Improving Response to Immunotherapy in Patients With Advanced Hepatocellular Carcinoma and Chronic Hepatitis C Virus Infection With Direct-Acting Antiviral Therapy
Phase: PHASE4
Conditions: Liver Cancer
Sponsor: M.D. Anderson Cancer Center

Protocol # 2022-0844  
Date: 04/23/2024 
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SPONSOR: Developmental Research Program (DRP) of the MD Anderson Cancer Center 
SPORE in Hepatocellular Carcinoma Grant P50 CA217674 
TITLE:  Improving Response to Immunotherapy in Patients with Advanced Hepatocellular 
Carcinoma and Chronic Hepatitis C Virus Infection with Direct-Acting Antiviral Therapy  
Principal Investigator: 
Harrys A. Torres, MD. Professor.  
Department of Infectious Diseases, Infection 
Control, and Employee Health.  
Adjunct Professor, Department of Gastroenterology, 
Hepatology, and Nutrition.  
1515 Holcombe, Unit 1460, Houston, TX 77030. 
Phone: (713) 792-6503  
Email: htorres@mdanderson.org  
Collaborators: 
Ahmed Omar Kaseb, MD, CMQ. Professor.  
Department of Gastrointestinal Medical Oncology.  
1515 Holcombe Blvd., Unit 426, Houston, TX 77030.  
Phone: (713) 792-2828  
Cara Haymaker, Ph.D. Assistant Professor.  
Department of Translational Molecular Pathology.  
So Campus Research Bldg 2 (2SCR2.3025).  
7435 Fannin St. Houston, TX 77054  
Phone (713) 792-1458 
David Tweardy, MD. Professor.  
Division Head, Internal Medicine. 
1515 Holcombe, Unit 1463 
Houston, TX 77030 
Phone (713) 792-6517 
Jagannadha K Sastry, BS, MS, Ph.D. Professor.  
Department of Thoracic and Head & Neck Medical Oncology. 
1515 Holcombe, Unit 0432 
Houston, TX 77030 
Phone (713) 563-3304 
Eduardo Yepez Guevara, MD 
Department of Infectious Diseases, Infection Control, and 
Employee Health.  
1515 Holcombe, Unit 1460, Houston, TX 77030.  
Phone: (713) 563-4422 
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Khaled M. Elsayes, MD 
 
Department of Abdominal Imaging 
 
University of Texas M. D. Anderson Cancer Center 
 
1515 Holcombe, Unit 1473, Houston, TX 77030.  
 
Phone: (713) 794-1191 
 
 
Statistician: 
Wei Qiao 
 
Sr Biostatistician, Biostatistics 
 
1400 Pressler St Unit 1411 
 
Houston, TX 77030 
 
Phone (713) 794-4163 
 
 
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1.0 TRIAL SUMMARY 
Title 
Improving Response to Immunotherapy in Patients with Advanced 
Hepatocellular Carcinoma and Chronic Hepatitis C Virus Infection with 
Direct-Acting Antiviral Therapy 
Trial Phase 
This is a Phase IV study/hypothesis-generating study 
Clinical Indication 
Hepatocellular carcinoma (HCC) 
Trial Type 
Interventional 
Drugs 
(all 
commercially 
available)  
HCC Agents: Atezolizumab + Bevacizumab (Atezo/Bev) 
 
Direct-Acting Antiviral Agents (DAAs): Sofosbuvir + velpatasvir, or 
sofosbuvir + velpatasvir + voxilaprevir  
Type of control 
No treatment control 
Route of administration 
Atezolizumab + Bevacizumab: Intravenous 
DAAs: Oral 
Trial Blinding 
Unblinded Open-label 
Eligibility 
Male/female subjects with hepatitis C virus (HCV) genotype GT1 through 
GT6 with advanced HCC with no curative option will be enrolled in this 
trial. 
Treatment Groups  
There will be only 1 treatment group within this trial. Patients will receive 
atezolizumab (1200 mg) plus bevacizumab (15 mg per kilogram of body 
weight) intravenously every 3 weeks combined with any of the following 
DAA regimens: 1) sofosbuvir (400 mg) + velpatasvir (100 mg), or 2) 
sofosbuvir  (400 mg) + velpatasvir (100 mg) + voxilaprevir (100 mg) 
administered once daily or twice daily, orally, for 12 to 24 weeks depending 
on the HCV GT and history of cirrhosis and DAA treatment failure. 
Ribavirin (RBV) will be combined with DAAs in cases of previous DAA 
treatment failure. RBV will be administered weight-based as follows <75 
kg: 1 g/day in 2 divided dose and ≥75 kg: 1.2 g/day in 2 divided doses. 
Number of trial subjects 
Approximately 15 subjects will be enrolled. 
Estimated enrollment period 
48 months 
Estimated duration of the trial 
It is estimated that the trial will require approximately 24 months from the 
time the first patient signs the informed consent form (ICF) until the last 
subject’s last study-related phone call or visit. 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs the 
ICF through the final contact.  After a screening phase of up to 30 days, each 
patient will receive Atezo/Bev beginning on Day 1 of each 3-week dosing 
cycle.  Patients will receive Atezo/Bev until unacceptable toxic effects 
occurred or there is a loss of clinical benefit. Patients could continue 
treatment beyond disease progression if the investigator observes evidence 
of clinical benefit and if symptoms and signs indicating unequivocal disease 
progression are absent. Any DAA combination above will be allowed. Dose 
modifications are not permitted with Atezo/Bev or DAAs.  RBV dose 
reduction will be permitted. Treatment will continue until progressive 
disease, unacceptable adverse events (AEs), and intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdrawal of consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements, or 
administrative reasons requiring cessation of treatment.  Patients who 
discontinued for reasons other than progressive disease will have post-
treatment follow-up visits for monitoring disease status until progressive 
disease, initiating a non-study cancer treatment, withdrawing consent from 
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study participation, or becoming lost to follow-up.  All subjects will be 
followed (by telephone or clinic visit [in person or telemedicine]) for overall 
survival until death, withdrawal of consent from study participation, or the 
end of the study.  After the end of the study treatment, each subject will be 
followed for 24 weeks days for adverse event monitoring.  Serious AEs 
(SAEs) will be collected for 24 weeks after the end of treatment or 4 weeks 
after the end of treatment if the subject initiates new anticancer therapy or 
has premature discontinuation of study treatment, whichever is earlier. 
Virologic response (sustained virologic response [SVR]) will be collected 
for 12 after the end of all HCV study therapy. 
 
The estimated average length of 
treatment per subject 
Patients will be treated with the study drugs until unacceptable toxic effects 
occur or there is a loss of clinical benefit. Patients could continue treatment 
beyond disease progression if the investigator observed evidence of clinical 
benefit and if symptoms and signs indicating unequivocal disease 
progression are absent. 
 
 
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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a pilot/ hypothesis-generating study investigating the combination of immune 
checkpoint therapy (ICT) atezolizumab + bevacizumab (Atezo/Bev) for patients with advanced 
hepatocellular carcinoma (HCC) with chronic   hepatitis C virus (HCV) infection who either 
progressed on or after previously systemically treated HCC. Patients will receive Atezo/Bev 
combined with any of the following direct-acting antiviral agents (DAAs) such as 1) 
Sofosbuvir + velpatasvir, or 2) sofosbuvir + velpatasvir + voxilaprevir. These DAAs are not 
known to be anti-cancer therapies. Ribavirin (RBV) will be combined with DAAs in cases of 
previous DAA treatment failure. To be eligible for the study, subjects must have chronic HCV 
infection with genotype (GT) 1 through 6 and Child-Pugh class A liver disease. All drugs used 
in this trial (Atezo/Bev plus sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir +/- 
RBV) are commercially available and will be administered and monitored according to the 
standard of care (SOC) practice.1,2 
These trial aims are to 1) determine whether HCV clearance with DAA therapy enhances 
response to ICT in patients with HCC and chronic HCV infection, and 2) determine whether 
HCV clearance with DAA therapy enhances the immune response against liver cancer cells by 
reversing the exhaustion of the overall T cells and virus-specific T cells in patients with HCC 
and chronic HCV infection. The inclusion and exclusion criteria will be the same for each 
combination of Atezo/Bev and DAAs unless stipulated by one of the added agents. To be 
eligible, patients must receive DAAs plus Atezo/Bev as first-line systemic therapy or 
subsequent line therapy if documented objective radiographic progression after stopping 
treatment with systemic anti-HCC treatment (other than ICT), progression on anti-HCC 
therapy other than ICT,  or intolerance to anti-HCC therapy (other than ICT), and have a 
disease not amenable to a curative treatment approach (e.g., transplant, surgery, or ablation).  
Intolerance to anti-HCC therapy is defined as: National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0) Grade ≥2 drug-related 
adverse event(s) (AE[s]) which both a) persisted despite comprehensive supportive therapy 
according to institutional standards and b) persisted or recurred after anti-HCC therapy 
interruption of at least 7 days and a dose reduction and resulted in the subject requesting or the 
physician recommending discontinuation due to the toxicity. To be eligible, subjects must have 
at least 1 measurable lesion that is confirmed by M.D. Anderson radiology faculty or M.D. 
Anderson study collaborator from radiology per Response Evaluation Criterin in Solid Tumors 
(RECIST) 1.1, Child-Pugh status score of A, an Eastern Cooperative Oncology Group (ECOG) 
performance score of 0 or 1, and life expectancy of greater than 3 months.  To be eligible for 
DAA treatment, the patients must have chronic HCV GT1 through GT6 and Child-Pugh class 
A liver disease.  
Patients will be required to provide a tumor tissue sample at enrollment and after DAA 
treatment to support the correlative endpoints of the study.  Approximately 15 patients will be 
allocated to receive standard of care treatment with atezolizumab (1200 mg) plus bevacizumab 
(15 mg per kilogram of body weight) intravenously every 3 weeks combined with any of the 
following DAA regimens: 1) sofosbuvir (400 mg) + velpatasvir (100 mg), or 2) sofosbuvir  
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(400 mg) + velpatasvir (100 mg) + voxilaprevir (100 mg) administered once daily or twice 
daily for 12 to 24 weeks depending on the HCV GT and history of cirrhosis and DAA treatment 
failure. Ribavirin (RBV) will be combined with DAAs in cases of previous DAA treatment 
failure. RBV will be administered weight-based as follows <75 kg: 1 g/day in 2 divided doses 
and ≥75 kg: 1.2 g/day in 2 divided doses. 
The overarching goal of this proposal is to determine the effect of HCV cure after DAA therapy 
on the response of patients with HCC to ICT.  
The primary aim of this trial is to determine whether HCV clearance with DAA therapy 
enhances response to ICT in patients with HCC and chronic HCV infection and the primary 
objective under this aim is to estimate the objective response rate with Atezo/Bev and DAAs. 
The objective response rate to ICT is defined as the proportion of confirmed complete or partial 
responses after receiving DAAs. Starting with screening, all imaging assessments will be 
determined at our institution  using RECIST 1.1. Imaging assessments will be performed every 
12 weeks (Q12W) calculated from the date of starting Atezo/Bev and independent of treatment 
delays.  RECIST 1.1 will be used for treatment decisions until the first radiologic evidence of 
progressive disease (PD). 
Patients may continue to be treated with Atezo/Bev and DAAs until PD is confirmed by 
RECIST, unacceptable AEs, an intercurrent illness that prevents further administration of 
treatment, the investigator decides to withdraw the subject, subject withdraws consent, 
pregnancy, noncompliance with trial treatment or procedure requirements, or administrative 
reasons.  Patients who discontinue trial treatment for a reason other than disease progression 
will move into the Follow-Up Phase and should be assessed every 12 weeks (Q12W; 84 ± 7 
days). All patients will be followed Q12W for overall survival (OS) until death, withdrawal of 
consent from participation in the study, or the end of the study, whichever comes first.   
Patients should complete 12 to 24 weeks of dosing of DAAs before the cessation of antivirals. 
Patients who attain a complete response (CR) by 2 tumor imaging assessments at least 4 weeks 
apart and who have received at least 8 treatments (approximately 6 months of therapy) with 
Atezo/Bev may discontinue treatment at the discretion of the investigator after receiving at 
least 2 treatments beyond the initial determination of a CR.   
Adverse events (AEs) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI CTCAE version 4.0.  After the end of the combination 
treatment with Atezo/Bev and DAA treatment, each subject will be followed for 24 weeks for 
AE monitoring.  Serious AEs (SAEs) will be collected for 24 weeks after the end of treatment 
or 4 weeks  after the end of treatment if the subject initiates new anticancer therapy or has 
premature discontinuation of study treatment, whichever is earlier.  Virologic responses will 
be collected for 12 and 24 weeks after the end of DAA therapy. 
This study will be conducted in conformance with Good Clinical Practices (GCP). 
2.2 
Determine the immune response against liver cancer cells after DAAs 
We plan on performing multiple experiments to determine whether HCV clearance with DAA 
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therapy enhances the immune response against liver cancer cells by reversing the exhaustion 
of the overall T cells and virus-specific T cells in patients with HCC and chronic HCV 
infection. Lymphocyte infiltrates, in particular tumor-infiltrating CD8+ T cells, have been 
associated with improved survival and lower relapse rates after liver resection.3 
 
Multiple lymphocyte and myeloid cell subsets (e.g., CD4+, CD8+, regulatory T cells [Tregs], 
natural killer [NK] cells, macrophages, dendritic cells [DCs], and myeloid-derived suppressor 
cells [MDSCs]) will be characterized using high-dimensional multi-parametric flow cytometry 
to detect and quantify the frequencies of cells exhibiting proliferation, cytotoxicity, and 
cytokine production, as well as changes in the expression levels of immune checkpoint 
signaling receptors and activation markers (e.g., PD-1, CTLA-4, Lag3, ICOS, and 4-1BB). The 
CD8+ T-cell response will also be correlated with activated T-cell subsets identified by 
multiplex immunofluorescence (mIF) analysis of tumor biopsy samples obtained before and 
after DAA treatment. Using this strategy, we reported earlier on the kinetics of changes in 
different immune cell subsets from blood and cytobrush samples from cervical cancer patients 
undergoing standard-of-care chemoradiation treatment.4  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
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2.3 
Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
The overarching goal of this proposal is to determine the effect of HCV cure after DAA therapy 
on the response of patients with HCC to ICT. We hypothesize that DAA treatment in HCV-
infected patients with HCC synergizes with concomitant ICT and improves oncologic 
outcomes via enhanced CD8+ T-cell responses by reversing the exhaustion of tumor-specific 
T cells that are associated with chronic HCV infection. 
3.1 Primary Objective(s) 
3.1.1. Estimate the  objective response rate (ORR) to ICT and estimate the sustained 
virologic response (SVR) in patients with HCC and chronic HCV infection using HCV 
clearance with DAA therapy. 
3.1.2. Estimate the change of the overall T cells and virus-specific T cells before and after 
the antiviral treatment in patients with HCC and chronic HCV infection using HCV 
clearance with DAA therapy. 
 
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3.2  Secondary objective: 
3.2.1. Collect the safety profile of the treatment and estimate the time-to-event variable 
such as overall survival (OS) and progression free survival (PFS). 
4.0 BACKGROUND & RATIONALE 
4.1 
Background  
4.1.1.1 Background on HCC 
Liver cancer is the third leading cause of cancer deaths in the world and has one of the most 
rapidly rising mortality rates of any cancer in the United States (US).5,6  Despite advances in 
early detection, liver transplantation, and liver-directed therapies, about 70% of HCC patients 
present with advanced disease with no curative option.  HCC is resistant to most traditional 
chemotherapy agents, and the median survival for patients with advanced disease is typically 
6 to 9 months without therapy.   
4.1.2 Background on immunotherapy for HCC 
Immune checkpoint therapy (ICT) seems to be particularly effective in patients with a T-cell-
recruiting tumor microenvironment.7 The antitumor effect of ICT is mediated by CD8+ T 
cells, but only 20–30% of all HCC patients have an immunologically active tumor 
microenvironment.8 Among patients with HCC, the overall response rate to ICT is only 
between 17%-33% (overall response rate of 27-30% on combination therapies, e.g., 
IMbrave150 study regimen of Atezolizumab + Bevacizumab), and median overall survival 
(OS) rate after ICT is only between 13.9-19.2 months.9 There is an urgent need to improve 
the rate of response to ICT in patients with HCC. 
4.1.2 Background on Infections, including HCV infection, and immune response 
Infectious pathogens or their components have been used to augment weak antitumor 
responses and to reprogram the tumor microenvironment to increase immune-mediated 
responses and improve cancer outcomes.10 DAA therapy improves the OS of HCC patients,11 
and clinical trials have shown that patients with HCV-associated HCC appear to be more 
sensitive to ICT but the reason remains unknown.12 
Chronic HCV infection is associated with T-cell exhaustion, which has been reversed 
through DAA therapy or checkpoint inhibition after DAA treatment. Chronic HCV infection 
is associated with a lower frequency of HCV-specific CD8+ T cells and an increase in the 
number of so-called exhausted T cells, which exhibit impaired proliferation, IFN-y 
production, and cytotoxicity.13-15 The use of DAAs has been associated with a remarkable 
HCV cure rate, and with enhanced hepatic and systemic immune responses.16-19 Studies have 
shown a decline in the number of peripheral exhausted T cells,18 specific restorations of the 
systemic immune response in terms of proliferating HCV-specific CD8+ T cells,20 and 
augmentation of HCV-specific immunity18 in patients in whom DAA treatment resulted in a 
sustained virologic response. Of note, in a study that failed to show restoration of HCV-
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specific CD8+ T-cell phenotypes and functional responses after DAA treatment, in vitro 
blockade of the PD-1/PD-L1 pathway resulted in enhanced proliferation of some HCV-
specific CD8+ T cells after HCV clearance.19 This finding suggests that HCV-specific CD8+ 
T cells that could not restore their proliferative capacity upon clearance of HCV can do so 
through immune checkpoint inhibition.19 These findings form the basis of the proposed 
study’s approach: combining ICT and DAAs. 
4.1.3 Pharmaceutical and Therapeutic Background on ICT treatment of HCC 
In 2017 the FDA granted accelerated approval to nivolumab for the treatment of HCC in 
patients who have been previously treated with sorafenib. Approval was based on a 154-
patient subgroup of CHECKMATE-040,21 a multicenter, open-label trial conducted in 
patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to 
sorafenib. In addition to including patients without active hepatitis viral infection, the trial 
enrolled patients with either active HBV (31%) or HCV (21%) but not those with active co-
infection with HBV and HCV or with hepatitis D virus infection. Patients received 
nivolumab 3 mg/kg by intravenous infusion every 2 weeks. The confirmed overall response 
rate, as assessed by blinded independent central review using RECIST 1.1, was 14.3% (95% 
CI: 9.2, 20.8), with 3 complete responses and 19 partial responses. Response duration ranged 
from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 
55% had responses lasting 12 months or longer. 
The IMbrave150 trial showed significantly better overall survival and progression-free 
survival outcomes with Atezo/Bev than with sorafenib in patients with unresectable 
hepatocellular carcinoma who had received no previous systemic treatment. The confirmed 
objective response rates were 27.3% (95% CI, 22.5 to 32.5) with Atezo/Bev and 11.9% (95% 
CI, 7.4 to 18.0) with sorafenib, according to independent assessment with RECIST 1.1 
(P<0.001), and 33.2% (95% CI, 28.1 to 38.6) and 13.3% (95% CI, 8.4 to 19.6), respectively, 
according to hepatocellular carcinoma–specific mRECIST (P<0.001).22. Atezo/Bev is now 
recommended as first-line or subsequent-line systemic therapy for patients with HCC.1  
Despite these advances, continued investigation of additional agents for advanced HCC 
patients without a curative option remains crucial.   
4.1.4. 
Background on HCV 
4.1.4.1 HCV Epidemiology and Natural History  
Globally, an estimated 58 million people have chronic HCV infection, with about 1.5 million new 
infections occurring per year, and approximately 80% of these will progress to chronic infection.23. 
HCV is also the most common bloodborne pathogen in the United States, chronically affecting 
approximately 2.4 million Americans.24  
Long-term complications of chronic HCV infection develop in chronically infected individuals for 
several years to decades, including cirrhosis, end-stage liver disease, and HCC.24 
   
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HCV has 6 major GTs, which can each be split into multiple subtypes. The global distribution of HCV 
GTs is diverse, which reflects differences in epidemiology, modes of transmission and ethnic 
variability. HCV GT1, GT2, and GT3 have a fairly broad geographical distribution, whereas HCV 
GT4, GT5, and GT6 are generally confined to specific geographical regions.24 
4.1.4.2 Overview of HCV Therapy 
Interferon-free regimens combining 2 or 3 direct-acting antiviral drugs (DAAs) with or 
without ribavirin are now the standard of care treatment for HCV.24 DAAs target specific 
nonstructural viral proteins involved in the replication cycle of HCV and include NS3/4A 
protease inhibitors (glecaprevir, voxilaprevir), NS5B nucleos(t)idic (sofosbuvir) and non-
nucleos(t)idic (dasabuvir) polymerase inhibitors, and NS5A replication complex inhibitors 
(ledipasvir, velpatasvir, pibrentasvir).2 The combinations are given for 8 to 24 weeks, 
according to baseline factors such as fibrosis stage, GT and subtype baseline viral load, prior 
therapeutic history of the patient (naïve or experienced), and pre-existing and SVR rates 
greater than 90% with good tolerance.2 Safety and SVR rates are similar in clinical trials and 
real-life studies, usually higher than 95% in the per-protocol analysis.2  In cancer patients, we 
have observed SVR12 rates over 80% to 90%, nearly matching the response rates in the 
general population of treatment-naïve or treatment-experienced patients.25,26 
Pharmaceutical and Therapeutic Background of Atezolizumab / Bevacizumab 
4.1.5.1 Overview 
Several cancer immunotherapies that target the PD-L1–PD-1 pathway (i.e., checkpoint 
inhibitors) are currently being evaluated in patients with HCC.9 Atezolizumab selectively 
targets PD-L1 to prevent interaction with receptors PD-1 and B7-1, thus reversing T-cell 
suppression. Bevacizumab is a monoclonal antibody that targets VEGF, inhibits angiogenesis 
and tumor growth, and showed response rates of 13 to 14% in single-agent phase 2 studies in 
patients with advanced liver cancer. A phase 1b study of atezolizumab plus bevacizumab in 
patients with untreated unresectable hepatocellular carcinoma showed an acceptable side-
effect profile and promising antitumor activity, with an objective response rate of 36% and a 
median progression-free survival of 7 months.27  
A global, open-label, phase 3 trial, patients with unresectable HCC who had not previously 
received systemic treatment (IMbrave150 trial), showed significantly better OS and PFS 
outcomes with Atezo/Bev than with sorafenib in patients with unresectable HCC who had  
received no previous systemic treatment. The confirmed objective response rates were 27.3% 
(95% CI, 22.5 to 32.5) with Atezo/Bev and 11.9% (95% CI, 7.4 to 18.0) with sorafenib, 
according to independent assessment with RECIST 1.1 (P<0.001), and 33.2% (95% CI, 28.1 
to 38.6) and 13.3% (95% CI, 8.4 to 19.6), respectively, according to HCC–specific mRECIST 
(P<0.001).22. In May 2020, following results from the phase III IMbrave150 trial, a new 
standard of care for advanced and unresectableHCCwas approved by the FDA: atezolizumab 
(an anti-PD-L1 ICT ) plus bevacizumab (an anti-VEGF monoclonal antibody).9 Atezo/Bev is 
now recommended as first-line or subsequent-line systemic therapy for patients with HCC.1 
4.1.5.2 
Preclinical and Clinical Trial Data 
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DAA therapy in HCV-infected cancer patients improves oncologic outcomes. DAA therapy 
improves the OS of HCC patients.11 We found that HCV‐infected patients with oropharyngeal 
cancers who received antiviral treatment against HCV, most of them treated with DAAs, had 
better 5‐year OS and 5‐year progression-free survival rates than untreated patients.28 We 
speculate that the improved tumor response in these patients was associated with elevated 
CD8+ T-cell infiltration, as has been described in patients with squamous cell carcinoma of 
the head and neck.29  
DAA treatment invigorates the CD8+ T cells with the specific restoration of a systemic 
immune response marked by proliferative HCV-specific CD8+ T cells20 or augmentation of 
HCV-specific immunity.18 ICT is known to assist in enhancing antitumor effector immunity.30 
Therefore, the combination of DAA and ICT should provide synergistic immune activation 
and thereby produce better oncologic outcomes. We aim to determine whether HCV 
eradication following DAA therapy enhances the response to ICT in patients with HCC and 
chronic HCV infection. We hypothesize that DAA therapy in HCV-infected patients with HCC 
synergizes with concomitant ICT and improves oncologic outcomes via enhanced CD8+ T-cell 
responses by reversing the exhaustion of tumor-specific T cells that is associated with chronic 
HCV infection. 
Completion of the proposed research would markedly expand knowledge of the systemic and 
local CD8+ T-cell responses associated with DAA therapy and have major patient-care 
implications, as HCV-infected patients with HCC would be started on DAA treatment as early 
as possible to improve the HCC response to treatment with ICT. For years, DAAs were not 
recommended as early treatment in patients with active HCC given the risk of HCC 
progression.31,32 Data from our center and large studies in the US and Europe,33-35 no longer 
support the theory of HCC progression on DAAs. Our proposed research will test innovative 
hypotheses and use innovative approaches to generate new insights into how the reversal of 
the exhaustion of the HCV-specific CD8+ T cell response16 associated with HCV clearance 
can lead to better ICT response. This project is novel as there are no recommendations 
regarding the timing of DAAs in HCV-infected patients with HCC who will receive ICT. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Hepatocellular carcinoma 
HCC is often driven by inflammation of various types, including viral infections. In a mouse 
model of HCC, blockade of PD-1 with immunostimulatory monoclonal antibodies extended 
survival.36 HCC patients with higher tumor expression of PD-L1 have a significantly poorer 
prognosis than patients with lower expression, and tumor expression of PD-L1 is also an 
independent predictor for postoperative recurrence in HCC.37 In addition, high expression 
levels of PD-1, both in TILs and peripheral blood mononuclear cells (PBMCs) also correlate 
with increased stage and recurrence in HCC patients after surgical resection.38  
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A T-cell-recruiting tumor microenvironment exhibits robust antigen presentation and T-cell 
activation that can develop a tumor-specific CD8+ T-cell response able to eliminate cancer 
cells, generate systemic tumor-specific immunity, and form long-term antitumor immune 
memory.39-41 We will study whether a novel approach converts immunologically inactive 
HCCs into ones with a T-cell-recruiting microenvironment. 
4.2.2 HCV infection, DAAs, and Selected Subject Population 
Chronic HCV infection is a major public health problem associated with a substantial medical, 
social, and economic burden. Despite the approval of several DAAs by the FDA, a great 
proportion of HCV-infected patients remains undiagnosed as routine screening is not yet 
common in most countries and is not widely implemented in the United States, and infected 
patients may not have any symptoms for many years after being infected.24 
DAA therapy against HCV is associated not only with a high cure rate but also with enhanced 
hepatic and systemic immune responses.16-19 DAA treatment has been associated with a decline 
in the number of peripheral exhausted T cells,18 restoration of a systemic immune response 
with proliferative HCV-specific CD8+ T cells,20 and augmentation of HCV-specific 
immunity.18 
Immunotherapy has been studied for the treatment of HCV infection and in chronic HCV 
patients with HCC. In a recent study from our group on 51 HCV-infected patients with solid 
tumors, including 17 patients (33%) with HCC, ICI  was safe in this patient population.42 
However, treating concomitantly HCV infection in the setting of active ICT in HCC has not 
been studied to date. 
We hypothesize that DAA treatment in HCV-infected patients with HCC synergizes with 
concomitant ICT and improves oncologic outcomes via enhanced CD8+ T-cell responses by 
reversing the exhaustion of tumor-specific T cells that is associated with chronic HCV 
infection. This will be a novel approach to ICT in HCC patients that may lead to improved 
HCC outcomes in patients with concomitant HCV infection. We anticipate that the information 
generated from the proposed work will support the prompt initiation of DAAs with HCC 
immunotherapy treatment in HCV-infected patients to improve ICT response. Further, the 
information gained will allow us to design studies in patients with different malignancies 
receiving ICT to determine the impact of HCV clearance, particularly among patients with 
immunologically inactive tumors such as lung cancer, glioblastomas, and ovarian, prostate, 
pancreatic, and breast cancers. 
4.2.3 Rationale for Dose Selection/Regimen/Modification  
4.2.3.1 
Atezolizumab/Bevacizumab Dose 
The planned dose of atezolizumab is 1200 mg plus bevacizumab (15 mg per kilogram of body 
weight) intravenously every 3 weeks as used in clinical trials (IMbrave150)22, and 
recommended on guidelines. Atezolizumab and bevacizumab are commercially available 
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cancer treatment drugs. Management of their administration and potential adverse events will 
be conduced as per SOC procedures. 
4.2.3.2 
DAA Dose and Duration 
DAA regimens used in this study include the following commercially available drugs 
4.2.3.2.1 Sofosbuvir (400 mg) + velpatasvir (100 mg) 
4.2.3.2.2 Sofosbuvir  (400 mg) + velpatasvir (100 mg) + voxilaprevir (100 mg)  
All these DAA regimens will be administered orally, once daily, or twice daily for 12 to 24 
weeks depending on the HCV GT and history of cirrhosis and DAA treatment failure.  
 
4.3.3.3 Ribavirin Dose and Duration 
Ribavirin (RBV) will be combined with DAAs in cases of previous DAA treatment failure. 
RBV will be administered weight-based as follows <75 kg: 1 gram, orally daily in 2 divided 
doses and ≥75 kg: 1.2 gram orally daily in 2 divided doses.  
4.2.4 Rationale for Endpoints 
4.2.4.1 
Primary Endpoints 
4.2.4.1.1 Objective response rate to ICT 
Objective response rate (ORR) to ICT is defined as the proportion of confirmed 
complete or partial responses after finishing the combination of Atezo/Bev and DAAs. 
ORR will be calculated using RECIST 1.1 as assessed by M.D. Anderson radiology and 
with confirmatory assessment as required per iRECIST at any time during the trial. 
Subjects with unknown or missing response information will be treated as non-
responders.  
The changes in CD8+ T-cell frequencies will be collected and summarized. 
4.2.4.1.2 Sustained Virologic Response 
The goal of therapy for chronic HCV infection is the eradication of the virus, which is 
typically measured as a Sustained Virologic Response (SVR). In our study, the 
virologic response (undetectable HCV RNA quantitative) at 12 weeks after the end of 
DAA therapy (SVR 12) will be measured and correlated to standard oncologic 
outcomes. SVR is an objective endpoint that signiﬁes long-term clearance of HCV and 
is generally regarded as a “virological cure.” Based on numerous observational cohorts 
showing strong correlations between SVR and multiple clinically important outcomes, 
such as the development of HCC, end-stage liver complications, and mortality.2 The 
FDA examined the correlation between SVR12 and SVR24 in over 13,000 subjects 
pooled from multiple clinical trials of Peg-IFN-based regimens and found a high rate 
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of concordance between SVR12 and SVR24; sensitivity and specificity forSVR12 
were 99% and 98%, respectively. Therefore, the FDA has concluded that SVR12 is 
suitable as a primary endpoint for regulatory approval of DAAs.43  
 
4.2.4.2 
Secondary/Exploratory Endpoints 
This study will also utilize standard endpoints used in oncology studies.  
Secondary/exploratory endpoints will include PFS, and OS as assessed per RECIST 
1.1.  
1) Progression-free survival (PFS), is defined as the time from the first dose of study 
treatment to the first documented progressive disease (PD) according to RECIST 
1.1 and with confirmatory assessment, as required per iRECIST, or death due to 
any cause, whichever occurs first. If a subject does not have a documented date 
of progression or death, PFS will be censored at the date of the last adequate 
assessment. 
2) Overall survival (OS), is defined as the time from the date of the first dose of 
study to the date of death due to any cause. Censoring will be performed using 
the date of last known contact for those who are alive at the time of analysis. 
4.2.4.3 
Safety Endpoints 
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence 
of, causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); 
and changes in vital signs and laboratory values. Adverse events will be assessed 
according to NCI Common Terminology Criteria for Adverse Events, version 4.0. 
4.2.4.4 Immune Response after DAA Research 
DAA treatment invigorates the CD8+ T cells with the specific restoration of a systemic 
immune response marked by proliferative HCV-specific CD8+ T cells20 or augmentation of 
HCV-specific immunity.18 Cancer immunotherapies represent an important and novel class of 
antitumor agents.  ICT is known to assist in enhancing antitumor effector immunity.30 
Therefore, the combination of DAA and ICT should provide synergistic immune activation 
and thereby produce better oncologic outcomes. 
We hypothesized that DAA treatment enhances the immune response against liver cancer cells 
by reversing the exhaustion of overall T cells and virus-specific T cells associated with chronic 
HCV infection. 
Preliminary data in the literature show that lymphocyte infiltrates, in particular tumor-
infiltrating CD8+ T cells, have been associated with improved survival and lower relapse rates 
after liver resection.3 
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Translational Molecular Pathology Immuno-Profiling Lab (TMP-IL): The biomarker 
analyses will be conducted in TMP-IL directed by Dr. Cara Haymaker, at the Department of 
Translational Molecular Pathology (TMP), MD Anderson Cancer Center, chaired by Dr. 
Ignacio Wistuba, Houston, TX. All biospecimens will be collected using the Biorepository 
NCI Best Practices, and standard operating procedures (SOPs). All specimens and derivatives 
are given de-identified numbers. 
Sample Collection 
1. Core needle biopsy (CNB) samples: A new fresh CNB will be obtained from liver tissue 
in all patients prior to treatment (15 samples), and 12 weeks (+/- 4 weeks) after the end 
of DAA treatment.  At least 5 cores will be obtained from the CNB procedure. The 
CNB cores (~6-8 mm in length) will be processed as FFPE or fresh frozen specimens.  
- Cores 1 to 3: Immediate and overnight fixation in 10% buffered formalin for paraffin 
embedding, usually within 20-24 hour after fixation. For biopsies performed on Friday, 
fixation time may extend to 48 hours (FFPE samples). 
- Cores 4 and 5: Flash freezing in liquid nitrogen. 
The CNB specimens will be examined for quality control and pathological 
characterization before being utilized for immune-profiling, as well as for DNA, RNA, 
protein extractions, and flow cytometry. These samples will be stored at -80°C. 
2. Blood specimens: Whole blood (60 mL, 4 x 10ml Green top Heparin tubes; 1 x10 ml 
EDTA purple top tube and 1 x10 Streck tube) containing ethylenediaminetetraacetic acid 
will be collected on 3 different occasions, day 0 (start of DAA treatment), week 4 of 
DAA treatment, and week 12 after the end of DAA treatment, using the same blood draw 
used to collect other blood samples as part of the standard-of-care laboratory studies (see 
study schema in Figure 1). The timing of the collection of blood samples and their storage 
and shipment will follow the standardized processes of MD Anderson’s Laboratory 
Medicine Reference Laboratory. Peripheral blood mononuclear cells (PBMCs) will be 
processed by the MDACC institutional tissue bank and cryopreserved for future flow 
cytometry in the Haymaker Lab.44-46 
Investigations may include but are not limited to: 
Blood Analysis 
Whole blood will be collected on 3 different occasions from patients (Figure 1).  
Flow cytometry: Multiple lymphocyte and myeloid cell subsets (e.g., CD4+, CD8+, 
regulatory T cells [Tregs], natural killer [NK] cells, macrophages, dendritic cells [DCs], and 
myeloid-derived suppressor cells [MDSCs]) will be characterized using high-dimensional 
multi-parametric flow cytometry to detect and quantify the frequencies of cells exhibiting 
proliferation, cytotoxicity, and cytokine production, as well as changes in the expression levels 
of immune checkpoint signaling receptors and activation markers (e.g., PD-1, CTLA-4, Lag3, 
ICOS, and 4-1BB). The CD8+ T-cell response will also be correlated with activated T-cell 
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subsets identified by multiplex immunofluorescence (mIF) analysis of tumor biopsy samples 
obtained before and after DAA treatment. Using this strategy, we reported earlier on the 
kinetics of changes in different immune cell subsets from blood and cytobrush samples from 
cervical cancer patients undergoing standard-of-care chemoradiation treatment.4 
HCV Markers 
Blood will also be obtained for HCV viral load using the COBAS assay. HCV RNA in serum 
will be quantified using the COBAS AmpliPrep/COBAS TaqMan HCV test (Roche Molecular 
Systems, Branchburg, NJ), which has a quantification range of 15 to 100,000,000 IU/mL (1.18 
log10 to 8.00 log10 IU/mL). 
 
Tissue Analysis 
Tissue immune monitoring will be conducted done at the following time points:  
A new fresh CNB will be obtained from liver tissue in all patients 1) prior to DAA treatment , 
and 2) after the end of DAA treatment.   
The analyses will be performed at M.D. Anderson Translational Immunoprofiling Laboratory 
Moonshots Platform (TMP-IL).  Assays may include but are not be limited to: 
Multiplex Immunofluorescence Analysis (MIF) 
MIF will be performed on tumor core samples utilizing immune marker panels to assess 
intratumoral T-cell activation. mIF image analysis uses a tyramide signal amplification 
methodology and the Opal workflow and chemistry, which allows simultaneous staining of 
multiple biomarkers within a single paraffin-embedded tissue section.47 Localization of 
tumor-infiltrating lymphocytes and engagement of the PD-1/PD-L1 axis will be assessed 
using mIF staining with a validated panel consisting of CD68, PD-L1, CD3, CD8, PD-1, 
FoxP3, Ki67, pancytokeratin, and DAPI (Figure 2). Tumor-cell presence will be assessed 
using hematoxylin-eosin before mIF staining. In addition, T helper cell subsets will be 
assessed using a validated panel including CD3, CD8, Tbet, GATA3, FoxP3, and DAPI.  
For the analysis, the scanning and image capture will be performed with a multispectral 
microscope (Vectra/Polaris, Akoya Biosciences) and specialized image analysis software 
(InForm, Akoya Biosciences) that permits the identification of co-expressed markers included 
in each panel. The tissue will be compartmentalized into the tumor and stromal compartments 
using key markers to identify tumor cells (e.g., pan-cytokeratin for carcinomas) with the tissue 
segmentation tool in InForm. The final results will be consolidated using the Phenoptr Reports 
& Phenoptr package (Akoya Biosciences). 
 
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4.3 Benefit/Risk 
Patients in clinical trials may not 
receive direct benefit from treatment 
during participation, as clinical trials 
are designed to provide information 
about the safety and effectiveness of 
an investigational medicine. However, 
data using similar drugs in HCC and 
other cancers suggests that some 
subjects may benefit from therapy. 
Additional details regarding specific 
benefits 
and 
risks 
for 
subjects 
participating in this clinical trial may 
be found in the accompanying 
Informed Consent document. 
5.0  METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male and female HCV-infected patients with advanced HCC with no curative option of at least 
18 years of age will be enrolled in this trial. 
5.1.2 Patient Inclusion Criteria 
To be eligible for participation in this trial, the patient must: 
1. Be willing and able to provide written informed consent for the trial.   
2. Be at least 18 years of age on the day of signing informed consent. 
3. Ability to comply with the study protocol, in the investigator's judgment 
4. Have histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and 
mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) based on 
pathology report. 
5. Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies  
6. No prior systemic therapy for HCC. 
7. Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous 
ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, 
transarterial chemoembolization, transarterial embolization, etc.) are eligible provided 
the target lesion(s) have not been previously treated with local therapy or the target 
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lesion(s) within the field of local therapy have subsequently progressed in accordance 
with RECIST version 1.1.  
8. ECOG Performance Status of 0 or 1 
9. Have a detectable HCV RNA quantitative based on the COBAS AmpliPrep/COBAS 
TaqMan HCV test (Roche Molecular Systems, Branchburg, NJ) at the time of 
screening. 
10. Have documented chronic HCV GT1 through GT6 including evidence of mixed 
genotype infection: 
a. Positive for anti-HCV antibody, HCV RNA, or any of the above HCV GTs at 
least 3 months before screening (HCV RNA and HCV GT must be confirmed 
by screening lab results) OR  
b. Positive for anti-HCV antibody or HCV RNA at the time of screening with a 
liver biopsy consistent with chronic HCV infection (or a liver biopsy performed 
before enrollment with evidence of chronic HCV disease, such as the presence 
of fibrosis) or a Fibroscan performed within 12 months of Day 1 of this study 
with a result of >12.5 kPa or a FibroSure® (Fibrotest®) performed during 
Screening with a score of ≥0.75 or aspartate aminotransferase (AST): platelet 
ratio index (APRI) of >2. APRI formula: AST ÷ lab upper limit of normal 
(ULN) for AST × 100 ÷ (APRI calculation to be provided by the central 
laboratory.) 
11. Have a Child-Pugh A liver score at screening or within 14 days of the first dose of the 
study drug. 
12. Have liver disease staging assessment as follows: 
Cirrhosis is defined as any one of the following 
a. A liver biopsy performed prior to Day 1 of this study showing cirrhosis (F4) 
b. Fibroscan performed within 12 calendar months of Day 1 of this study showing 
cirrhosis with result >12.5 kPa 
c. A FibroSure® (Fibrotest®) performed during Screening with a score of ≥0.75 or 
an aspartate aminotransferase (AST): platelet ratio index (APRI) of >2. APRI 
formula: AST ÷ lab upper limit of normal (ULN) for AST × 100 ÷ (APRI 
calculation to be provided by the central laboratory.) 
Absence of cirrhosis is defined as any one of the following: 
a. Liver biopsy performed within 24 months of Day 1 of this study showing 
absence of cirrhosis 
b. Fibroscan performed within 12 months of Day 1 of this study with a result of 
≤12.5 kPa 
c. A Fibrosure (Fibrotest) score of ≤0.27 or AST to Platelet Ratio Index (APRI) 
of ≤1 during Screening 
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Fibroscan cut-off of 12.5 kPa has a positive predictive value of 90% and a 
sensitivity of 95% for ≥F3. Based on box and whisker plot of interquartile 
distribution >12.5 kPa will exclude the majority of subjects with metavir F3 
fibrosis. In the absence of a definitive diagnosis of presence or absence of 
cirrhosis by the above criteria, a liver biopsy is required. Liver biopsy results 
supersede the results obtained by Fibroscan, Fibrosure or Fibrotest. 
13. Have a predicted life expectancy of greater than 3 months. 
14. Have measurable disease based on RECIST 1.1 as confirmed by M.D. Anderson 
radiology.  Target lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
Note: the same image acquisition and processing parameters should be used throughout 
the study for a given subject. 
15. Patients with a past or resolved hepatitis B virus (HBV) infection, defined as having a 
negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and 
negative HBV DNA test at screening, are eligible for the study. 
16. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.   
17. Male patients of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.5.3 - Contraception, starting with the first dose 
of trial therapy through 120 days after the last dose of trial therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
18. Be willing to use an adequate method of contraception for the course of the study 
through 120 days after the last dose of study medication (male and female subjects of 
childbearing potential [Section 5.5.3]). Acceptable methods of contraception are as 
follows: 
Single method (one of the following is acceptable): 
a. intrauterine device (IUD) 
b. vasectomy of a female subject’s male partner 
c. contraceptive rod implanted into the skin 
Combination method (requires the use of 2 of the following): 
d. diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
e. cervical cap with spermicide (nulliparous women only) 
f. contraceptive sponge (nulliparous women only) 
g. male condom or female condom (cannot be used together) 
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h. hormonal contraceptive: oral contraceptive pill (estrogen/ progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
Note:  Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and Institutional Review 
Boards (IRBs)/Ethics Review Committees (ERCs).  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not 
acceptable methods of contraception.  
If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating 
at sites in this country/region. 
19. Patients treated with RBV must agree to double barrier birth control from Day 1 to 6 
months following last dose of study therapy or they are excluded from this trial. 
20. Have adequate organ function as defined in Table 1.  Specimens must be collected 
within 14 days before the start of trial treatment. 
 
Table 1 
Adequate Organ Function Laboratory Tests 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
≥1500/µL 
Platelets 
≥100,000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine 
OR 
Measured 
or 
calculatedb 
creatinine 
clearance 
(GFR can also be used in place of creatinine or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for subject with creatinine levels 
>1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for subjects 
with total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for subjects with liver 
metastases) 
Coagulation 
INR or PT/aPTT 
 
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic 
range of intended use of anticoagulants 
Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; EPO = erythropoietin; GFR = glomerular filtration rate; INR = 
international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; SGOT = serum 
glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of 
normal.   
 
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5.1.3 
Patient Exclusion Criteria 
1. Is currently participating in or has participated in a trial of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of trial 
treatment. 
Note: Patients must have recovered from all AEs due to previously therapies to ≤ Grade 
1 or baseline. Subjects with ≤ Grade 2 neuropathy may be eligible Note:  Subjects who 
have entered the follow-up phase of an investigational trial may participate as long as 
it has been 4 weeks after the last dose of the previous investigational agent. 
Note:  Patients who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent. 
2. Has had esophageal or gastric variceal bleeding within the last 6 months.  All subjects 
will be screened for esophageal varices, unless such screening has been performed in 
the past 12 months before first dose of treatment.  If varices are present, they should be 
treated according to institutional standards before starting study treatment.   
3. Subjects with persistent alanine aminotransferase (ALT) >5 × ULN at screening are 
not eligible for enrollment. 
4. Subjects with persistent Total Bilirubin (Tbil) >2.0 mg/dL at screening are not 
eligible for enrollment 
5. Subjects with clinically apparent ascites or encephalopathy, or untreated varices are 
not eligible for enrollment. Subjects with Child-Pugh class B and C liver disease are 
also ineligible. 
6. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac 
involvement of HCC based on imaging.   
7. Has had encephalopathy in the last 6 months.  Subjects on rifaximin or lactulose to 
control their encephalopathy are not allowed. 
8. Had a solid organ or hematologic transplant. 
9. Had prior systemic therapy for HCC other than sorafenib and/or regorafenib, or 
intercurrent local therapy to the liver tumor between sorafenib and/or regorafenib and 
study drug. 
10. Has evidence of history of chronic active hepatitis not caused by HCV, including but 
not limited to untreated active HBV (see criteria below under criterion 27), drug-
induced hepatitis that is not resolved clinically, and autoimmune hepatitis. 
11. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease-modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed. 
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12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial drug. 
13. Has received locoregional therapy to the liver (TACE, TAE, radiation, 
radioembolization, or ablation) or surgery to the liver or other site within 6 weeks 
before the first dose of the study drug.  Minor surgery must have occurred at least 7 
days before the first dose of study treatment (Cycle 1, Day 1).  Subjects must have 
recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications 
from any intervention before starting therapy. 
14. Has a known history of an additional malignancy, except if the participant has 
undergonepotentially curative therapy with no evidence of that disease recurrence for 
5 years since initiation of that therapy. 
a. Note: The time requirement does not apply to participants who underwent 
successful definitive resection of basal cell carcinoma of the skin, superficial bladder 
cancer,squamous cell carcinoma of the skin, in situ cervical cancer, in situ breast 
cancer, or other in situ cancers.  
15. Has radiographically detectable (even if asymptomatic and/or previously treated) 
central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed 
by local site investigator.  
16. Has a history of (non-infectious) pneumonitis that required treatment with steroids or 
has current pneumonitis. 
17. Has an active infection requiring systemic therapy. 
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator, including dialysis. 
19. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
21. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, 
OX-40, CD137).. 
22. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
23. Has a known history of human immunodeficiency virus (HIV) infection.   
24. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). 
25. Has received a live vaccine within 30 days before the first dose of trial drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
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varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines and are not allowed. 
26. Has untreated active HBV.  
Note:  Antiviral therapy for HBV must be given for at least 3 months before the first 
dose of the study drug, and HBV viral load must be less than 100 IU/mL before the 
first dose of the study drug.  Those on active HBV therapy with viral loads under 
100 IU/mL should stay on the same therapy throughout the study treatment.  HBsAg, 
HBsAb, anti-HBe, anti-HBc, and HBV DNA must be measured at baseline and during 
the study.  Those subjects who are anti-HBc (+) and negative for HBsAg and HBV 
DNA do not require HBV prophylaxis but need monitoring with HBsAg, HBsAb, anti-
HBe, anti-HBc, and HBV DNA  
27. Has received a live vaccine within 30 days of the planned start of study therapy (Cycle 
1, Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for 
injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed. 
28. Subjects with a history of significant or unstable cardiac disease are excluded due to 
the hemolytic anemia associated with RBV.  Subjects with proven coronary artery 
disease or angina. 
29. Has received prior first-line therapy within 14 days of the first dose of study 
medication. 
30. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject's participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
31. Has known psychiatric or substance abuse disorders that would interfere with 
cooperating with the requirements of the trial. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial are outlined in Table 2, Table 3, and Table 4.  
Table 2 
Trial Treatments 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Sofosbuvir + 
velpatasvir  
Tablet: sofosbuvir 
(400 mg) and  
velpatasvir (100 
mg) 
qday 
PO 
Daily 
SOC  
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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Sofosbuvir + 
velpatasvir + 
voxilaprevir 
Tablet: sofosbuvir  
(400 mg) and 
velpatasvir (100 
mg) and 
voxilaprevir (100 
mg) 
qday 
PO 
Daily 
SOC 
RBV 
Capsule: 200 mg 
See Table 4 
qday 
PO 
Daily 
SOC 
Abbreviations: IV = intravenous; PO = oral; Q3W = every 3 weeks; qday = once daily; RBV = ribavirin; 
SOC = standard of care. 
 
The duration of DAA is dependent upon HCV GTs and presence or absence of resistance 
polymorphisms.  Please see Table 3. 
Table 3 
DAA Trial Treatment Duration With or Without Cirrhosis2 
Patient Population 
Treatment 
Duration 
Treatment-Naive Genotype 1a Patients 
Without Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 1a Patients 
With Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Patients Genotype 1b 
Without Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 1b Patients 
With Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 2 Patients 
Without Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 2 Patients 
With Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 3 Patients 
Without Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 3 Patients 
With Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) for patients without 
baseline NS5A RAS Y93H for velpatasvir 
12 weeks 
Treatment-Naive Genotype 4 Patients 
Without Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 4 Patients 
With Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Treatment-Naive Genotype 5 or 6 
Patients With and Without Compensated 
Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg) 
12 weeks 
Sofosbuvir-Based Treatment Failures, 
With or Without Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg)/voxilaprevir (100 mg)a 
12 weeks 
Glecaprevir/Pibrentasvir Treatment 
Failures (All Genotypes), With or 
Without Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg)/voxilaprevir (100 mg)b 
 
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Sofosbuvir/Velpatasvir/Voxilaprevir 
Treatment Failures, With or Without 
Compensated Cirrhosis 
Daily fixed-dose combination of sofosbuvir (400 
mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) 
plus weight-based ribavirin 
24 weeks 
Abbreviations: GT = genotype; NS5A = non-structural protein 5A; PegIFN = pegylated interferon; RBV = ribavirin. 
a Genotype 3: Add weight-based ribavirin if cirrhosis is present and there are no contraindications. 
b For patients with compensated cirrhosis, addition of weight-based ribavirin is recommended. 
 
 
In patients with CrCl greater than 50 mL per minute, RBV will be administered twice a day 
(BID) PO (in RBV containing arms) at a total daily dose of 1,000 mg to 1,200 mg based on 
subject weight on Day 1 (Table ). RBV will be used for 12 to 24 weeks. 
Table 4 
Recommended Dosing for RBV in Combination Therapy for Subjects with 
CrCl Greater Than 50 mL Per Minute. 
Body Weight in kg  
RBV Dose 
RBV capsules or tablets 
<75 kg 
1,000 mg/day in 2 divided doses 
2 × 200 mg capsules or tablets A.M.  
3 × 200 mg capsules or tablets P.M. 
≥75 kg 
1,200/mg day 
3 × 200 mg capsules or tablets A.M.  
3 × 200 mg capsules or tablets P.M. 
Abbreviations: A.M. = ante meridian; P.M. = post meridian; RBV = ribavirin. 
 
Trial Treatment should begin within 3 days of allocation/assignment. However, every effort 
should be made to begin trial treatment on the day of allocation (ie, Cycle 1 Day 1). 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of trial 
treatments by the protocol and any applicable laws and regulations. 
All trial treatments will be administered on an outpatient basis. 
All products indicated in the Table are commercially available. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for the selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on the preparation and administration of DAAs, and RBV are provided in the Pharmacy 
Manual.   
5.2.1.2 Dose Modification and Toxicity Management Guidelines for atezolizumab 
or bevacizumab 
AEs associated with ICT exposure may represent an immunologic etiology. There will be no 
dose modifications for atezolizumab or bevacizumab in this study. Management of toxicity 
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related to Atezo/Bev will be conducted per SOC of these commercially available cancer 
treatment drugs.  These patients will be managed by Dr. Kaseb, director of the HCC program 
at MD Anderson Cancer Center, and by our experienced team in the Department of 
Gastrointestinal Medical Oncology. 
5.2.1.3 DAAs Dose Modification (Escalation/Titration/Other) 
Modification of the DAAs is not permitted except for hepatic events, SAEs, or laboratory 
abnormalities. 
The DAAs used in this clinical trial have been approved by the FDA since 2013. Management 
of toxicity related to DAAs will be conducted per SOC of these commercially available 
antivirals.  These patients will be managed by Dr. Torres, director of the HCV clinic at MD 
Anderson Cancer Center, and by our experienced team of the Department of Infectious 
Diseases.  
5.2.1.4 RBV Dose Modification (Escalation/Titration/Other) 
If DAAs are administered with RBV refer to the RBV prescribing information for a description 
of RBV-associated adverse reactions.  Monotherapy RBV for HCV is not permitted in this 
trial. 
The primary toxicity of RBV is hemolytic anemia, which was observed in approximately 10% 
of RBV/Intron A-treated subjects in clinical trials. While this study does not include Intron A 
treatment hemolytic anemia surveillance is still warranted. The anemia associated with RBV 
capsules occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in 
hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained before 
the start of treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically 
indicated. Subjects should then be followed as clinically appropriate Fatal and nonfatal 
myocardial infarctions have been reported in patients with anemia caused by RBV. Subjects 
should be assessed for the underlying cardiac disease before initiation of RBV therapy. 
Subjects with pre-existing cardiac disease should have electrocardiograms (ECGs) 
administered before treatment and should be appropriately monitored during therapy. If there 
is any deterioration of cardiovascular status, therapy should be suspended or discontinued. 
Because the cardiac disease may be worsened by drug-induced anemia, patients with a history 
of significant or unstable cardiac disease should not use RBV. 
RBV should not be used in subjects with CrCl less than 50 mL/min. Subjects with impaired 
renal function and those over the age of 50 should be carefully monitored concerning 
development of anemia.  
If severe AEs or laboratory abnormalities develop during the study, RBV can be modified 
based on the recommended guidelines provided in Table 5 . 
For subjects with a history of stable cardiovascular disease, a permanent dose reduction is 
required if the hemoglobin decreases by greater than or equal to 2 g/dL during any 4 weeks. In 
addition, for these cardiac history patients, if the hemoglobin remains less than 12 g/dL after 4 
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weeks on a reduced dose, the patient should discontinue combination therapy.  It is 
recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her RBV 
dose modified or discontinued per 6. 
Subjects exhibiting the following conditions should be closely monitored and may require dose 
reduction or discontinuation of RBV therapy. Refer to the prescribing information: 
• Hemolytic anemia may occur with a significant initial drop inhemoglobin 
• Pancreatitis 
• Pulmonary infiltrates or pulmonary function impairment 
• New or worsening ophthalmologic disorders 
• Concomitant administration of azathioprine 
• Severe decreases in neutrophil and platelet counts and hematologic, endocrine and 
hepatic abnormalities 
• Dental/periodontal disorders with combination therapy 
 
Table 5 
Dose Reduction Rules for RBV 
Laboratory  Parameters 
Reduce RBV if 
Discontinue Therapy if 
HGB without a history of cardiac 
disease 
8.5 to <10 g/dl 
< 8.5 g/dl 
HGB with a history of stable cardiac 
disease 
<2 g/dL decrease in hemoglobin 
during any 4-week period 
during treatment 
<8.5 g/dL or 
<12 g/dL after 4 weeks of 
dose reduction 
Abbreviations: HGB = hemoglobin; RBV = ribavirin 
 
Table 6 
Dose Modification for RBV 
Any weight 
1 x 200 mg capsule or tablet A.M.  
2 x 200 mg capsule or tablets P.M. 
Abbreviations:  AM = ante meridian; FDD = full daily dose; PM = post meridian; RBV = ribavirin 
Once RBV has been withheld due to either a laboratory abnormality or clinical adverse 
reaction, an attempt may be made to restart RBV at 600 mg daily and further increase the dose 
to 800 mg daily. However, it is not recommended that RBV be increased to the originally 
assigned dose (1,000 mg to 1,200 mg). 
5.2.1.5 
Dose Interruptions 
If a subject misses a dose of DAAs and it is less than 8 hours before the next dose, the missed 
dose should be skipped and the normal dosing schedule resumed. Patients should not double 
the next dose to compensate for what has been missed. 
If for any reason DAAs need to be interrupted they can be interrupted for up to 3 days. If DAAs 
are interrupted for more than 3 days, consult HCV experts for that patient. RBV is not to be 
taken as monotherapy in the absence of DAAs. 
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If Atezolizumab plus Bevacizumab treatment is interrupted then maintain the subject on DAAs 
(±RBV) unless due to severe liver toxicity. No dosage adjustment of DAAs is recommended 
in patients with mild hepatic impairment (Child-Pugh A).  
If a patient misses a dose of RBV, then they should take the missed dose as soon as possible 
with food on the same day. If an entire day has gone by, then these missed doses should be 
skipped, and the normal dosing schedule should be resumed. Patients should not double the 
next dose to "make up" what has been missed. 
If for any reason RBV needs to be interrupted (e.g. for safety reasons), if possible, it should 
be restarted within 3 days. 
5.2.2 Timing of Dose Administration 
Day 1 of treatment should begin on the day of starting DAAs on patients receiving Atezo/Bev. 
DAAs and Atezo/Bev will be administered per SOC.1,2  
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigators and patients will know the treatment 
administered. 
5.3 
Randomization or Treatment Allocation 
This is a non-randomized trial single-arm study. Patients will be enrolled based upon inclusion 
and exclusion criteria.  
5.4 
Stratification 
No stratification based on age, sex, or other characteristics will be used in this trial 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
5.5.1 Acceptable or Concomitant Medications/Vaccinations 
All treatments necessary for a patient’s welfare may be administered at the discretion of the 
investigator in keeping with the SOC for atezo/bev or DAAs with or without RBV.  
5.5.2 Prohibited Concomitant Medications 
Per SOC, patients are prohibited from receiving therapies in the risk category “X” to be avoided 
with the study drugs atezo/bev or DAAs with or without RBV. 
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5.5.3 Contraception 
Reproductive considerations are applicable to both males and females only in subjects 
receiving RBV. For atezo/bev, these considerations are only relevant to female of childbearing 
potential. Atezo/bev and RBV may have adverse effects on a fetus in utero.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria:  
• She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause.  In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state.  In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
• She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion, at least 6 weeks before screening. 
• She has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving the trial drug and for 120 days after the 
last dose of trial drug by complying with 1 of the following:  
• Practice abstinence from heterosexual activity. 
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and IRBs/ERCs.  Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
• Use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
• Single method (1 of the following is acceptable): 
o IUD 
o Vasectomy of a female subject’s male partner  
o Contraceptive rod implanted into the skin 
• Combination method (requires use of 2 of the following): 
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o Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
o Cervical cap with spermicide (nulliparous women only)   
o Contraceptive sponge (nulliparous women only)  
o Male condom or female condom (cannot be used together) 
o Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
Subjects should be informed that taking the trial medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the trial.  In order to participate in the 
trial, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 180 days (Arm B) 
after the last dose of trial medication.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the trial.  
5.5.4 Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with Atezo/bev and RBV, the 
patient will be immediately discontinued from trial treatment.  Female patients of childbearing 
potential will be instructed to immediately inform the investigator if they become pregnant 
during the study or within 5 months after the last dose of atezolizumab or 6 months after the 
last dose of bevacizumab or DAAs, or 9 months after the last dose of RBV. The investigator 
should counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until the conclusion of the pregnancy. Any 
serious AEs associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported per SOC.  
5.5.5 Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform 
the investigator if their partner becomes pregnant during the study or within 6 months after the 
last dose of bevacizumab or DAAs or within 9 months after the last dose of RBV. Attempts 
should be made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study treatment. An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the pregnancy and 
the possible effects on the fetus, to support an informed decision in cooperation with the 
investigator and/or obstetrician. 
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5.5.6 Discontinuation of Treatment 
Discontinuation of study treatment does not represent a withdrawal from the study. 
As certain data on clinical events beyond study treatment discontinuation may be important to 
the study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued study treatment.  
Subjects may discontinue study treatment at any time for any reason or be dropped from the 
study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a subject may be discontinued from study treatment by the investigator if study 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.   
5.6 
Beginning and End of the Trial 
The overall trial begins when the first subject signs the informed consent form (ICF).  The 
overall trial ends when the last subject completes the last study-related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator). 
5.7 
Clinical Criteria for Early Trial Termination 
The clinical trial may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the trial population as a whole is 
unacceptable based on the prinicipal investigators’ discretion.   
 
5.8 Data and Safety Monitoring Committees 
MD Anderson’s Data and Safety Monitoring Committees will be responsible for monitoring 
this trial. This trial will adhere to institutional data safety monitoring plans.
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6.0 TRIAL FLOW CHART  
6.1 
Study Flow Chart Initial Treatment with DAAs on Patients on Atezolizumab + Bevacizumab 
Trial Period: 
 
Screening Phase 
Period 
of 
combination 
treatment 
with 
DAAs 
and 
Atezolizumab + Bevacizumab (Weeks) 
 
DAA Untreated Follow Up (Weeks) 
 
Follow-up 
Premature 
Discontinuation 
 
Treatment Title: 
Screening 
B 
2 
4 
EOT 
+4 
+12 
+24 
4 
12 
Week (approximate) 
0 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
ICF 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication review 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Study medication adherence 
 
X 
X 
X 
X 
 
 
 
 
 
Survival status 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Clinical 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
Review AEs 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Full physical examination 
X 
 
 
 
 
X 
 
X 
 
 
Directed physical 
examination 
 
X 
X 
X 
X 
 
 
 
 
 
Child-Pugh score 
X 
 
 
 
 
 
 
 
 
 
Height, weight, and vital 
signs (T, P, RR, BP)c 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (blood or 
urine) 
X 
 
 
 
 
 
 
 
 
 

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Trial Period: 
 
Screening Phase 
Period 
of 
combination 
treatment 
with 
DAAs 
and 
Atezolizumab + Bevacizumab (Weeks) 
 
DAA Untreated Follow Up (Weeks) 
 
Follow-up 
Premature 
Discontinuation 
 
Treatment Title: 
Screening 
B 
2 
4 
EOT 
+4 
+12 
+24 
4 
12 
Week (approximate) 
0 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR 
Xe 
 
X 
X 
X 
X 
 
X 
 
 
CBC with differential 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry panel 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
Liver panela 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibrotest or APRI 
X 
 
 
 
 
 
 
 
 
 
AFP 
X 
 
 
 
X 
 
X 
X 
 
 
Viral testing 
 
 
 
 
 
 
 
 
 
 
HCV Ab 
X 
 
 
 
 
 
 
 
 
 
HCV genotype  
X 
 
 
 
 
 
 
 
 
 
HCV viral load  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBc, HBsAg, anti-HBs 
X 
 
 
 
 
 
 
 
 
 
If Anti-HBc + and HBsAg +:  
HBsAg and HBV viral load 
 
X 
X 
X 
X 
X 
X 
X 
 
 
If Anti-HBc + and HBsAg -:  
HBsAg and HBV viral load 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma for HCV viral 
resistance testingb  
 
X 
 
 
 
 
Xs 
 
 
 
Laboratory Immune 
Assessments 
 
 
 
 
 
 
 
 
 
 
Blood for immune analysisc 
 
X 
 
X 
 
 
X 
 
 
 
Liver tissue Collectiond 
X 
 
 
 
 
 
X 
 
 
 
Liver tissue for immune 
analysis 
X 
 
 
 
 
 
X 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 

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Trial Period: 
 
Screening Phase 
Period 
of 
combination 
treatment 
with 
DAAs 
and 
Atezolizumab + Bevacizumab (Weeks) 
 
DAA Untreated Follow Up (Weeks) 
 
Follow-up 
Premature 
Discontinuation 
 
Treatment Title: 
Screening 
B 
2 
4 
EOT 
+4 
+12 
+24 
4 
12 
Week (approximate) 
0 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor imaginge 
X 
 
 
 
X 
 
X 
 
 
 
Abbreviations:  AEs = adverse events; AFP = alpha fetoprotein; APRI = aspartate aminotransferase:platelet ratio index; BP = blood pressure; CBC = complete blood count; 
DC = discontinuation; EOT- end of treatment (DAA); HBV = hepatitis B virus; HBcAg = hepatitis B core antigen; HBsAb = anti-HBsAg antibody; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; ICF = informed consent form; INR = international normalized ratio; RR = respiratory rate; T = temperature; PT = prothrombin time.  
a. 
Liver panel (albumin, ALT, AST, total and direct bilirubin, and alkaline phosphatase).   
b. 
Blood samples will be collected for HCV resistant testing at baseline on selected cases of difficult-to-treat HCV genotypes or treatment failure. 
c. 
Blood samples will be obtained at baseline, at Week 4 of DAAs,  Week 12 after EOT.  There will be up to a total of 45 blood samples (15 patients × 3 samples = 45 blood 
samples), which will be collected in Green top Heparin tubes, EDTA purple top tubes and Streck tubes.  
d. 
Liver biopsies will be required pre-treatment with DAAs, and week 12 after the end of DAA treatment. This sample should be drawn for planned multiplex 
immunofluorescence (MIF). Pre-treatment or baseline biopsy can be obtained between 90 days and 1 day before combination treatment  
e. 
The following imaging studies are required at baseline:  CT abdomen with or without contrast; MRI of abdomen and pelvis with or without contrast unless patient has a 
contraindication for MRI or severely claustrophobic.     
 

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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative before participating in a clinical trial. 
If there are changes to the subject’s status during the trial (e.g., health or age of majority 
requirements), the investigator or qualified designee must ensure the appropriate consent is in 
place. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. Remote consenting will not be utilized in this study.  
The initial ICF, any subsequent revised written ICF and any written information provided to 
the subject must receive the IRB approval/favorable opinion in advance of use.  The subject or 
his/her legally acceptable representative should be informed promptly if new information 
becomes available that may be relevant to the subject’s willingness to continue participation 
in the trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s dated 
signature or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB requirements, applicable laws and regulations.   
In this study, we will adhere to the Office of the Clinical Research SOP 04:  Informed Consent 
Process.  
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8.0 STATISTICAL ANALYSIS PLAN 
This section outlines the statistical analysis strategy and procedures for the study.  If, after the 
study has begun, but before any final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the protocol 
will be amended. 
8.1 
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized in Table 6. The comprehensive 
plan is provided in Sections 8.2 to 8.13.   
Table 1 
Key Elements of the Statistical Analysis Plan 
Study Design Overview 
Improving Response to Immunotherapy in Patients with Advanced 
Hepatocellular Carcinoma and Chronic Hepatitis C Virus Infection with
Direct-Acting Antiviral Therapy 
Treatment Assignment 
This is a pilot/ hypothesis-generating study  
Analysis Populations 
Efficacy: All Subjects as Treated (ASaT) 
Safety: ASaT 
Primary Endpoints 
ORR, SVR, overall T cells and virus-specific T cells 
Statistical 
Methods 
for 
Key
Efficacy Analyses 
Objective Response Rate (ORR) based on RECIST 1.1 on patients on
Atezo/Bev receiving DAAs. The ORR is defined as the proportion of
responders with a confirmed complete response or partial response. The 
sustained virologic response (SVR).  The response rate and SVR  will be 
estimated with 90% exact confidence  interval (CI).  Descriptive statistics such
as mean, median, and standard deviation, etc.  in terms of T cells or other 
virus-specific T cell measurements. 
Statistical Methods for Key Safety
Analyses 
Counts and percentages of subjects with AEs will be provided.  
Interim Analysis 
No planned interim analysis for this pilot study.  
Multiplicity 
Multiplicity adjustment is planned in this pilot study. 
Sample Size and Power  
The planned sample size is 15 subjects 
8.2 
Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Biostatistics department of MD Anderson. 
This trial is being conducted as a non-randomized, open-label study, i.e., patients, and 
investigators will be aware of patient treatment assignments after each patient is enrolled and 
treatment is assigned. 
8.3 
Hypotheses/Estimation 
The objectives and hypotheses of the study are stated in Section 3. 
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8.4 
Analysis Endpoints 
Efficacy and safety endpoints that will be evaluated are listed below. 
8.4.1 Exploratory Efficacy Endpoints 
8.4.1.1 Primary Endpoints 
• Objective response rate (ORR) to ICT: defined as the proportion of confirmed complete 
or partial response after finishing the combination of Atezo/Bev and DAAs. ORR will be 
calculated using RECIST 1.1 as assessed by M.D. Anderson radiology and with 
confirmatory assessment as required per iRECIST at any time during the trial. Subjects 
with unknown or missing response information will be treated as non-responders.   
• Sustained Virologic Response (SVR): the virologic response (undetectable HCV RNA 
quantitative) at 12 weeks after the end of DAA therapy (SVR 12) will be measured and 
correlated to standard oncologic outcomes (Section 4.2.4.1.1). 
• The changes in CD8+ T-cell frequencies will be collected and summarized. 
8.4.1.2 Secondary Exploratory/Efficacy Endpoints 
This study will also utilize standard endpoints used in oncology studies.  
Secondary/exploratory endpoints will include PFS, and OS as assessed per RECIST 1.1.  
• Progression-free survival (PFS), defined as the time from the first dose of study 
treatment to the first documented progressive disease (PD) according to RECIST 1.1 
and with confirmatory assessment, as required per iRECIST, or death due to any 
cause, whichever occurs first. If a subject does not have a documented date of 
progression or death, PFS will be censored at the date of the last adequate assessment. 
• Overall survival (OS), defined as the time from the date of the first dose of study to 
the date of death due to any cause. Censoring will be performed using the date of last 
known contact for those who are alive at the time of analysis. 
8.4.2 Safety Endpoints 
• Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence 
of, causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and 
changes in vital signs and laboratory values. Adverse events will be assessed according 
to NCI Common Terminology Criteria for Adverse Events, version 4.0. Safety 
endpoints are described in Section 4.2.4.3. 
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8.5 
Analysis Populations 
Eligible patients enter the study after enrolment.  
8.5.1 Efficacy Analysis Populations 
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, SVR, 
PFS, and OS.  The ASaT population consists of all patients who received at least one dose of 
study treatment. 
Details on the approach to handling missing data are provided in Table 8. 
8.5.2 Safety Analysis Populations 
The ASaT population will be used for the analysis of safety data in this study.  The ASaT 
population consists of all patients who received at least one dose of study treatment.  
At least one laboratory or vital sign measurement obtained after at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter.  To assess change 
from baseline, a baseline measurement is also required. 
8.6 
Statistical Methods 
8.6.1 Statistical Methods and Data Analysis 
This section describes the statistical methods that address the primary and secondary 
objectives.  
The ORR and SVR will be estimated with 90% exact confidence  interval (CI). With 15 
patients, assuming the response rate is 27% (4/15), the 90% exact confidence interval (CI) is 
(10%, 51%). Table 7 listed more scenario regarding difference response rates. We would also 
characterize the change in the phenotypic and functional status of the systemic and local CD8+ 
T cells between before and after DAA therapy and summarize the time-to-event outcomes. 
Descriptive statistics such as the mean, standard deviation will be summarized in terms of the 
changes in CD8+ T-cell frequencies. Changes in immune cell frequencies will be explored 
between DAA responders and non-responders using Wilcoxon rank-sum test or Fisher’s Exact 
test as appropriate. When multiple comparisons are made, we will report P-values both before 
and after false discover rate adjustments. Time-to-event variables such as overall survival (OS) 
and progression-free survival (PFS) will be estimated using Kaplan-Meier methods. 
Table 2 
Analysis Strategy for Efficacy Variables 
Total evaluable 
patients 
Number of responders 
Response rate 
Lower 90% 
CI* 
Upper 90% 
CI* 
15 
0 
0% 
<1% 
18% 
15 
1 
7% 
<1% 
27% 
15 
2 
13% 
2% 
36% 
15 
3 
20% 
6% 
44% 
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Total evaluable 
patients 
Number of responders 
Response rate 
Lower 90% 
CI* 
Upper 90% 
CI* 
15 
4 
27% 
10% 
51% 
15 
5 
33% 
14% 
58% 
15 
6 
40% 
19% 
64% 
15 
7 
47% 
24% 
70% 
15 
8 
53% 
30% 
76% 
15 
9 
60% 
36% 
81% 
15 
10 
67% 
43% 
86% 
15 
>10** 
>67% 
>43% 
>86% 
* Exact confidence interval computed by the method of Clopper and Pearson (Biometrika 26:404-413, 1934) 
**Actual response rate with corresponding CI will be calculated.  Exact confidence interval was calculated 
for all responses. 
 
The efficacy in biomarker subgroups will be summarized by descriptive statistics.  
Table 3 
Statistical Methods Per Endpoint Analysis  
Endpoint/Variable 
(Description, Time Point) 
Statistical Method 
Analysis 
Population 
Missing Data 
Approach 
Primary Endpoint 
ORR   
 the 90% exact 
confidence 
interval estimate 
ASaT 
Subjects with missing 
data are considered 
non-responders 
Key Secondary/Exploratory Endpoints 
PFS – RECIST 1.1 by M.D. Anderson 
radiology  
Summary statistics 
using Kaplan-Meier 
method 
ASaT 
Censored at last 
assessment 
OS 
Summary statistics 
using Kaplan-Meier 
method 
ASaT 
Censored at last known 
alive date 
 
8.6.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. 
Counts and percentages of subjects with AEs will be provided. Analysis of AEs will be 
descriptive.  
8.6.3 Demographic and Baseline Characteristics 
The number and percentage of subjects screened, the primary reasons for screening failure and 
the primary reasons for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized either by descriptive statistics or categorical tables for all 
enrolled subjects.  
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8.7 
Interim Analyses 
No Interim analysis is planned.  
8.8 
Multiplicity 
Multiplicity adjustment is planned in this study. 
8.9 
Sample Size  
In this study, approximately 15 subjects will be enrolled.   
8.10 Subgroup Analyses and Effect of Baseline Factors 
No subgroup analysis is planned. 
8.11 Compliance (Medication Adherence) 
No drug accountability data is planned.  
 
Data Security/Confidentiality 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This 
confidentiality is extended to the data being collected as part of this study. Data that could be 
used to identify a specific study participant will be held in strict confidence within the research 
team. No personally identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency, as 
applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
Access to Study Records 
Study records may be accessed by IRB approved study personnel, or authorized inspectors. 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or representatives 
from companies or organizations supplying the product, may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
 
Methods of Storage of Study Records 
All data collected from MD Anderson Cancer Center (MDACC) sources will be maintained 
on a password protected server compliant with HIPAA. Study staff will have role based 
restricted access to directories and files on the server, according to project responsibilities. 
Only those with data entry permissions can add records. The PI or a delegate will review the 
conditions under which data will be released to recipient- investigators. Each application for 
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use will need IRB approval and consents, if appropriate. The level of identifiability will 
determine the process for review and approval as well as the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the offices of the 
PI or other delegated study staff, in a locked cabinet or other comparable controlled 
environment, and will be accessible only to authorized study team members or authorized 
inspectors.   
 
Duration of Study Record Storage 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor/funding agency requirements. 
 
Sharing of Study Records 
There are no plans to share study data with entities external to MD Anderson Cancer Center, 
aside from authorized inspectors as applicable (i.e. authorized representatives of the sponsor 
or funding agency, representatives of the Institutional Review Board (IRB), regulatory 
agencies or representatives from companies or organizations supplying the product).  If data 
will be shared, IRB approval will be sought, and applicable inter-institutional agreements 
executed, prior to data sharing.   
 
 
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36. 
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