfactory explanation other than the study drug for the changes observed 
• 
death, or  
• 
until 90 days following the last dose of the study drug 
7.3 
Safety Reporting Requirements 
7.3.1 
 Reporting to the Principal Investigator 
The Principal Investigator (PI) must be notified by study staff or co-investigators within 24 hours 
of learning of any SAEs, regardless of attribution and expectedness, occurring during the study or 
within 90 days following the last dose of the study drug.  
 
Contact for Expedited Reporting: 
Ju Dong Yang, MD, MS 
JuDong.Yang@cshs.org 
310-423-6000 
 
Alternate Contact for Expedited Reporting: 
Emily Kaymen, MD 
Emily.Kaymen@cshs.org 
310-888-8680 
 
7.3.2 
Reporting to DSMC:  
Serious Adverse Events deemed to be related to the protocol and on-study deaths, including 
death of a research subject unless the death is expected (e.g., due to disease progression) are to 
be reported to the DSMC within 24 hours of awareness. Hardcopies or electronic versions of the 
MedWatch Form 3500A (Mandatory Reporting) or a narrative report, along with any other 
supporting documentation available, should be submitted to the DSMC Coordinator. The DSMC 
Coordinator will forward the information to the DSMC Chair, and/or medical monitor. The DSMC 
Chair will review all documentation upon receipt from the DSMC Coordinator and determination of 
whether the following actions are required: 1) takes action immediately, 2) convenes a special 
DSMC session (physical or electronic), or 3) defers the action until a regularly scheduled DSMC 
meeting. Reports are to be emailed to the DSMC team at 
GroupSOCCICCTODSMCAdmin@cshs.org.  
 
7.3.3 
 Reporting to the Institutional Review Board (IRB) 
As per the Cedars-Sinai IRB Reporting Possible Unanticipated Problems Involving Risks to 
Subject or Others (UPIRSO) Policy: Institutional Review Board/Research Compliance and Quality 
Improvement v.5, the IRB must be notified of all UPIRSOs as soon as possible, but no later than 
10 business days from when the study team learned of any of the following events:   

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1. 
Any internal SAE, AE or Research-Related Subject Injury (RRSI), which in the opinion of 
the Principal Investigator was unanticipated or unexpected and has a reasonable 
possibility of relationship to the research. 
2. 
Any actionable external SAE, AE, SUSAR, development safety update 
report (DSUR), or FDA MEDWATCH report deemed to be a UPIRSO. An event is 
considered “actionable” if it warrants a change to the conduct of the study.  
3. 
Any internal or external UADE. 
4. 
Any accidental, unintentional protocol or consent/HIPAA related deviation that may 
impact subjects’ rights, safety, or welfare. See section 10.8.3. 
5. 
Any planned protocol exception or eligibility waiver. See sections 10.8.2 and 10.8.3. 
6. 
Changes to the research or protocol deviations made without prior IRB approval in order 
to eliminate apparent immediate hazard to a research subject.(Note: These must be 
reported to the IRB within 72 hours.) 
7. 
Problems, events, unanticipated incidental findings, billing problems, or other events, 
outcomes, or new information related to the research (e.g., publication, safety monitoring 
report, interim findings, product labeling changes, findings generated from preclinical, 
animal studies) that may adversely affect the rights, safety, or welfare of the subjects or 
others, put subjects or others at increased risk, compromise the research data, or 
require/recommend changes to the study conduct. 
8. 
Subject complaints or concerns that cannot be resolved by the research staff to the 
subject’s satisfaction. 
9. 
Breach or potential breach of confidential or sensitive information.  
10. 
Incarceration of a subject who is enrolled in a study that is not approved by the IRB to 
include prisoners. 
 
 
8.0 
CORRELATIVES/SPECIAL STUDIES 
8.1 
Assay Methodology 
We will test checkpoint molecules (Tim3, CTLA4, PD1, PDL1) IFNg, IL27 in circulation/serum, in 
tumor/liver CD8 cytotoxic cells (cell numbers, markers of exhaustion, markers of cytotoxicity 
(Granzymes, Perforin), IFNg, markers of activation Innate cytotoxic cells (NK, ILC1; cell numbers, 
markers of exhaustion, markers of cytotoxicity (Granzymes, Perforin) Neutrophils (long-lived=  tumor 
promoting neutrophils) Tumor associated macrophages/DC  (pro-inflammatory (former M1) vs anti-
inflammatory (former M2); cDC1 vs cDC2 B cells (Bregs (IL10+)-poor prognosis; B cells -good 
prognosis) Tregs (numbers, suppressor functions, conversion to effect cells (by scRNAseq trajectory 
analyses)   Microbiota analysis (if we go this way). Proposed correlative study will involve 1)scRNA seq 
of biopsies vs PBMC 2) spatial analyses (biopsies) 3) multi-color FACS 4)cytokine multiplex 5) 
microbiota 16s seq-> metabolomics.  

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8.2 
Sample Collection / Specimen Banking 
Study will use consistent institutional laboratory method throughout study. Blood and stool sample will 
be collected for the study as outlined below: 
Research stool samples will be collected at Screening, Day 1, Every treatment cycle, and End of 
treatment visits, we will obtain stool samples using a stool collection kit. This kit will be provided 
during the research visit by the research team along with instructions on the stool collection 
process. You will have the option to collect the stool during the study visit or at home. If you 
collect the stool sample at home, then you may return the stool sample to the site by mail or in 
person.  
Research blood samples will be collected at Screening, Day 1, Every treatment cycle, and End of 
treatment visits, four (4) 8.5 mL (two purple tops, one red top, and one yellow top ACD tube) will 
be provided in a research kit from the Yang lab and will be used when collecting blood from 
patients. 
A baseline liver biopsy must be obtained during the screening period; a historical liver biopsy 
performed within 3 months prior to initiation of study treatment is acceptable and does not need to 
be repeated. A second liver biopsy must be conducted under the research protocol concurrently 
when receiving LRT therapy, research biopsy with be performed at Cedars Sinai imaging facility 
(Ultrasound Guided Liver biopsy), and read by Cedars Sinai radiologist, remnant liver tissue for 
biopsy may be retained for further future analysis. 
All collected study biospecimens will be processed, and bio banked at CSMC Dr Yang lab space.  
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Design and Sample size 
This is a single arm Phase-II study focused on the preliminary efficacy of administering ICI and LRT 
combination therapy to downstage patients with (intermediate to advance stage) HCC to Milan Criteria 
within 12 months of enrollment. Simon two-stage design will be used to test for efficacy [20]. Due to the 
use of standard treatments and enrichment for compliant patients who are eligible for liver 
transplantation, we anticipate a low drop-off rate of 10%. Thus, our target patient accrual is 41 with an 
addition of 4 patients if replacement is required. 
 
Using the Simon’s two-stage design we will test the following hypothesis 𝐻0: 𝑃≤0.25  𝑣𝑠 𝐻1: 𝑃≥0.50. 
The trial will be carried out in two stages. In stage I, a total number of 15 patients will be enrolled. If 
there are 4 or fewer downstages among these 15 patients, the study will be stopped early for futility. 
Otherwise, the study will enroll additional 26 patients in stage II, resulting in a total number of sample 
size of 41. The null hypothesis will be rejected if 15 or more HCC patients downstage to MILAN criteria. 
The design attains a one-sided type-I error rate of 0.028 and power of 90.2% when the true response 

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rate is 50%. The probability of early termination under the null hypothesis is 68.6%. When the null 
hypothesis is true, the expected sample size is 23 patients. The sample sizes are calculated using 
admissible design [21]. 
 
9.2 
Stopping Rules: 
We will conduct safety assessment during the phase II trial using Bayesian sequential monitoring. Let 
Pt be the true probability of grade 3 or more irAE during the study treatment (defined as grade 4–5, or 
grade 3 irAE requiring hospitalization, IV steroids, or permanent ICI discontinuation; endocrinopathies 
controlled on replacement therapy are excluded). The trial will stop if there is statistical evidence that 
Pt>30%. We will use Bayesian design to check whether Pt > 30% after 15, 25, 35 and 41 patients 
complete the study treatment (up to 12 months). The trial will stop if the posterior probability that 
Pt>0.30 is 0.948 or more, i.e. Pr (Pt >0.30 | data)>0.948. Using a non-informative Jeffery’s prior 
distribution for Pt, Table 1 shows the stopping rules at each interim look. The column 2 shows the 
maximum number of patients with grade 3 or more irAE allowed for trial to continue. For example, if 8 
patients develop grade 3 or more irAE after enrolling first 15 patients, the trial stops. The third column 
gives the probability to stop the trial when true Pt =0.30. The target type I probability was set at 0.10. 
Enrollment will continue uninterrupted during interim assessments (after 15 evaluable patients). These 
reviews are intended for monitoring only and will not require suspension of accrual. 
Safety stopping rules will be based on Grade ≥3 adverse events occurring within one cycle (4 weeks). 
Enrollment will not be halted at the 15-, 25-, or 35-patient reviews; these checkpoints are intended 
solely for ongoing safety monitoring. 
 
Table 9.1: Safety Stopping Rule* (15 Patients) and Ongoing Monitoring Checkpoints (25, 35, 41 
Patients) 
Number of 
Patients 
Maximum number of patients with undesirable 
events at which trial will continue 
Probability 
to Stop 
Cumulative 
Probability to stop 
15 
7 
0.0500 
0.0500 
25 
11 
0.0217 
0.0717 
35 
15 
0.0117 
0.0834 
41 
17 
0.0103 
0.0938 
• The stopping rule applies only at the 15-patient interim analysis. The 25-, 35-, and 41-patient reviews are safety monitoring checkpoints only and do not mandate 
trial suspension unless recommended by Data and Safety Monitoring Committee (DSMC). 
Table 9.1 shows the design operating characteristic under different values of the true probability of Pt with 
the probability of stopping the trial under alternative hypothesis, the expected sample size and the 
average sample size given that the trial is stopped. For example, if the true value of Pt is 0.4, then there is 
a 45.98% chance that the trial will be stopped early, and the average sample size is about 33. When the 
true Pt is 0.1, the chance of stopping the trial is very low <0.1%. 

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Table 9.2: Design operating characteristics under different true probability of Pt 
True value of Pt 
Probability to Stop 
Expected N 
 
Expected N given the 
trial stopped 
0.1 
< 0.001 
41 
 
15.27 
0.3 
0.0938 
39.28 
 
22.68 
0.4 
0.4598 
33.23 
 
24.1 
0.6 
0.9912 
17.91 
 
17.71 
 
 
9.3 
Primary endpoint 
Proportion of patients who meet Milan criteria by mRECIST within 12 months of first STRIDE dose. 
 
9.4 
Primary Analysis 
The downstaging rate and exact Clopper-Pearson 95 % CI will be reported. Operating characteristics of 
the two-stage design (stop probability under H₀/H₁, expected sample size) will accompany the results. 
 
9.5 
Secondary Analysis 
The Incidence and grade of treatment-emergent AEs and hepatic decompensation events summarized 
descriptively; cumulative incidence curves for first severe irAE.  
 
The ORR at Months 3, 6 and 12 with 95 % CIs; PFS and TTP estimated by Kaplan Meier, censored at 
12 months. The PFS will be analyzed similarly as well. Rate and grade of hepatic decompensation 
events will be summarized descriptively. 
 
9.6 
Exploratory analysis 
Post-LT outcomes (RETREAT score, allograft rejection and time to rejection) will be analyzed 
descriptively using mean, SD, median and IQR. RFS will be estimated with Kaplan Meier estimator 
along with 95% confidence interval. Associations with ICI washout interval will be assessed either using 
Cox or logistic regression. Correlative biomarker changes (immune profiling, microbiome shifts) versus 
clinical outcomes will be analyzed appropriately using bi-variate analysis, e.g. LMM or GEE. Omics 
endpoints will be tested using two-sided t-test or Mann-Whitney test at 10% False discovery rate using 
Benjamini-Hochberg adjustment. All analyses will be conducted either in SAS or R 
 
9.7 
Safety and Data Sets Analyzed 
All eligible patients who are enrolled into the study and receive at least one dose of a study agent will 
be included in the efficacy and safety analysis.  

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The safety profile of ICI and locoregional treatment combination is well known in HCC. Grade 3,4 AE 
were reported up to 70s% in HCC trials thus, we will closely monitor unexpected or severe irAEs (e.g., 
grade 4 hepatitis, grade 3 pneumonitis needing oxygen, grade 3 colitis requiring IV steroids). Please 
refer to the safety plan described in Section 5.5. 
A potential risk of this study is allograft loss due to rejection after liver transplantation, which will be 
reported descriptively as a exploratory endpoint as there are retrospective evidence suggesting safety 
of ICI treatment as long as there is an adequate washout period (at least 6 weeks or longer)(see 
Section 9.3.2). 
 
 
10.0 
STUDY MANAGEMENT 
10.1 Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in the Informed 
Consent Form. 
 
10.2 Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations.  
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’s written approval of the study protocol and the informed consent form will be in the possession of 
the Investigator before the study is initiated and prior to the shipment of study supplies to participating 
sites, if applicable.  This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the patient and the investigator is assured that the 
patient understands the implications of participating in the study, the patient will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
 

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10.3 Registration/Enrollment Procedures 
All patients will be tracked following written informed consent.  Those patients who are consented to 
participate in the clinical trial but do not meet one or more criteria required for participation during the 
screening phase will be listed as screen failures on the master list of consented subjects.  Eligible 
subjects, as determined by screening procedures and verified by a treating investigator, will be 
registered on study at Cedars Sinai Medical Center by the Study Coordinator. 
Issues that would cause treatment delays after registration should be discussed with the Principal 
Investigator (PI). If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of cancellations 
as soon as possible. 
Assignment of Subject ID: The study teams will track all subjects who sign consent using OnCore. 
Subjects found to be ineligible will be recorded as screen failures. Subjects found to be eligible will be 
registered using a three-digit numeric ID that follows the standard CSCC format (001, 002, etc.).   
 
A) Eligibility Verification 
Prior to registration/enrollment, all subjects must undergo eligibility verification by the Cancer 
Clinical Trials Office (CCTO) Quality Management Core (QMC). The following documents will 
be organized into an eligibility packet, scanned as a pdf, and emailed to 
GroupCCTOQMC@cshs.org for review: 
 
• 
QMC approved Eligibility Checklist signed by investigator and 2 members of the study team 
(or equivalent) 
• 
Source documents substantiating eligibility that cannot be located in the subject’s CS Link 
medical record  
• 
Signed consent form with Subject’s Bill of Rights, HIPAA authorization form, consent 
progress note, and any optional consent forms, as applicable, if not available in CS Link  
 
 
B) Registration 
After eligibility is verified, each site will assign the subject a study number and site staff will then 
register the patient in OnCore®.   
 
Registration is completed as follows: 
 
• 
Assignment of a patient study number 
• 
Assignment to the patient a dose/treatment arm as determined through communication with 
Biostatistics and the principal investigator, if applicable  

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• 
Enter the patient in OnCore 
• 
Notify the investigational pharmacy and treating physicians that a subject has gone on 
study and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire registration process. 
 
10.4 Data Management, Quality Assurance, Quality Control and Reporting 
REDCap is the Cedars-Sinai Cancer institutional choice for the electronic data capture of case report 
forms for CSCC Investigator Initiated Trials. REDCap, a HIPAA-compliant database, will be used for 
electronic case report forms in accordance with institutional requirements, as appropriate for the 
project. The Study Staff will be responsible for data processing, in accordance with procedural 
documentation. Database lock will occur once quality assurance procedures have been completed. See 
also Section 10.6.2, Monitoring.  
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 
10.5 Data and Safety Monitoring 
10.5.1 Safety Oversight 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research 
Group (DRG) meetings (or equivalent). The PI will maintain continuous safety monitoring 
for the duration of the study by reviewing subject/study data. It is the responsibility of the 
principal investigator to adhere to the Data Safety Monitoring Plan throughout the life of 
the study. 
In addition, safety oversight and efficacy data will be reviewed by the CSCC Data and 
Safety Monitoring Committee (DSMC). The DSMC will review this trial commensurate 
with the assigned risk class as categorized by the PRMC. The DSMC membership and 
responsibilities are governed by the committee charter. The DSMC findings and 
recommendations will be reported in writing to the Principal Investigator as a summary 
letter which will be forwarded by the Principal Investigator or designee to the CS-IRB. 
The DSMC outcome letters will be furnished to the FDA, as applicable. Refer to the 
DSMC Charter for details of the DSMC review.  
 
10.5.2 Monitoring and Auditing 
The CSCC Cancer Clinical Trials Office (CCTO) Quality Management Core (QMC) will 
conduct internal monitoring visits to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and 

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verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s). 
The Cedars-Sinai IRB and Office of Research Compliance & Quality Improvement 
(ORCQI) may conduct auditing activities to ensure compliance with institutional policies, 
procedures, applicable laws, regulations and codes designed to protect the rights, safety 
and welfare of human subjects. 
Refer to the DSMP for details pertaining to the type, frequency, and extent of auditing 
and monitoring that will be performed.   
 
10.6 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, monitoring/auditing logs/letters, records of study drug receipt, dispensation, destruction and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. Study documents should be 
kept on file in accordance with all applicable federal guidelines and local guidelines. 
Investigators must make study data accessible to the monitor, other authorized representatives of the 
Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors upon request. 
 
10.7 Adherence to Protocol 
It is the responsibility of the Investigator-sponsor to ensure that patient recruitment and enrollment, 
treatment, follow-up for toxicities and response, and documentation and reporting at CSCC are all 
performed as specified in the protocol. Except for an emergency situation in which proper care for the 
protection, safety, and well-being of the study patient requires alternative treatment, or a protocol 
exception request approved by the IRB of record, the study shall be conducted exactly as described in 
the approved protocol. 
 
10.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, the IRB must be notified as soon as possible, but 
no more than 72 hours from the investigator’s awareness of the event. 
 
 

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10.7.2 
Protocol Exceptions and Eligibility Waivers  
 
Moderate Risk or High Risk 
A protocol exception is an anticipated or planned deviation from the IRB-approved 
research protocol, as described in the IRB Policy, Reporting Possible Unanticipated 
Problems Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement. A protocol exception most often 
involves a single subject and is not a permanent revision to the research protocol. 
Protocol exceptions that extend beyond a single subject should result in a protocol 
amendment to avoid serial violations.  
Planned exceptions to the protocol that are more than logistical in nature and/or affect 
timing of study drug administration, or the investigator assesses the event may impact 
subject safety and/or study integrity, may not be implemented without prior approval from 
the IRB. The PI or her/his designee is responsible for submitting a protocol exception and 
its supporting documents for IRB review.   
Study team should refer to the IRB Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement guidelines to determine which deviations and 
exception requests meet reporting guidelines. The deviation or exception request must 
be submitted to the IRB for review and approval prior to implementation.   
 
Special considerations for Eligibility Waivers (EW) 
Subjects who do not meet the eligibility requirements should not be enrolled. Eligibility 
waivers are not permitted.  
 
10.7.3 Other Protocol Deviations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an 
individual subject) do not require prior IRB approval unless the deviation has the potential 
to affect the subject’s safety or study integrity. Such planned deviations that do meet this 
definition and do not affect the subject’s safety or study integrity should be noted in the 
subject’s research record or deviation log as described in the CSCC CCTO’s Standard 
Operating Procedure 12: Deviation and Noncompliance Reporting. 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB within 10 days from when the investigator 
becomes aware that such a deviation has occurred, as outlined in the CSCC CCTO’s 
Standard Operating Procedure 12: Deviation and Noncompliance Reporting (or local 
policy, for multi-site studies). In this case, a Protocol Deviation report must be submitted 

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in CS-IRB, per CSMC IRB policy, Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement. All submissions should include a description of the 
plan to avoid similar deviations or exceptions in the future.   
 
10.7.4 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
 
10.8 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The Principal 
Investigator must assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding 
clinical trials both during and after study completion. 
The Principal Investigator will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms and/or into a HIPAA-compliant study database. Periodically, 
monitoring visits will be conducted, and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case report 
forms will be reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
10.9 Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the sponsor-investigator 
and participating institutions.  The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
 
 

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11.0 
APPENDICES 
 
• 
Summary of Changes 
• 
Modified RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (mRECIST 
VERSION 1.1) for Hepatocellular Carcinoma 
• 
ECOG Performance Status Scale 
• 
Child-Pugh Score 
• 
Milan Criteria 
• 
UCSF Criteria 
• 
Retreat Score 
• 
BCLC Staging 
 
11.1  Summary of Changes 
 
 

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11.2 Response Evaluation Criteria in Solid Tumors mRECIST Version 1.1 
 
Eligibility  
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. 
 
Measurable lesions - lesions that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray. 
 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At Baseline and follow-up, only the short axis will be measured and 
followed. 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
• For special considerations regarding lesion measurability for bone lesions, cystic lesions and 
lesions with prior local treatment, consult the RECIST 1.1 guidelines. 
• All measurements should be taken and recorded in metric notation using a ruler or calipers. 
• All baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before beginning of treatment. 
• The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
• Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, either a CT scan or documentation by 
color photography, including a ruler to estimate the size of the lesion, is to be done. 
 
 

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Methods of Measurement 
Optimization of image acquisition protocol and consistence in the use of the same protocol 
throughout follow-up examinations are key proper application of mRECIST. Patients can be 
followed with either contrast-enhanced spiral computed tomography (CT) – preferably with use of 
multislice scanners – or contrast-enhanced dynamic magnetic resonance imaging (MRI). The 
administration of intravenous contrast is recommended for all CT or MRI studies if not medically 
contraindicated. In contrast-enhanced studies, it is mandatory to obtain a dual-phase imaging of 
the liver. Every effort should be made to time the contrast administration so that high-quality 
arterial-phase imaging is obtained throughout the liver on the first run, and high-quality portal 
venous-phase imaging is obtained throughout the liver on the second run. Delayed imaging 
obtained in the equilibrium phase may be useful, but it is not mandatory and should only be done 
if it is part of clinical practice. For multidetector CT scanners that are capable of acquiring very 
thin slices, it is necessary to keep in mind that it is mandatory to use contiguous slices for image 
read and interpretation, to avoid missing small lesions. For example, the analysis of contiguous 
slices with traditional 5 mm reconstruction interval is acceptable; however, the analysis of 2.5 mm 
thickness sliced at 5 mm intervals is not acceptable. 
According to RECIST, tumor lesions are categorized at baseline as follows: measurable (lesions 
that can be accurately measured in at least one dimension as ≥1 cm with a spiral CT scan) or 
nonmeasurable [all other lesions, including small lesions (longest diameter <1 cm with spiral CT 
scan) and truly nonmeasurable lesions]. The original RECIST publication states that all 
measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. The recent 1.1 release of RECIST has reduced the number of lesions to 
select as target lesions to a maximum of two lesions per organ and five lesions in total 
(Eisenhauer et al., 2009). In fact, analyses on a large prospective database has shown that 
assessment of five versus 10 lesions per patient did not affect the overall response rate, and that 
progression-free survival was only minimally affected (Bogaerts et al., 2009) Target lesions 
should be selected on the basis of their size (those with the longest diameter) and their suitability 
for accurate repeated measurements. All other lesions (or sites of disease) should be identified 
as nontarget lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
It is our understanding that the measurement of the longest viable tumor diameter for the 
assessment of response according to mRECIST can be only applied in case of typical lesions. 
Conversely, for non- enhancing atypical lesions, as well as for any extrahepatic neoplastic niches, 
the measurements of the longest overall tumor diameter as per conventional RECIST should 
prevail. 

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To be selected as a target lesion using mRECIST, an HCC lesions should meet all the 
following criteria: 
• 
The lesion can be classified as a RECIST measurable lesion (i.e., the lesion can be 
accurately measured at least one dimension as 1 cm or more). 
• 
The lesion is suitable for repeat measurement. 
• 
The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
 
Non-target lesions - all other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up. 
 
 
Response Criteria Evaluation of Target Lesions 
 
Complete Response (CR): 
 
 
 
Disappearance of any intratumoral 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 
 
Progressive Disease (PD): 
 
At least a 20% increase 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  
 
Stable Disease (SD): 
 
Any cases that do not qualify for either partial response or 
progressive disease 
 
Evaluation of non-target lesions 
 
 
Complete Response (CR): 
 
Disappearance of all non-target lesions 
 
Incomplete Response/ Stable 
Disease (SD): 
 
Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): 
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions* 
 

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* 
Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
Evaluation of best overall response 
o 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
o 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
o 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 

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Confirmation 
 
o 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
 
o 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
 
o 
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol. 
 
 
Duration of overall response 
 
o 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded since 
the treatment started. 
 
Duration of stable disease 
 
o 
SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
o 
The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD. This time interval should take into 
account the expected clinical benefit that such a status may bring to the population under study. 
 
 
 
 

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Response review 
 
o 
For trials where the response rate is the primary endpoint it is strongly recommended that 
all responses be reviewed by (an) expert(s) independent of the study at the study’s completion. 
Simultaneous review of the patients’ files and radiological images is the best approach. 
 
Reporting of Results 
 
o 
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 8) unknown (not assessable, insufficient data). 
 
o 
All of the patients who met the eligibility criteria should be included in the main analysis of 
the response rate. Patients in response categories 4-8 should be considered as failing to respond 
to treatment (disease progression). Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate. Precise definitions for categories 
4-8 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
 
o 
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.). However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported. 
 
o 
The 95% confidence intervals should be provided. 
 
 
 
 
 
 
 
 

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Definition of CT tumor response by RECIST 1.1 criteria: 
The following table outlines the response categories by RECIST 1.1 criteria. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
Complete Response 
(sum of diameters=0 
mm) 
 
Complete response 
No 
Complete Response 
Complete Response 
Non-complete 
response, non-
progressive disease 
No 
 
 
 
 
 
Partial Response 
 
 
 
 
Complete Response 
Not evaluated 
No 
Partial Response 
(decrease in sum of 
target lesions by 
≥30%) 
Non-progressive       
disease OR 
Not evaluated 
No 
Stable Disease 
Non-progressive 
disease OR 
Not evaluated 
No 
Stable Disease 
Not all evaluated 
Non-progressive 
disease 
No 
Not Evaluable 
Progressive 
Disease (increase in 
sum of target lesions 
by ≥ 20% with an 
absolute increase in 
summed diameters 
by 5mm) 
Any 
Yes or No 
 
 
 
 
Progressive 
Disease 
Any 
Progressive 
Disease 
Yes or No 
 (Eisenhauer et al. 2009; Lencioni et al. 2010) 

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11.3 ECOG Performance Status Scale 
 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
 
11.4  Child-Pugh Scoring 
 
 
 
 
 
 
 
 
 

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11.5 UCSF vs Milan Criteria 
 
 
11.6 RETREAT Score 
 
11.7 BCLC Staging 
 
 

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12.0 
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