Clinical trial NCT04541173
Conditions: Hepatocellular Carcinoma
Sponsor: Aiwu Ruth He, MD
Start date: 2020-11-30; Completion date: 2023-06-30
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, multi-center, randomized phase II study comparing the Y90 TARE followed by bevacizumab and atezolizumab treatment to the Y90 TARE treatment alone in unresectable advanced stage HCC.

Detailed description:
Subjects will be randomized to Y-90 TARE alone (Arm A) or Y-90 TARE followed by the combination of atezolizumab and bevacizumab (Arm B). The first 10 subjects randomized to Arm B (Y-90 TARE + bevacizumab + atezolizumab) will be assessed for safety after two cycles. If there are no Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to TARE in combination with bevacizumab and atezolizumab the combination will be deemed safe and accrual will resume.

Subjects randomized to receive bevacizumab and atezolizumab (Arm B) will start the combination of bevacizumab and atezolizumab 4 weeks (± 1 week) after TARE treatment. Full recovery from the procedure is required prior to systemic treatment:

* AST and ALT ≤ 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL
* Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, and abdominal pain) have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 Grade 1
* No significant medical events (e.g., gastrointestinal \[GI\] bleeding, cardiac events, hepatorenal syndrome) during or after the TARE procedure.

Arm B subjects will continue the study drugs for a total of 24 months from the TARE treatment, until intolerable toxicity or disease progression occur.

Arms: arm 1: TARE alone arm 2: TARE then Bevacizumab and Atezolizumab
Interventions: intervention 1: Y-90 TARE intervention 2: Atezolizumab intervention 3: Bevacizumab
Intervention descriptions: intervention 1: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution).

The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. intervention 2: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. intervention 3: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
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A Randomized Phase II Study of Atezolizumab and Bevacizumab with Y-90 TARE in 
Patients with Unresectable Hepatocellular Carcinoma (HCC) 
 
 
Sponsor Investigator 
Aiwu Ruth He, MD, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University 
3800 Reservoir Road, NW 
Washington DC, 20007 
Tel: 202-444-8642 
Fax:202-444-9429 
arh29@georgetown.edu 
 
Co-Investigator 
Interventional Radiologist 
Filip Banovac, MD 
 
 
Statistician 
Hongkun Wang, PhD 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way Suite 120 
Indianapolis, IN 46278 
 
 
Trial Supported by  
Genentech ML41891 
 
 
IND exemption from FDA 5/7/2020 
 
 
Initial Protocol Version Date: 09JUN2020 (LEAD INSTITUTION) 
Protocol Amendment Version Date:  
22SEP2020 (INITIAL VERSION FOR PARTICIPATING SITES) 
02DEC2021 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Randomized Phase II Study of Atezolizumab and Bevacizumab with Y-90 TARE in 
Patients with Unresectable Hepatocellular Carcinoma (HCC) 
 
 
 
VERSION DATE: 02DEC2021 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 
 
____________________________________ 
________________________ 
Signature of Site Investigator  
 
 
  
Date 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
Name of Facility 
 
 
Location of Facility (City and State) 
 
____________________________________
____________________________________


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SYNOPSIS 
TITLE 
A Randomized Phase II Study of Atezolizumab and Bevacizumab 
with Y-90 TARE in Patients with Unresectable Hepatocellular 
Carcinoma (HCC) 
SHORT TITLE 
Phase II study evaluating atezolizumab and bevacizumab with Y-90 
TARE in unresectable HCC
PHASE  
II 
OBJECTIVES 
Primary Objective 
Assess the progression-free survival (PFS) per RECIST 1.1 of 
patients receiving Y-90 transarterial radioembolization (TARE) 
combined with atezolizumab and bevacizumab. 
 
Secondary Objectives  
 Safety and tolerability of Y-90 TARE combined with 
atezolizumab and bevacizumab in patients with HCC. 
 Assess the progression-free survival (PFS) per mRECIST of 
patients receiving Y-90 transarterial radioembolization (TARE) 
combined with atezolizumab and bevacizumab. 
 Time to Progression (TTP) per RECIST 1.1 and mRECIST 
 Overall response rate (ORR) determined per RECIST 1.1 and 
mRECIST 
 Overall survival (OS) 
 Evaluate PROs of physical functioning, role functioning, social 
functioning, and global health status/quality of life experienced 
by patients receiving Y-90 TARE and bevacizumab plus 
atezolizumab treatment
STUDY DESIGN 
This is an open-label, multi-center, randomized phase II study 
comparing the Y90 TARE followed by bevacizumab and 
atezolizumab treatment to the Y90 TARE treatment alone in 
unresectable intermediate stage HCC.  
 
Regarding TARE treatment, a comprehensive plan will be made 
for each patient’s liver-targeted therapy. This plan will involve 
treating the predominant liver lesions with segmental TARE or 
unilobar TARE using predetermined dosimetry, while keeping 
FLR ≥ 40% (FLR is estimated by excluding the liver volume of 
Y90 infused distribution area). Any patient who is not a TARE 
candidate, as defined by a lung dose threshold for Y90 of 30Gy 
and an estimated FLR of less than 40% at the time of forming the 
comprehensive treatment plan will be excluded from this study. 
All candidates who meet the inclusion criteria will be randomized 
at a 1 to 1 ratio to TARE (Arm A; control arm) or TARE followed 


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by the combination of atezolizumab and bevacizumab (Arm B; 
experimental arm).  
 
Patient will have TARE mapping followed by TARE treatment. In 
Arm B, patient will start the combination of bevacizumab and 
atezolizumab 4 weeks (± 1 week) after TARE treatment. 
 
Patients on study will have abdominal MRI or CT scans every 12 
weeks and CT scans of the chest every 24 weeks to evaluate for 
disease progression. In the case of cancer progression, patients will 
be taken off study treatment and followed as described in Section 7. 
All patients will be taken off study treatment at the end of two years 
from TARE treatment and followed as described in Section 7.   
 
Disease progression will be captured by both RECIST 1.1 and 
mRECIST for the primary and secondary objectives. Infiltrative 
HCC cannot be evaluated by mRECIST and will only be evaluated 
by RECIST 1.1. 
 
We plan to assess the safety of TARE with bevacizumab and 
atezolizumab in the first 10 patients randomized to Arm B for two 
cycles. If there are no Grade ≥ 3 unexpected toxicities possibly, 
probably or definitely related to TARE in combination with 
bevacizumab and atezolizumab, the study will continue to accrue an 
additional 108 patients/to a total of 128 patients.  
 
Patients will continue study treatment for a total of 24 months from 
TARE, or until intolerable toxicity or disease progression occur, 
whichever is earlier. 
 
Archived tumor tissue biopsies or fresh biopsies will be obtained, 
followed by mapping and Y-90 treatment, as per standard of care. 
Tissue and blood will be collected for correlative studies. 
KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
Inclusion 
 
1. Patients must demonstrate adequate hepatic, bone marrow, and 
renal function as defined in Table below. All screening labs 
should be performed within 14 days of treatment initiation.   
 
2. ECOG Performance Status of 0-1 at screening. 
 
3. Histological or cytological evidence/confirmation per AJCC, 
8th edition, of hepatocellular carcinoma (HCC). 
 
4. Patients must have at least Barcelona Clinic Liver Cancer 
(BCLC) stage B HCC and must be outside of Milan Criteria; 


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and/or HCC with peripheral vascular involvement with any size 
or number of tumor (segment peripheral, vp1 and vp2 are 
allowed, but vp3 and vp4 are excluded). NOTE: absence of 
extrahepatic spread, must be confirmed by computed 
tomography (CT) or magnetic resonance imaging (MRI) scan of 
the chest, abdomen, and pelvis. 
 
5. Patient must either (1) not be a candidate for liver 
transplantation as determined by the liver transplant service or 
(2) refuse evaluation by the liver transplant service. 
 
6. Patients must have a Child-Pugh score of A, or selected B7. 
NOTE: Definition of the selected B7 patients: Child Pugh B7 
patients are allowed if they meet the inclusion criteria 11 and 
they do not have hepatic encephalopathy or more than a 
moderate amount of ascites. 
 
7. Archival tissue obtained within 6 months of registration is 
required. If archival tissue is not available, subjects are not 
eligible. 
 
8. No prior systemic therapy is permitted. NOTE: Patients who 
received prior local therapy (e.g., radiofrequency ablation, 
percutaneous ethanol or acetic acid injection, cryoablation, 
high-intensity focused ultrasound) are eligible provided the 
target lesion(s) have not been previously treated with local 
therapy or the target lesion(s) within the field of local therapy 
have subsequently progressed in accordance with RECIST 
version 1.1. Prior TACE IS allowed if FLR is ≥ 40%. 
 
9. Patient must be a TARE candidate, as defined by a lung dose 
threshold for Y-90 of 30 Gy (equal or less than 20% in 99mTc 
macro-aggregated albumin scan for resin and 30 Gy per 
treatment for glass) and an estimated (future liver remnants) 
FLR of ≥ 40% at the time of forming the comprehensive 
treatment plan. Both the lung dose threshold and FLR values 
must be obtained and available in source documentation. 
 
Exclusion 
 
1. Have signs of liver failure, e.g. clinically significant ascites, 
encephalopathy, or variceal bleeding within six months from 
enrollment. 
 
2. Have evidence of excessive hepatopulmonary shunting (> 20% 
in 99mTc macro-aggregated albumin scan for resin and 30 Gy 


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per treatment for glass) or angiographically demonstrable and 
non-occludable gastrointestinal shunting, precluding from Y-90 
treatment).  
 
3. Have active autoimmune disease that has required systemic 
treatment in the past 2 years  
 
4. Have history of idiopathic pulmonary fibrosis (including 
bronchiolitis obliterans with organizing pneumonia) drug-
induced pneumonitis, or idiopathic pneumonitis or evidence of 
active pneumonitis on screening chest CT scan. NOTE: History 
of radiation pneumonitis in the radiation field (fibrosis) is 
permitted. 
 
5.  Patients with CNS metastatic disease. 
 
6. Have unresolved toxicities from prior anticancer therapy, 
defined as having not resolved to National Cancer Institute 
(NCI) CTCAE v5 grade 0 or 1 with the exception of alopecia 
and laboratory values listed per the inclusion criteria.  NOTE: 
Subjects with irreversible toxicity that is not reasonably 
expected to be exacerbated by any of the investigational 
products may be included (e.g., hearing loss) after consultation 
with the sponsor-investigator.
STATISTICAL 
CONSIDERATIONS 
 
The primary objective of this study is to compare the PFS of 
patients with HCC receiving a combination of bevacizumab, 
atezolizumab, and Y90 TARE therapy with that for patients on Y90 
TARE therapy alone.  
 
The estimated PFS for patients receiving segmental TARE (Arm A) 
is 9 months.  It is hypothesized that the addition of combined 
bevacizumab and atezolizumab (Arm B) will improve the PFS from 
9 months (control arm receiving segmental Y90) to 15 months 
(bevacizumab plus atezolizumab following Y90 TARE). Assuming 
a hazard ratio of 0.6 (median PFS of 9 months in Arm A and 15 
months in Arm B) and an exponential distribution for PFS in each 
treatment arm, a total of 97 PFS events (53 in the control group, 44 
in experimental arm) are needed to detect a statistically significant 
difference using a 1-sided alpha of 0.05 with 80% power.  With an 
expected accrual rate of 10 patients per month, and 24 months of 
follow up after last patient in, a total of evaluable 118 patients will 
be needed.  
 
A total of 128 HCC subjects will be enrolled during the 
assuming ~8% of dropout/ineligibility and randomized to the 
two treatment arms at a 1:1 ratio. The study will stratify for AFP 


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level (high is defined as ≥ 400; low as < 400), presence or 
absence of vascular invasion. 
TOTAL  
NUMBER OF 
SUBJECTS 
N = Up to 128 subjects 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 14 months after all participating sites are open to 
accrual 
ESTIMATED 
STUDY DURATION  
Estimated 40 months 
 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 9 
1. 
Background and Rationale ................................................................................... 10 
2. 
Study Objectives and Endpoints........................................................................... 20 
3. 
Eligibility Criteria .................................................................................................. 21 
4. 
Subject Registration............................................................................................... 27 
5. 
Treatment Plan....................................................................................................... 28 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 32 
7. 
Study Calendar & Evaluations ............................................................................. 34 
8. 
Biospecimen Studies and Procedures ................................................................... 42 
9. 
Criteria for Disease Evaluation ............................................................................ 44 
10. Drug Information ................................................................................................... 52 
11 
Adverse Events ....................................................................................................... 55 
12 
Statistical Methods ................................................................................................. 62 
13 
Trial Management ................................................................................................. 65 
14. Data Handling and Record Keeping .................................................................... 66 
15 
Ethics ....................................................................................................................... 67 
16 
References ............................................................................................................... 69 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
Screening 
Archival tissue 
required 
Angiography 
to confirm  
FLR ≥ 40% 
TARE 
Mapping 
Eligible and 
Randomized 
ARM B 
TARE then 
Bevacizumab/Atezolizumab 
Day 1 of every 3 week cycle 
Continue until progression, 
toxicity or a total of 24 
months of treatment from 
TARE. 
ARM A 
TARE alone  
Safety Cohort 
Assess first 10 
subjects that 
received Arm B  
Treatment. If no 
Grade ≥ 3 
unexpected 
toxicities possibly, 
probably or 
definitely related to 
TARE plus 
bevacizumab and 
atezolizumab, 
continue accrual. 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Hepatocellular Carcinoma  
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and is the second 
most deadly cancer (International Agency for Research on Cancer 2012). There are over 700,000 
new cases diagnosed each year worldwide with large geographic variation in both risk factors 
and incidence (Ferlay et al. 2010; El-Serag 2011). The majority (about 80%) of cases occur in 
sub-Saharan Africa and eastern Asia, and China alone accounts for 55% of cases worldwide. 
Hepatitis B virus infection is the main risk factor for HCC in Asia and Africa, while in Western 
countries and Japan, the main risk factor is hepatitis C virus (HCV) infection and excessive 
alcohol intake, along with other causes of cirrhosis. 
 
HCC is a highly lethal disease with the highest mortality-to-incidence rate ratio of 0.98 of any 
solid tumor (Kamangar et al. 2006). Up to 80% of patients first presenting with HCC have 
advanced incurable disease because of the late appearance of symptoms. It is a medically 
complex and difficult to treat disease as the majority of HCC patients have underlying cirrhosis 
requiring management of both the malignancy and the cirrhosis. In the United States, at 5 years, 
the overall survival (OS) rate of HCC patients is 17% and falls substantially to only 3% if 
present with distant metastasis (Siegel et al. 2016).  In China, at 5 years, the OS rate of HCC 
patients is 10.1% (Chen et al. 2016).  
 
1.2 
Current Systemic Treatment for Intermediate Stage Hepatocellular Carcinoma  
Curative treatment of HCC includes surgical resection and liver transplant. Beyond Milan 
transplant criteria (as defined as patients with one less < 5cm, 2-3 lesions the largest one < 3cm), 
patients with one lesion 5-8 cm; 2-3 lesions 3-5 cm, or 4-5 lesions each < 3cm, with total tumor 
volume <8cm, show comparable outcome when they were down-staged meeting Milan criteria 
and received a liver transplant to patients have disease within Milan criteria and received a liver 
transplant, with a 5-year post OLT: 78% vs.81% (p=0.69), respectively.  (Yao et al Hepatology 
2015). 
 
For patients beyond curative resection or outside transplant or downstage criteria, locoregional 
therapies (LRT) remain excellent treatment options (EASL, 2012). These include direct lesion 
ablation and transarterial approaches such as chemoembolization (TACE) and radioembolization 
(TARE) (NCCN, 2017).  
 
1.2.1 TARE Treatment 
Radioembolization (RE) with yttrium-90 (90Y) microspheres is a form of brachytherapy 
delivered via the hepatic artery, that allows targeted delivery of high-dose radiation to liver 
tumors. Several retrospective and large cohort studies showed an acceptable safety profile of RE, 
and good results in terms of local control of the disease and long-term survival in patients with 
unresectable HCC limited to the liver in the intermediate and advanced stages (Salem, 2010; 
Sangro, 2011, Mazzaferro, 2013). 
 
1.2.2.1 TARE in Combination with Systemic Therapy 
Until recently two randomized clinical trials (RCTs) comparing the efficacy of TARE with 
respect to sorafenib had been published. SIRveNIB (selective internal radiation therapy vs. 


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sorafenib) is a recently published open-label phase III trial that compared 90Y-resin 
microspheres TARE with sorafenib 800 mg/d in patients with locally advanced HCC, in a two-
tailed study designed for superiority/detriment; the primary end point was overall survival (OS). 
The trial randomized 360 patients (182 to RE, 178 to sorafenib) across 11 countries in the Asia-
Pacific region. The study failed to meet the primary endpoint: in fact, median OS in the 
intention-to-treat population was 8.8 and 10.0 months with TARE and sorafenib, respectively 
(hazard ratio, 1.1; 95% CI: 0.9–1.4; P=0.36). Similarly, no differences in OS were demonstrated 
in the treated population (11.3 and 10.4 months in the RE and sorafenib arms, respectively, 
P=0.27), nor in subgroup analyses. Tumor response rates (TRR) were significantly higher in the 
RE arm, however disease control rates were similar and no differences in progression-free 
survival were observed. Fewer patients in the RE group (20.8%) than in the sorafenib group 
(35.2%) had serious AEs, and mean duration of side effects was shorter in the RE arm. (Chow, 
2018). The SARAH trial (SorAfenib versus Radioembolization in Advanced Hepatocellular 
carcinoma) enrolled 467 patients (237 RE, 222 sorafenib) from 25 centers in France.  
 
Similarly, to SIRveNIB, it was a phase III trial designed for superiority that compared 90Y-resin 
microspheres TARE with sorafenib 800 mg/d in patients with locally advanced HCC. This 
Western-based trial failed to meet the primary endpoint since median OS was 8.0 months in the 
TARE group vs. 9.9 months in the sorafenib group (hazard ratio, 1.15; 95% CI: 0.94–1.41; 
P=0.18) (Vilgrain, 2017).  
 
In these studies, HCC patients with more than one BCLC stage are included in each study. 
Patient with BCLC A, B, or C stages of HCC and liver function as determined by Child Pugh 
class A, B or C, have different clinical outcome after TARE treatment (Salem, 2018), therefore 
interpretation of the clinical study endpoints of a study with mixed BCLC stage HCC and Child 
Pugh class liver function is challenging. Studies with more homogenous HCC population in 
BCLC stage and Child Pugh class are needed to evaluate the efficacy of local regional therapy.  
 
1.3 
Atezolizumab  
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 
and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as 
CD80), both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and 
quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding to Fc 
receptors, thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells. Atezolizumab shows anti-tumor activity in both 
nonclinical models and cancer patients and is being investigated as a potential therapy in a wide 
variety of malignancies.  Atezolizumab is being studied as a single agent in the advanced cancer 
and adjuvant therapy settings, as well as in combination with chemotherapy, targeted therapy, 
and cancer immunotherapy. 
 
Atezolizumab is approved in multiple countries for the treatment of urothelial carcinoma (UC) 
non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and triple negative breast 
cancer. Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.  


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1.4 
Bevacizumab  
Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and 
in vivo assay systems.  Bevacizumab contains human framework regions and the 
complementarity-determining regions of a murine antibody that binds to VEGF, and has an 
approximate molecular weight of 149 kD.  Bevacizumab is produced in a mammalian Chinese 
hamster ovary cell line.   
 
Bevacizumab was first granted marketing approval in the United States on 26 February 2004 
(international birth date) in combination with IV 5-fluorouracil (5-FU)based chemotherapy for 
the first-line treatment of patients with metastatic carcinoma of the colon or rectum (CRC).  As 
of November 2016, bevacizumab has been approved for use in over a 100 countries worldwide in 
a variety of indications, including locally recurrent or metastatic breast cancer; advanced, 
metastatic, or recurrent NSCLC; advanced and/or metastatic renal cell cancer (RCC); newly 
diagnosed glioblastoma multiforme (GBM) and GBM after relapse or disease progression; 
persistent, recurrent, or metastatic cervical cancer; front-line treatment of epithelial ovarian 
cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC); and treatment of 
platinum-sensitive and platinum-resistant recurrent EOC, PPC, or FTC.  
 
1.5 
Clinical Development Program in Hepatocellular Carcinoma  
 
1.5.1 Atezolizumab Monotherapy  
A comprehensive overview of atezolizumab efficacy across all indications is provided in the 
atezolizumab Investigator's Brochure.  This section provides an overview of the available 
efficacy data in patients with HCC treated with atezolizumab as monotherapy.  To date, 
atezolizumab as single agent has shown minimal activity in the treatment of HCC patients with 
similar characteristics as those that would be included in this study. Safety findings in the HCC 
cohort are in line with expectations for an HCC population and with the atezolizumab safety 
profile observed in the overall study population across multiple tumor types. No new safety 
signals related to atezolizumab monotherapy were observed in the HCC population.  
 
1.5.1.1 Study PCD4989g  
Study PCD4989g is a Phase Ia, multicenter, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab administered 
as a single agent by IV infusion every 3 weeks (Q3W) to patients with locally advanced or 
metastatic solid malignancies or hematologic malignancies.  The largest cohorts enrolled into 
this trial consisted of patients with NSCLC, RCC, and UC.  Expansion cohorts have included 
patients with CRC, melanoma, NSCLC, pancreatic cancer, UC, breast cancer, esophageal cancer, 
prostate cancer, small cell lung cancer, malignant lymphoma, multiple myeloma, HCC, and other 
less common tumor types. 
 
In the analysis of Study PCD4989g (clinical cutoff date of 31December 2016) conducted in 15 
patients with first- and later-line HCC, the median duration of treatment was 2.0 months (range: 
0.7- 6.3months).  At the time of the clinical cutoff date, 1patient remained on treatment, 12 


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patients had discontinued treatment due to disease progression, 1patient discontinued because of 
an adverse event, and 1 patient was discontinued as per the physician's decision.   
 
Of the 15 response-evaluable patients, none had an objective response (confirmed complete 
response [CR] or partial response [PR] as assessed by investigator per Response Evaluation 
Criteria in Solid Tumors [RECIST] v1.1).  Four patients (33.3%) had stable disease (SD) at 24 
weeks. No patients had SD at 24 weeks.  Median progression-free survival (PFS) per investigator 
assessment per RECIST v1.1 was 2.3 (95% CI: 1.3, 3.4) months and median OS was 5.3 (95% 
CI: 2.4, NE) months.  
 
1.5.1.2 Study YO29233  
StudyYO29233 is a Phase I, open-label, multicenter study evaluating the pharmacokinetics, 
safety, and preliminary anti-tumor activity of atezolizumab as monotherapy in Chinese patients 
with locally advanced or metastatic gastric cancer, nasopharyngeal carcinoma, esophageal 
cancer, HCC and other solid tumors, and the safety and preliminary anti-tumor activity of 
atezolizumab in combination with gemcitabine and cisplatin in Chinese patients with Stage IV, 
treatment-naive NSCLC. For monotherapy cohorts, atezolizumab is administered as a single 
agent at a dose of 1200 mg IV Q3W. 
 
Based on a clinical cutoff date of 1 April 2018, 21patients with HCC had received atezolizumab 
monotherapy. At the time of the clinical cutoff date, 7 patients remained on treatment (3 first-line 
HCC patients), while 7 patients had discontinued treatment due to disease progression, 2 patients 
discontinued treatment due to an adverse event, 2 patients discontinued treatment due to non-
compliance with study drug, and 1 patient each discontinued treatment due to a protocol 
deviation, physician decision, and death due to progression of disease. 
 
Of the 21 efficacy-evaluable patients (first-line and second-line or greater), 2 patients (9.5% 
[95% CI: 1.17%, 30.38%]) had a confirmed objective response and 11 patients (52.4% [95% CI: 
29.78%, 74.29%]) had a best response of SD.  Median PFS was 2.8months (95% CI: 1.4, 7.8 
months) and median OS was 11.1 months (95% CI: 4.7months, NE).  
 
1.5.2 Bevacizumab Monotherapy  
A comprehensive overview of bevacizumab efficacy across all indications is provided in the 
bevacizumab Investigator's Brochure.  This section provides an overview of the available 
efficacy data in patients with HCC treated with bevacizumab as monotherapy.  Overall, 
bevacizumab as a single agent demonstrated minimal activity in HCC, and is unlikely to 
demonstrate a meaningful clinical benefit over current standard of care (sorafenib) based on the 
survival data observed. Bevacizumab monotherapy was generally safe and well tolerated in the 
HCC population, and safety findings were consistent with the HCC population and established 
safety profile of bevacizumab.  No new safety signals related to bevacizumab monotherapy were 
observed in this patient population.   
 
1.5.2.1 Phase II Study of Bevacizumab in Unresectable Hepatocellular Carcinoma  
This study was a Phase II, single center, single arm trial designed to evaluate the clinical and 
biological effects of bevacizumab in unresectable HCC (Siegel et al. 2008).  Adult patients with 
organ-confined HCC, ECOG Performance Status of 0-2, and compensated liver function (Child-


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Pugh class A or B7), received bevacizumab 5 mg/kg or 10mg/kg every 4 weeks (Q2W) until 
disease progression or treatment-limiting toxicity.  Of note, patients with extrahepatic disease, 
tumor invasion of the main portal vein or inferior vena cava were excluded. Given the known 
prognostic value of these factors, the study likely enrolled a population with a more favorable 
prognosis and treatment outcome compared with a population that would typically be enrolled in 
a first-line HCC study. The primary objective was to determine whether bevacizumab improved 
the 6-month PFS rate from 40% to at least 60%.  Overall, 46 patents were enrolled, including 12 
patients who received bevacizumab 5mg/kg and 34patients who received bevacizumab 10mg/kg 
Q2W. 
 
Clinical activity of bevacizumab was observed in patients with nonmetastatic HCC.  Of the 
46patients, 6 patients (13%) had objective responses (95% CI: 3%, 23%), and 65% (95% CI: 
51%, 79%) of patients were progression free at 6months.  Median PFS was 6.9months (95% CI: 
6.5, 9.1) and median OS was 12.4months (95% CI: 9.4, 19.9).  No significant changes were seen 
with respect to dose and outcome.  The response rates for the 5mg/kg and 10mg/kg groups were 
8.3% and 14.7%, respectively (p=0.99 by Fisher's exact test).  Median OS times for patients 
receiving 5mg/kg and 10 mg/kg were 15.1months and 12.2months, respectively (p= 0.64 by the 
log-rank test) (Siegel et al. 2008). Phase II Study of Bevacizumab in Advanced Hepatocellular 
Carcinoma This study was a Phase II, single-center, single-arm trial designed to evaluate the 
efficacy, safety, and potential biomarkers of activity of bevacizumab in patients with advanced 
HCC (Boigeet al. 2012).  Patients with histologically confirmed advanced HCC that was not 
amenable to curative-intent therapies (e.g., resection, liver transplantation, or percutaneous 
ablation) received bevacizumab 5 mg/kg or 10mg/kg Q2W until disease progression or 
unacceptable toxicity.  The primary objective was to determine the disease-control rate at 16 
weeks (16W-DCR) defined as the proportion of patients with a CR, PR, or SD at 16weeks after 
study entry, according to RECIST v1.0. 
 
Overall, 48 patients were enrolled, of which 25 patients were planned to receive bevacizumab 
5mg/kg and 23 patients were planned to receive bevacizumab 10mg/kg, Q2W. Of the 48 patients 
enrolled, 43patients received at least one dose of bevacizumab.  
 
Among the 38 response-evaluable patients, six patients achieved a PR (intent-to-treat [ITT] 
objective response rate [ORR], 14%; 95% CI: 4%, 24%), median duration of response (DOR) 
was 148 days (range, 55-362days), 18 patients had SD (DCR, 56%), including 12 patients who 
experienced SD for 16 weeks. The 16W-DCR was 42% (95% CI: 27%, 57%) in the overall 
population, 39% (95% CI: 19%, 59%) in patients treated with 5mg/kg bevacizumab, and 45% 
(95% CI: 23%, 67%) in those treated at the 10 mg/kg dose. In the overall population (n = 43), 
median PFS was 3 months (95% CI: 2, 4); median OS was 8 months (95% CI: 4, 9) (Boige et al. 
2012).  
 
 
 


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1.6 
Study Rationale and Benefit-Risk Assessment  
 
1.6.1 Rationale for the Combination of Anti-PD-L1 and Anti-VEGF Therapy in 
Hepatocellular Carcinoma  
Strong scientific rationale and emerging clinical data suggest that the combined VEGF/PD-L1 
blockade may be clinically beneficial in a number of tumor types including HCC.   
It is known that HCC is a highly vascularized tumor, and that several proangiogenic factors play 
a role in HCC pathogenesis.  For example, in HCC, increased VEGF correlates with vascular 
density, tumor invasiveness and metastasis, and poor prognosis (Boigeet al. 2012; Frenette2012).  
The VEGF pathway also plays a crucial role in exerting and maintaining an immunosuppressive 
tumor microenvironment through several mechanisms.  For instance, VEGF-A has been shown 
to induce FasL expression on endothelial cells, which have the ability to kill effector CD8+ T 
cells, but not T-reg cells.  Administration of anti-VEGF-A attenuated tumor endothelial FasL 
expression and produced a significant increase in the influx of tumor-rejecting CD8+ over 
FoxP3+ T cells, which was FasL-dependent, and led to CD8-dependent tumor growth 
suppression (Motz et al. 2014).  Furthermore, bevacizumab can restore and/or maintain the 
antigen presentation capacity of dendritic cells, leading to enhanced T-cell infiltration in tumors 
(Oelkrug and Ramage 2014; Wallin et al. 2016). In addition to increased trafficking of T cells 
into tumors (Manning et al. 2007), several publications have illustrated that antiVEGF therapies 
can also reduce frequency of myeloid-derived suppressor cells, decrease production of 
suppressive cytokines, and lower expression of inhibitory checkpoints on CD8+ T cells in 
tumors (Roland et al. 2009; Voronet al. 2015). Therefore, the immunomodulatory effect of 
bevacizumab is expected to increase CD8-positive T-cell recruitment and relieve intratumoral 
immunosuppression, thereby boosting the effects of atezolizumab.   
 
1.6.2 Clinical Data of Atezolizumab in Combination with Bevacizumab in Hepatocellular 
Carcinoma  
Preliminary data from Study GO30140 indicates substantial numerical improvement in ORR for 
the combination of atezolizumab + bevacizumab compared to sorafenib, the current global 
standard of care, in patients with locally advanced or metastatic HCC, supporting the hypothesis 
of a synergistic/complementary effect of atezolizumab and bevacizumab. 
 
1.6.2.1 
Efficacy: Study GO30140  
StudyGO30140 is a Phase Ib, multicenter study of atezolizumab in combination with 
bevacizumab and/or chemotherapy for first-line metastatic cancer patients.  Arm A is designed to 
test the combination of atezolizumab and bevacizumab in patients with locally advanced or 
metastatic HCC who have not received prior systemic therapy. Patients receive 1200mg of 
atezolizumab plus 15 mg/kg of bevacizumab on Day 1 of every 21-day cycle (Q3W). 
 
Based on a clinical cutoff date of 26 July2018, 103 patients (recruited from United States and 
South Korea) with HCC had received atezolizumab + bevacizumab combination therapy.  All 
received atezolizumab + bevacizumab as first-line therapy.  At the time of the clinical cutoff 
date, 70 patients remained on treatment, 18 patients had discontinued treatment due to disease 
progression, 2 patients discontinued treatment due to symptomatic deterioration, 6 patients 
discontinued treatment due to an adverse event, 4 patients discontinued treatment due to death, 
and 3 patients discontinued treatment due to patient decision or other reasons.   


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Efficacy analyses were performed in the efficacy-evaluable population, defined as all patients 
who received any amount of the combination treatment and have been followed on study for at 
least 16 weeks.  Based on a clinical cutoff date of 26 July2018, 73 patients enrolled into Arm A 
were efficacy-evaluable with a median duration of survival follow-up of 7.2 months.   
 
Based on IRF assessment per RECIST v1.1, the confirmed ORR was 27.4% (95% CI: 17.6, 
39.1).  Among the 20 responders, 4 (20%) achieved a CR and the remaining 16 (80%) achieved 
PR.  The ORR based on investigator-assessment per RECIST v1.1 was numerically similar to the 
ORR based on IRF-assessment per RECIST v1.1.  According to investigator-assessment per 
RECIST v1.1, 23 of the 73 efficacy-evaluable patients (31.5% [95% CI: 21.1, 43.4]) achieved 
confirmed objective responses, with 1 patient (1.4%) achieving a CR.  When tumor scans were 
assessed by the IRF according to HCC mRECIST criteria, 25 of the 73 efficacy-evaluable 
patients (34.2% [23.5, 46.3]) achieved a confirmed objective response, 8 of those 25 responders 
(32%) achieved a best overall response of CR, and 17 of the 25 responders (68%) achieved a best 
overall response of PR.  Importantly, responses were observed in all assessed patient subgroups, 
including etiology, region, and baseline AFP and tumor burden.   
 
At the time of the clinical cutoff date, 80% (16 of 20) of the IRF-assessed responses per RECIST 
v1.1 were ongoing, with durations ranging from 1.6 to 22.0 months (denotes censored data).  
Nine patients had responses of 6 months or longer per IRF assessment by RECIST v1.1.   
 
The median duration of response (DOR) has not been reached by IRF-assessment (per RECIST 
v.1.1 or HCC mRECIST) or INV-assessment (per RECIST v1.1), nor has the median OS been 
reached.  The median PFS by IRF-assessment per RECIST v1.1 and per HCC mRECIST was 7.5 
months (95% CI: 5.4- 14.9) and the median PFS by INV-assessment per RECIST v1.1 was 14.9 
months (95% CI: 7.4- NE).  The 6-month PFS rate was 56% by IRF-assessment per RECIST 
v1.1, 65% by INV-assessment per RECIST v1.1 and 58% by IRF-assessment per HCC 
mRECIST.  These estimates of median PFS are considered to be unstable and expected to change 
with longer follow-up.   
 
1.6.2.2 
Safety: Study GO30140  
In the analysis of safety data from Study GO30140 (clinical cutoff date of 26 July 2018) in 103 
patients with HCC (median treatment duration with atezolizumab was 3.5 months [range: 0-24 
months]; median treatment duration with bevacizumab was 3.5 months [range: 0-23 months]), 
the combination of atezolizumab + bevacizumab was generally safe and well tolerated; no new 
safety signals related to the combination therapy were identified beyond the established safety 
profile for each individual agent.    Furthermore, no unexpected adverse events were observed.   
 
Overall, 95 patients (92.2%) experienced at least one adverse event.  The most common adverse 
events (≥ 20%) were decreased appetite (28.2%) and fatigue, pyrexia, and rash (20.4% each).  
Forty-one patients (39.8%) experienced a Grade 3- 4 adverse event, with the most common 
Grade 3- 4 adverse events (≥ 4%) being hypertension (11.7%) and increased AST (4.9%). 
Treatment-related Grade3- 4 adverse events were reported in 28 patients (27.2%), the most 
common being hypertension (9.7%) and neutrophil count decreased (2.9%).  A total of 36 
patients (35%) experienced serious adverse events.  Treatment-related serious adverse events 
occurred in 19 (18.4%) patients, most of which were single occurrence except colitis, esophageal 


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varices hemorrhage and pneumonitis (1.9% each).  Five patients (4.9%) experienced Grade 5 
adverse events, of which 2 patients (1.9%) experienced Grade 5 treatment-related adverse events.  
 
Six patients (5.8%) discontinued both atezolizumab and bevacizumab treatment due to adverse 
events. Eight patients (7.8%) discontinued atezolizumab and 10 patients (9.7%) discontinued 
bevacizumab due to adverse events. All adverse events leading to any atezolizumab and/or 
bevacizumab withdrawal were single occurrence except esophageal varices hemorrhage (n = 2, 
1.9%), which led to discontinuation of bevacizumab only.  
 
1.6.2.3 
IMbrave 150  
The landmark IMbrave150 trial, was a trial that testing the combination of atezolizumab plus 
bevacizumab and has solidified immunotherapy's role in advanced HCC. Atezolizumab plus 
bevacizumab is the first therapy to show improved PFS, OS, and improved quality of life when 
compared to sorafenib.  The novel combination of the PD-L1 inhibitor atezolizumab combined 
with the VEGF inhibitor bevacizumab were thought to both decrease angiogenesis and tumor 
growth as well as decrease immunosuppression while, at the same time promote T-cell migration 
into the tumor (Finn). This combination was first testing in a phase Ib GO30140 trial in which 
untreated unresectable HCC patients (N=119) were randomized to receive atezolizumab 1200 
mg IV every 3 weeks alone or with bevacizumab 15 mg/kg IV every 3 weeks until unacceptable 
toxicity or loss of clinical benefit (Lee). The sixty patients who received the combination showed 
better results than monotherapy atezolizumab with an ORR of 36%, with a PFS of 5.6 months 
with acceptable side-effect profile (Lee).  
 
This early phase trial led to the global open-label phase 3 IMbrave150 trial which randomized 
501 treatment naive advanced HCC patients with a 2:1 ratio to either combination atezolizumab 
1200 mg IV combined with bevacizumab 15 mg/kg IV every 3 weeks or standard of care 
sorafenib 400mg twice a day (Finn). The results, after 8.6months median duration of follow-up, 
revealed improved survival in the combined therapy group with a hazard ratio (HR) of 0.58 (95% 
CI 0.42-0.79, p=<0.001) (Finn). The survival at 6 months and 12 months were 84.8% (95% CI, 
80.9-88.7) and 67.2% (95% CI, 61.3-73.1), respectively, in the atezolizumab–bevacizumab 
group and 72.2% (95% CI, 65.1-79.4) and 54.6% (95% CI, 45.2-64.0) in the sorafenib group 
(Finn). The median PFS was longer with the atezolizumab-bevacizumab combination than with 
sorafenib (6.8 months [95% CI, 5.7 to 8.3] vs. 4.3 months [95% CI, 4.0 to 5.6]; stratified HR for 
progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001) (FInn). Secondary outcomes include 
ORR of 27.3% in the atezolizumab-bevacizumab group versus 11.9% in sorafenib group (95% 
CI, 7.4-18.0) with sorafenib based on RECIST 1.1 (P<0.001), and 33.2% (95% CI, 28.1-38.6) 
and 13.3% (95% CI, 8.4-19.6), respectively, hepatocellular carcinoma–specific mRECIST 
(P<0.001) (Finn). The study also explored quality of life outcomes utilizing the EORTC QLQ-30 
questionnaire. Results showed a combination atezolizumab plus bevacizumab delayed time to 
deterioration compared to sorafenib (11.2 months with combination vs. 3.6months with 
sorafenib; HR 0.63; 95% CI, 0.46 to 0.85). The most common grade 3 or 4 adverse events with 
the combination therapy was hypertension (15.2%), elevated AST (7%), and elevated ALT 
(3.6%) (Finn). Though this landmark trial has changed the landscape of treating advanced HCC, 
it is not an approved therapy for all patients. The exclusion criteria for the trial included patients 
with Child-Pugh B and C, ECOG 2 or greater, a history of autoimmune diseases, coinfections 


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with hepatitis B or C, and untreated esophageal or gastric varices with bleeding or risk of 
bleeding. 
 
1.7 
Summary  
Overall, the combination of atezolizumab + bevacizumab may be a promising treatment option 
for patients with HCC.  To address the ongoing high unmet medical need for patients with HCC, 
Study YO40245 aims to evaluate the efficacy and safety of atezolizumab + bevacizumab against 
the current standard of care, sorafenib, in patients with locally advanced or metastatic HCC. 
 
1.8 
Rationale and Study design 
 
1.8.1 Rationale for LRT using TARE as the control arm and treatment plan 
Y-90 TARE treatment of HCC lesions provides good disease control; however, radiation 
from TARE may result in liver fibrosis (Tomozawa, 2018, Spina, 2019), which may have a 
negative impact on the survival of patients, especially when systemic treatment options are 
now available that can extend patient survival to 2 years or beyond.  TARE treatment of 
individual liver segments is preferred to avoid extensive liver fibrosis and liver 
decompensation post TARE treatment. Data on the maximum number of segments that can 
receive TARE without causing liver decompensation 2 years or beyond post Y-90 is lacking. 
The minimum functional liver reserve (FLR) used to guide liver resection in compensated 
cirrhosis may be extrapolated and used to guide this study design. When liver resection is 
considered for a patient with compensated cirrhosis, FLR >/= 40% is required to minimize 
post-surgical liver failure (Vauthey, 2000). When segment TARE treatment is planned, the 
FLR can be estimated by excluding the Y-90 infused liver volume and infusion distribution 
area and the untreated HCC area, and if the resulting FLR is equal to or more than 40%, Y-90 
TARE is an option.  In addition, dosimetry will be defined. 
 
Segmental TARE often results in less long-term liver damage compared to lobar TARE and 
is the preferred method as long as it can treat the entirety of the predominant lesion and its 
blood supply. To simplify the treatment plan, if segmental TARE is not sufficient to treat the 
predominant lesion we will limit the maximal amount of TARE treatment to only one lobe of 
the liver.  
 
1.8.2 LRT treatment plan 
In this study, a comprehensive plan will be made for each patient’s liver-targeted therapy; 
this plan will involve treating the liver lesions with segmental TARE or unilobar TARE using 
predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by 
excluding the liver volume of Y-90 infused distribution area). Any patient who is not a 
TARE candidate, as defined by a lung dose threshold for Y-90 of 30Gy and an estimated 
FLR of less than 40% at the time of forming the comprehensive treatment plan will be 
excluded from this study. All candidates who meet the inclusion criteria and are registered 
will be randomized to TARE alone (Arm A; control arm) or TARE followed by the 
combination of atezolizumab and bevacizumab (Arm B; experimental arm).  
 


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1.8.3 Definition of response to LRT 
The standard of care for intermediate stage HCC with increased risk of disease progression is 
TARE, and this is reflected in our control arm (Arm A). In order to demonstrate benefit of 
combination immune therapy to standard of care, in our experimental arm we plan to add 
atezolizumab and bevacizumab to TARE (Arm B).  
 
The effect of Y-90 TARE will be evaluated at three months and six months after treatment as the 
response of Y-90 TARE treatment can be observed in 3-6 months from the TARE treatment. The 
disease progression on HCC lesions treated with TARE at 12 weeks will be confirmed at 6 
months to be counted as having disease progression at 12 weeks as determined by mRECIST for 
endpoint analysis. If additional treatment is needed after the 12 week assessment that will be 
considered the date of confirmed progression. 
 
1.8.4 Combination of LRT with the combination of bevacizumab and atezolizumab as the 
experimental arm 
This study rationale is based on compelling preclinical and clinical studies: The anti–PD-L1 
antibody atezolizumab prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating 
anti-tumor T-cell activity. At the same time, anti-VEGF bevacizumab can increase dendritic cell 
(DC) maturation, enhance T-cell infiltration, and reduce myeloid-derived suppressor cells 
(MDSCs) and regulatory T-cells (Tregs) in tumors. These additive mechanisms of action provide 
a strong scientific rationale for the combination of atezolizumab with bevacizumab. 
 
On the other hand, radiotherapy (RT) enhances the diversity of the T cell receptor repertoire 
(TCR) of intratumoral T cells (Chow et al 2020). Based on this preclinical and clinical data, we 
hypothesize that the combination of Y-90 TARE, bevacizumab, and atezolizumab induces 
synergistic tumor killing by the following mechanism:  radiation diversifies the TCR repertoire 
of TILs (Tumor-infiltrating lymphocytes); bevacizumab inhibits the activity of Tregs and 
increases DC differentiation to promote tumor antigen presentation via the inhibition of VEGF; 
and atezolizumab reverses T cell exhaustion and inhibits PD-1-PD-L1 signaling. 
 
1.8.5 Rationale for Patient-Reported Outcome Endpoints  
Intermediate-stage HCC comprises a heterogenous patient population with respect to liver 
function, as well as size and number of tumors, and is often minimally symptomatic or 
asymptomatic, with the majority of patients exhibiting few to no disease-specific, discernable 
symptoms. Instead, it is largely the impact of treatment and the associated burden, rather than 
disease burden, that defines the patient experience. Therefore, it is important to document the 
burden associated with HCC treatment and understand the impact of therapy as reported by 
patients to inform benefit-risk assessment and treatment decision making.  
 
A fit-for-purpose assessment of function, health related quality of life (HRQoL), and relevant 
symptoms will be collected in the study. The assessment will include validated physical function, 
role function, social functioning, global health status (GHS)/HRQoL scales and relevant 
symptoms (fatigue, pain, lack of appetite, nausea/vomiting) of the European Organisation for 
Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30), 
(Aaronson et al. 1993; Fitzsimmons et al. 1999), as well as two relevant symptoms from the 
EORTC QLQ-HCC18 (fever, abdominal pain) (Blazeby et al 2004, Chie et al 2012).  


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
 Assess progression free survival (PFS) per RECIST 1.1 
 
2.1.2 Secondary Objectives 
 Assess safety and tolerability of Y-90 TARE combined with atezolizumab and 
bevacizumab in patients with HCC. 
 Assess the progression free survival (PFS) per mRECIST  
 Assess Time to Progression (TTP) per RECIST 1.1 and mRECIST  
 Assess Overall response rate (ORR) per RECIST 1.1 and mRECIST  
 Assess Overall survival (OS) 
 Evaluate PROs of physical functioning, role functioning, social functioning, and global 
health status/quality of life experienced by patients receiving Y-90 TARE and 
bevacizumab plus atezolizumab treatment. 
 
2.1.3 Correlative/Exploratory Objectives 
 Explore the role of immunoscore and PD-L1 expression in the prediction of improved 
clinical outcome in patients receiving Y-90 TARE and bevacizumab plus atezolizumab 
treatment 
 Explore the composition of subtypes of tumor infiltrating immune cells in predicting 
response to a chosen therapy. 
 Investigate how Y-90 therapy affects the proportion of antigen presenting cells in the 
tumor.    
 Evaluate PROs of specific symptoms experienced by patients receiving Y-90 TARE and 
bevacizumab plus atezolizumab treatment.   
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
PFS is defined as the time from randomization to the first occurrence of disease progression or 
death from any cause (whichever occurs first) according to RECIST v1.1  
 
2.2.2 Secondary Endpoints 
 Safety and tolerability will be assessed according to CTCAE v5. 
 PFS is defined as the time from randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs first) according to mRECIST 
 TTP is defined as the time from randomization to the first occurrence of disease 
progression according to RECIST v1.1 and mRECIST 
 ORR is defined as a complete or partial response according to RECIST v1.1 or 
mRECIST 
 OS is defined as the time from randomization to death from any cause. 


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 Change from baseline in physical functioning, role functioning, social functioning, and 
global health status/quality of life scores as assessed by a fit for purpose EORTC 
instrument 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. Patients must be willing and able to provide 
written informed consent for this trial. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0-1 at screening 
 
4. Histological or cytological evidence/confirmation per AJCC, 8th edition, of 
hepatocellular carcinoma (HCC). 
 
5. Measurable disease by RECIST 1.1.  
 
6. Patients must have a Child-Pugh score of A. or selected B7. NOTE: Definition of the 
selected B7 patients: Child Pugh B7 patients are allowed if they meet the inclusion 
criteria 11 and they do not have hepatic encephalopathy or more than a moderate amount 
of ascites. 
 
7. Patients must have at least Barcelona Clinic Liver Cancer (BCLC) stage B HCC and must 
be outside of Milan Criteria; and/or HCC peripheral vascular involvement of any size or 
number of tumor (segment peripheral, vp1 and vp2 are allowed, but vp3 and vp4 are 
excluded). NOTE: absence of extrahepatic spread, must be confirmed by computed 
tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and 
pelvis. 
 
8. Patient must either (1) not be a candidate for liver transplantation as determined by the 
liver transplant service or (2) refuse evaluation for transplantation. 
 
9. Archival tissue obtained within 6 months of registration is required. If archival tissue is 
not available, subjects are not eligible. 
 
10. No prior systemic therapy is permitted. NOTE: Patients who received prior local therapy 
(e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, 
high-intensity focused ultrasound or TACE) are eligible provided the target lesion(s) 
have not been previously treated with local therapy or the target lesion(s) within the field 


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of local therapy have subsequently progressed in accordance with RECIST 1.1. Prior 
TACE is allowed if FLR is ≥ 40%. 
 
11. Patient must be a TARE candidate, as defined by a lung dose threshold for Y-90 of 30Gy 
and an estimated (future liver remnants) FLR of ≥ 40% at the time of forming the 
comprehensive treatment plan. Both the lung dose threshold and FLR values must be 
obtained and available in source documentation. 
 
12. Patients must demonstrate adequate hepatic, bone marrow, and renal function as defined 
in Table below. All screening labs should be performed within 14 days of treatment 
initiation.   
 
System 
Laboratory Value 
Hematological
Lymphocyte Count 
500/L
Absolute Neutrophil Count (ANC)
≥ 1,500 /μL
Hemoglobin (Hgb) 
≥ 9 g/dL without transfusion or EPO 
dependency (within 7 days of assessment)
Platelet count (Plt)
≥ 75,000 / μL
Renal
Serum creatinine OR 
Measured or calculated CrCl 
(GFR can also be used in place of creatinine 
or CrCl) 
≤ 1.5 X upper limit of normal (ULN) OR ≥ 
60 mL/min for subject with creatinine levels 
> 1.5 x institutional ULN 
Hepatic
Bilirubin
≤ 3.0 
Aspartate aminotransferase (AST) 
≤ 5 X ULN for subjects with cancer in liver
Alanine aminotransferase (ALT) 
≤ 5 X ULN for subjects with cancer in liver
Albumin
> 2.5 mg/dL
Urine Protein 
Urine dipstick for proteinuria ≤ 2 g (within 
14 days prior to initiation of study treatment) 
Patients discovered to have >2+ proteinuria 
on dipstick urinalysis at baseline should 
undergo a 24-hour urine collection and must 
demonstrate < 1 g of protein in 24 hours.
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT)
≤ 1.5 X ULN  
Calcium-Subjects with uncontrolled or symptomatic hypercalcemia are NOT eligible 
Ionized Calcium
< 1.5 mmol/L
Serum Calcium OR 
Corrected serum calcium
< 12 mg/dL OR 
< ULN
 
 
 


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13. Documented virology status of HIV; NOTE: Patients with a positive HIV test at 
screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 
count  200/µL, and have an undetectable viral load.  
 
14. Documented virology status of hepatitis, as confirmed by screening HBV and HCV 
serology test: For patients with active hepatitis B virus (HBV): HBV DNA <500 IU/mL 
obtained within 28 days prior to initiation of study treatment, and Anti-HBV treatment 
(per local standard of care; e.g., entecavir) for a minimum of 14 days prior to study entry 
and willingness to continue treatment for the length of the study. 
 
15. Subjects with chronic infection by HCV who are untreated or who failed previous 
therapies for HCV are allowed on study. In addition, subjects with successful HCV 
treatment (defined as sustained virologic response [SVR] 12 or SVR 24) are allowed as 
long as patients are not actively receiving anti-HCV treatment at the time of study 
enrollment. Investigators can stop anti-HCV treatment at their discretion prior to 
enrolling patients on study. 
 
16. Females of childbearing potential must have a negative serum pregnancy test within 14 
days prior to study treatment. NOTE: Females are considered of child bearing potential 
unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 
consecutive months. 
 
17. Female participants of childbearing potential must be willing to abstain from 
heterosexual intercourse or to use contraception as outlined in Section 5.6. Male 
participants capable of fathering children must be willing to abstain from heterosexual 
intercourse or to use contraception as outlined in Section 5.6. 
 
18. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Have signs of liver failure, e.g. clinically significant ascites, encephalopathy, or variceal 
bleeding within six months from enrollment.  
 
2. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., 
PleurX® are allowed. 
 
3. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or 
high-risk for bleeding. 
 
 
 


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4. Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to 
initiation of study treatment. NOTE: Patients must undergo an 
esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be 
assessed and treated per local standard of care prior to enrollment. Patients who have 
undergone an EGD within 6 months of prior to initiation of study treatment do not need 
to repeat the procedure. 
 
5. Have evidence of excessive hepatopulmonary shunting (> 20% in 99mTc macro-
aggregated albumin scan for resin and 30 Gy per treatment for glass) or angiographically 
demonstrable and non-occludable gastrointestinal shunting, precluding from Y-90 
treatment.  
 
6. Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥ 
150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of ≥ 3 BP 
readings on ≥ 2 sessions. NOTE: Anti-hypertensive therapy to achieve these parameters 
is allowable. 
 
7. Prior history of hypertensive crisis or hypertensive encephalopathy.  
 
8. Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 
months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 
 
9. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 
 
10. Major surgery within 4 weeks prior to registration or anticipation of a major surgical 
procedure during study.  
 
11. Have had prior transplant of any kind (stem cell or solid organ). 
 
12. Have active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis with the following exceptions:  
 Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 
 Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
 Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
 Rash must cover < 10% of body surface area 
 Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 


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 No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months 
 
13. Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with 
organizing pneumonia) drug-induced pneumonitis, or idiopathic pneumonitis, or evidence 
of active pneumonitis on screening chest CT scan. NOTE: History of radiation 
pneumonitis in the radiation field (fibrosis) is permitted. 
 
14. Treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies. 
 
15. Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever 
is longer) prior to initiation of study treatment. 
 
16. Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of 
need for systemic immunosuppressive medication during study treatment, with the 
following exceptions: 
 Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 
hours of corticosteroids for a contrast allergy) are eligible for the study after 
sponsor-investigator confirmation has been obtained. 
 Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study 
 
17. Uncontrolled tumor-related pain 
 Patients requiring pain medication must be on a stable regimen at study entry. 
 Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
 Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
18. Patients with brain metastases. 
 
 
 


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19. Have unresolved toxicities from prior anticancer therapy, defined as having not resolved 
to National Cancer Institute (NCI) CTCAE v5 grade 0 or 1 with the exception of alopecia 
and laboratory values listed per the inclusion criteria.  NOTE: Subjects with irreversible 
toxicity that is not reasonably expected to be exacerbated by any of the investigational 
products may be included (e.g., hearing loss) after consultation with the sponsor-
investigator. 
 
20. Diagnosed or treated for malignancy other than HCC, unless they meet one of the 
following exceptions: 
 Malignancy treated with curative intent and with no known active disease present 
for ≥ 2 years before registration and felt to be at low risk for recurrence by the 
treating physician. 
 Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 Adequately treated cervical carcinoma in situ without evidence of disease. 
 
21. Have a known or suspected allergy to bevacizumab or atezolizumab or known 
hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or bevacizumab formulation. 
 
22. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment.  
 
23. History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior to 
initiation of study treatment. 
 
24. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation). 
 
25. Current or recent (within 10 days of first dose of study treatment) use of aspirin (≥325 
mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 
 
26. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose. NOTE: Prophylactic anticoagulation for the patency of venous 
access devices is allowed provided the activity of the agent results in an INR ≤1.5 x ULN 
and aPTT is within normal limits within 14 days prior to initiation of study treatment. 
 
27. Have an uncontrolled intercurrent illness including, but not limited to any of the 
following: 
 Psychiatric illness/social situations that would limit compliance with study 
requirements 
 Have any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of an investigational drug or that may affect the 


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interpretation of the results or render the patient at high risk from treatment 
complications.  
 Active alcohol use, drug use, or a psychiatric disease that would, in the opinion of 
the sponsor-investigator or a sub-investigator (sub-I), prevent the subject from 
complying with the study protocol and/or endanger the subject during their 
participation in the study. 
 
28. Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia. NOTE: Treatment with therapeutic oral or IV antibiotics within 2 weeks 
prior to initiation of study treatment Patients receiving prophylactic antibiotics (e.g., to 
prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) 
are eligible for the study. 
 
29. Active tuberculosis. 
 
30. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
31. Have received a live attenuated vaccine (e.g., FluMist) within 30 days of the planned 
start of study therapy and 180 days after the last dose of the study treatment. NOTE:  
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
32. Have received or are receiving any investigational therapy within 28 days prior to the 
first dose of bevacizumab and atezolizumab. NOTE: Subjects may be enrolled in an 
observational (non-interventional) clinical study or in the follow-up period of an 
interventional study. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. Subjects 
must be registered and randomized prior to starting protocol therapy. Subjects will sign consent 
and undergo screening for study. Subjects must be eligible for TARE to participate in this 
clinical trial with radiology imaging confirming FLR of ≥ 40%. Subjects must have archival 
tissue (obtained within the previous 6 months) to be eligible for the trial. Treatment should start 
within 14 business days of randomization. 
 
4.1 
Randomization  
Subjects will be randomized with 1:1 ratio to Arm A (Y-90 TARE) or Arm B (Y-90 TARE + 
bevacizumab + atezolizumab).  
 
4.2 
Stratification 
The study will stratify for: 
 AFP level  
o High ≥ 400 


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o Low < 400  
 Presence or absence of vascular invasion 
 
5. 
TREATMENT PLAN 
This is an open-label, multi-center, randomized phase II study of combination therapy with Y-90 
TARE, bevacizumab, and atezolizumab versus Y-90 TARE alone in patients with advanced 
HCC. Subjects will be randomized to Y-90 TARE alone (Arm A) or Y-90 TARE followed by 
the combination of atezolizumab and bevacizumab (Arm B). Subjects randomized to receive 
bevacizumab and atezolizumab (Arm B) will start the combination of bevacizumab and 
atezolizumab 4 weeks (± 1 week) after TARE treatment.  
 
Full recovery from the procedure is required prior to systemic treatment:  
 AST and ALT ≤ 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL 
 Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, and 
abdominal pain) have resolved to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 Grade 1  
 No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events, 
hepatorenal syndrome) during or after the TARE procedure. 
 
Arm B subjects will continue the study drugs for a total of 24 months from the TARE treatment, 
until intolerable toxicity or disease progression occur.  
 
 
 
 
 


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5.1 
Safety Cohort 
A safety cohort of 10 subjects randomized to Arm B (Y-90 TARE + bevacizumab + 
atezolizumab) will be assessed for safety after two cycles. Accrual will be halted during this 
review. Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to TARE in 
combination with bevacizumab and atezolizumab will be reviewed (specifically, toxicities 
beyond those from TARE or the combination of bevacizumab and atezolizumab treatment when 
used independent to each other). If there are no Grade ≥ 3 unexpected toxicities; possibly, 
probably or definitely related to TARE in combination with bevacizumab and atezolizumab the 
combination will be deemed safe and accrual will resume. The decision to resume accrual will be 
made by the DSMC and sponsor-investigator. Each toxicity meeting the outlined criteria will be 
reviewed as a separate event.  
 
Toxicities will be graded based on the CTCAE criteria v5. Adverse events will be 
recorded/reported as outlined in Section 11 regardless of the way in which the information was 
obtained (email, virtual visit, in person). Adverse event information will be provided to the 
sponsor-investigator on a weekly basis. If at any time an AE meeting the criteria outlined above 
occurs during enrollment in the safety cohort, accrual will be halted until the sponsor-
investigator or designee reviews the event and determines that accrual can resume. 
 
5.2 
Y-90 TARE Administration (Arm A and Arm B) 
All subjects will receive Y-90 TARE. Institutional standards will be utilized for Y-90 TARE 
preparation and administration. A comprehensive plan will be made for each patient’s liver-
targeted therapy; this plan will involve treating the predominant liver lesions with segment Y-90 
TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is 
estimated by excluding the liver volume of Y-90 infused distribution).  
 
The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if 
segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 
TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 
TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to 
treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver 
function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass 
microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 
Gy should be used for resin microspheres. 
 
5.3 
Study Drug(s) Administration (Arm B) 
Subjects randomized to Arm B will receive atezolizumab and bevacizumab as intravenous 
infusions (IV) at least 4 weeks (± 1 week) after completion of Y-90 TARE. Atezolizumab will 
be administered first followed by bevacizumab. The study drug administration will be 
captured in “cycles” of study treatment. Each cycle lasts 3 weeks. A window of ± 3 days will be 
applied to all study visits/study drug administration. All dates/times of study treatment will be 
documented in the EDC system. Institutional standards may be used for study treatment 
administration (including dosing based on weight changes) and where applicable the 
investigator’s brochure can provide detailed information regarding study drug administration.   
 
 
 


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5.3.1 Bevacizumab Administration 
Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle. The 
initial dose will be delivered over 90 minutes (±15 minutes) at least 4 weeks (± 1 week) after Y-
90 TARE.  If the first infusion is tolerated without infusion associated adverse events (fever 
and/or chills), the second infusion may be delivered over 60 minutes (±10 minutes).  If the 60 
minute infusion is well tolerated, all subsequent infusions may be delivered over 30 minutes 
(±10 minutes).   
 
If a subject experiences an infusion–associated adverse event, he or she may be premedicated for 
the next study drug infusion; however, the infusion time may not be decreased for the subsequent 
infusion.  If the next infusion is well tolerated with premedication, the subsequent infusion time 
may then be decreased by 30 minutes (±10 minutes) as long as the subject continues to be 
premedicated.  If a subject experiences an infusion associated adverse event with the 60 minute 
infusion, all subsequent doses should be given over 90 minutes (±10 minutes).  Similarly, if a 
subject experiences an infusion associated adverse event with the 30 minute infusion, all 
subsequent doses should be given over 60 minutes (±10 minutes). 
 
5.3.2 Atezolizumab Administration  
Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 
weeks). The initial dose will be delivered over 60 (± 15) minutes. If the first infusion is tolerated, 
all subsequent infusions may be delivered over 30 minutes. Atezolizumab infusions instructions 
outlined in Appendix A. 
 
No premedication is indicated for the administration of the first treatment of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with the first treatment of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
5.4 
Standard of Care Medications 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated, per local standard practice. 
 
5.5 
Concomitant Medications for Atezolizumab 
 
5.5.1 Allowed Concomitant Medications with Atezolizumab 
Patients are permitted to use the following therapies during the study: 
 Oral contraceptives 
 Hormone-replacement therapy 
 Inactivated influenza vaccinations 
 Megestrol acetate administered as an appetite stimulant  
 Mineralocorticoids (e.g., fludrocortisone) 
 Corticosteroids administered for COPD or asthma 
 Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency (ie, prednisone 10 mg or equivalent)  
 


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Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
second and subsequent atezolizumab infusions only, at the discretion of the investigator. 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated, per local standard practice.  Patients who experience infusion-associated symptoms 
may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard 
practice.  Serious infusion associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 
managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists; see above for infusion reaction guidelines. 
 
5.5.2 Cautionary Therapy for Atezolizumab-Treated Patients 
 
5.5.2.1 
Corticosteroids and Tumor Necrosis Factor- Inhibitors 
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab.  Therefore, in situations in which systemic 
corticosteroids or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic corticosteroids 
and TNF- inhibitors may be administered at the discretion of the investigator.  
 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the treatment 
of specific adverse events when associated with atezolizumab therapy (refer to the Atezolizumab 
Investigator's Brochure for details). 
   
5.5.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety 
profiles, and potential drug-drug interactions are generally unknown.  However, herbal therapies 
not intended for the treatment of cancer may be used during the study at the discretion of the 
investigator. 
 
5.5.3 Prohibited Therapy for Atezolizumab 
 Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether health authorityapproved or experimental, is prohibited for various time periods 
prior to starting study treatment, depending on the agent, and during study treatment, 
until disease progression is documented and the patient has discontinued study treatment, 
with the exception of palliative radiotherapy and local therapy under certain 
circumstances. 
 Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation 
of study treatment, during treatment with atezolizumab, and for 5 months after the last 
dose of atezolizumab. 
 Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) 
are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination with 
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 Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during 
study treatment because these agents could potentially alter the efficacy and safety of 
atezolizumab. 
 
5.6 
Reproductive Information 
Participants of childbearing potential who are sexually active and their partners must agree to (1) 
abstain from heterosexual intercourse or (2) use 2 forms of contraception: two barrier methods, 
or a barrier method plus a hormonal method.  
 
5.6.1 Subjects randomized to the experimental arm  
Female participants of child-bearing potential that are sexually active with a male capable of 
fathering children must agree to use contraception from the time of informed consent, during the 
study and for 180 days after the last dose of study drug(s). Male participants capable of fathering 
children that sexually active with a female of child-bearing potential must agree to use 
contraception from the time of informed consent, during the study and for 180 days after the last 
dose of study drug(s). This timeframe is also applicable to breast feeding and sperm donation. 
 
5.6.2 Subjects randomized to the control arm 
Female participants of child-bearing potential must agree to use contraception from the time of 
informed consent and for 60 days after TARE procedure. Male participants must agree to use 
contraception from the time of informed consent, during the study and for 60 days after the 
TARE procedure. This timeframe is also applicable to breast feeding and sperm donation. 
 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations.   
 
6.1 
Dose Delays/Dose Modifications 
Unless otherwise noted in the dose modification tables in the Appendix A and B, treatment 
(bevacizumab and atezolizumab) may be delayed ≤ 12 weeks from the expected day of the next 
treatment for any reason. Patient will continue to receive scans on schedule. If bevacizumab and 
atezolizumab treatment has to be put on hold, as long as the treatment hold is ≤ 12 weeks from 
the expected day of the next treatment, patient may resume therapy without making up any 
doses.  
 
6.2 
Dose Levels for Dose Reductions 
There is no dose reduction for either bevacizumab or atezolizumab. 
 
 
 


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6.3 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
 Documented disease progression per RECIST 1.1; NOTE: patient can continue treatment 
beyond image progression if there is no intolerable toxicity, no clinical decline, until 
confirmation of disease progression at the next scheduled scan or scan sooner than 
scheduled scan but at least 4 weeks from the previous scan.  
 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
 
Female subject becomes pregnant  
 
Protocol therapy is interrupted for > 12weeks  
 
6.4 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


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7. 
STUDY CALENDAR & EVALUATIONS 
 
7.1 
Arm A Calendar (Control) 
 
Study Evaluation  
 
Screening 
Pre-TARE 
TARE 
Safety follow up visit9 
Long-term Follow up10 
-28 days 
- 14 days 
30 days post TARE 
± 7 days 
Every 3 months 
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History1 
X
Physical Exam
X
X
Vital signs and ECOG Performance Status2 
X
X
Angiography3 
X
X
TARE Mapping3 
X
AEs & concomitant medications
X
X
PRO instrument11 
X11 
X11 
X11 
X11 
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X
X
X4
Comprehensive Metabolic Profile (CMP)
X
X
X4 
PT/INR and aPTT4 
X
 
Thyroid Function Testing4 
X
HIV, Hepatitis B and C testing4 
X
Pregnancy test (serum or urine) (WOCBP)4 
X
Urine protein4 
X
DISEASE ASSESSMENT 
CT of chest5 
X
 
X5 
MRI or CT of abdomen and pelvis5 
X
 
X5 
Brain or Bone Scan5
Done ONLY if clinically indicated  
RECIST 1.1 and mRECIST evaluations5 
X
X5 
TREATMENT EXPOSURE 
TARE6 
X
CORRELATIVE STUDIES SPECIMEN COLLECTION 
Archival Tumor Tissue7 
X
Blood Samples8 
X8 
X
X8 
BANKING SAMPLES 
Tissue12 
X


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Study Evaluation  
 
Screening 
Pre-TARE 
TARE 
Safety follow up visit9 
Long-term Follow up10 
-28 days 
- 14 days 
30 days post TARE 
± 7 days 
Every 3 months 
(±14 days) 
Blood12 
X
X
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase  
 
Key to Footnotes  
1: Medical History; other data to be obtained during this assessment includes a smoking history questionnaire and trial awareness question.  In 
addition, prior anti-cancer treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.  
If prior genomic results are available those are required for EDC entry. Diagnosis and staging to include pathology report and TNM staging 
documentation (date of first biopsy and date of first radiology imaging to be included). AJCC staging manual v8 will be utilized. 
 
2: Vital signs to include temperature, pulse, respirations, blood pressure weight, and height (screening only) and ECOG performance status.   
 
3: Angiography will be used to confirm FLR ≥ 40%. If FLR is < 40% the subject is not eligible for the study. Angiography will also be done prior 
to the TARE treatment. A window of -14 days for TARE mapping may be applied. Both the lung dose threshold and FLR values must be obtained 
and available in source documentation. 
 
4: PT/aPTT/INR will be performed at screening. After screening, monitoring of PT/aPTT/INR is at the investigator’s discretion. Thyroid Function 
testing should be performed at screening then as clinically indicated. TSH will be obtained. T4 and T3 including free versus total testing is at the 
discretion of the site investigator. HIV and Hepatitis testing required at screening. Women of childbearing potential (WOCBP) will have a urine or 
serum βhCG performed if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  Testing is required within 14 days prior to initiation of study treatment. Urine protein will be obtained within 14 days prior to 
treatment initiation. During long term follow up, the type and frequency of laboratory monitoring should be done per standard of care. 
 
 
 


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5: Tumor response assessment will consist of evaluation by MRI (preferred) or CT (triple phase CT scan with a liver protocol) of abdomen and 
pelvis at screening then every 3 months and CT scan of the chest every 6 months (imaging selected for each subject should remain the same 
throughout the study). If tumor assessments are available for subjects who have not yet experienced progressive disease (PD) after TARE 
treatment, the follow-up tumor evaluations will be documented in the eCRF.  Brain or Bone scans should be performed ONLY if clinically 
indicated at investigator’s discretion. CT/MRI image scans may be submitted for central analysis once funding is available. Images will be de-
identified prior to sending to a central location. Window of ± 7 days for radiology imaging is allowed. Disease assessment per RECIST 1.1 and 
mRECIST will be done based on radiology imaging performed (abdomen/pelvis ± chest CT/MRI) at the disease assessment timepoints previously 
described. These results will be captured in the EDC system.  
 
6: Details regarding treatment administration can be found in Section 5. 
 
7: Archival tissue from a biopsy obtained in the last 6 months is required. Archival tissue will be identified at screening and shipped by the day of 
TARE treatment. If archival tissue is not available, the subject is not eligible for the trial. Any leftover samples after protocol specified testing 
complete will be banked for future unspecified cancer related research after subject consent obtained. 
 
8: Whole blood, plasma, serum and buffy coat samples will be collected (1) after consent, during screening or day of TARE treatment prior to 
procedure, (2) 4 weeks after TARE during safety follow up visit, (3) 12 weeks after TARE treatment during long term follow up, and (4) at 
progression. All blood samples are required. Any leftover samples after protocol specified testing complete will be banked for future unspecified 
cancer related research after subject consent obtained. 
 
9: Safety Follow Up: The safety follow-up visit should be performed 30 days (± 7 days) after TARE. Subjects who have an ongoing Grade ≥ 2 or 
serious AE (SAE) at this visit will continue to be monitored by a member of the study team until the event is resolved, stabilized, determined to be 
irreversible by the site investigator or a new anti-cancer treatment starts, whichever occurs earlier.  
 
10: Long Term Follow Up: Subjects will have tumor response assessment consisting of evaluation by MRI (preferred) or CT (triple phase CT scan 
with a liver protocol) of abdomen and pelvis every 3 months and CT scan of the chest every 6 months (imaging selected for each subject should 
remain the same throughout the study) for up to 3 years until progression, initiating a new cancer treatment, withdrawing consent or becoming lost 
to follow-up. The scan interval may be reset if scans were done sooner for clinical reasons. This imaging may be done locally. Once disease 
progression is documented, subjects will be followed for survival every 6 months for 5 years from the time of documented progression. Follow up 
may be accomplished via clinic visit, phone call, or other avenues as appropriate. Information regarding scans and lab results should be obtained if 
available. Information regarding scans and lab results should be obtained if available. A window of ± 14 days will be applied to follow up.  
 
11: The EORTC fit-for-purpose instrument will be completed after consent, during screening or day of TARE treatment prior to procedure then at 
the D30 safety visit (4 weeks after TARE) then every 3 months for 1 year to coincide with radiology imaging if possible. The instrument should be 
completed prior to any other assessment(s) at the clinical site. Study personnel should review the instrument for completeness before the patient 
leaves the investigational site. The PRO instrument may be completed at the investigational site or be administered via telephone calls. 


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12: All banking samples are optional. Whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. Serum and plasma for banking 
are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Safety Follow up visit. Submission of unstained slides for banking from an 
archived FFPE tumor block (if available). See CLM for collection, labeling, and shipping instructions. Subjects will also be consented for optional 
storage of any remaining tissue/blood samples after protocol-specified studies are complete. These samples will be stored for future unspecified 
cancer-related research and are considered “banking samples”. 
 
 
 


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7.2 
Arm B Calendar  
 
Study Evaluation  
Cycle = 21 days 
Screening 
Pre-TARE 
TARE 
On Treatment 
Cycle 1-n 
Safety follow up 
visit9 
Long-term  
Follow up10 
-28 days 
- 14 
Days 
Day 1 
± 3 days 
30 days  
post last dose  
± 7 days
Every 3 months 
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History1 
X
Physical Exam
X
X
X
Vital signs and ECOG Performance Status2 
X
X
X
Angiography3 
X3 
X
TARE Mapping3 
X3 
AEs & concomitant medications
X
X
X
PRO instrument11 
X
X11 
X11 
 
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X
X
X
X4
Comprehensive Metabolic Profile (CMP)
X
X
X
X4 
PT/INR and aPTT4 
X
 
Thyroid Function Testing4 
X
X4 
HIV, Hepatitis B and C testing4 
X
Pregnancy test (serum or urine) (WOCBP)4 
X
Urine protein4 
X
X4 
DISEASE ASSESSMENT 
CT of chest5 
X
X5 
 
X5 
MRI or CT of abdomen and pelvis5 
X
X5 
 
X5 
Brain or Bone Scan5 
Done ONLY if clinically indicated
RECIST 1.1 and mRECIST Evaluations5 
X
X5
X5
TREATMENT EXPOSURE 
TARE6 
X
Bevacizumab and Atezolizumab6 
X
CORRELATIVE STUDIES SPECIMEN COLLECTION 
Archival Tumor Tissue7 
X
Fresh Tissue7 
X7 
Blood Samples8 
X8 
X8 
X8 
BANKING SAMPLES 
Tissue12 
X


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Study Evaluation  
Cycle = 21 days 
Screening 
Pre-TARE 
TARE 
On Treatment 
Cycle 1-n 
Safety follow up 
visit9 
Long-term  
Follow up10 
-28 days 
- 14 
Days 
Day 1 
± 3 days 
30 days  
post last dose  
± 7 days
Every 3 months 
(±14 days) 
Blood12 
X
X
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase  
 
Key to Footnotes  
 
1: Medical History; other data to be obtained during this assessment includes a smoking history questionnaire and trial awareness question.  In 
addition, prior anti-cancer treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.  
If prior genomic results are available those are required for EDC entry. Diagnosis and staging to include pathology report and TNM staging 
documentation (date of first biopsy and date of first radiology imaging to be included). AJCC staging manual v8 will be utilized. 
 
2: Vital signs to include temperature, pulse, respirations, blood pressure weight, and height (screening only) and ECOG performance status.   
 
3: Angiography will be used to confirm FLR ≥ 40%. If FLR is < 40% the subject is not eligible for the study. Angiography will also be done prior 
to the TARE treatment. A window of 7-14 days for TARE mapping may be applied. Both the lung dose threshold and FLR values must be 
obtained and available in source documentation. 
 
4: PT/aPTT/INR will be performed at screening. After screening, monitoring of PT/aPTT/INR is at the investigator’s discretion. Thyroid Function 
testing should be performed at screening then every 3 cycles. TSH will be obtained. T4 and T3 including free versus total testing is at the 
discretion of the site investigator. HIV and Hepatitis testing is required at screening. Women of childbearing potential (WOCBP) will have a urine 
or serum βhCG performed if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.  Testing is required within 14 days prior to the initiation of study treatment. Urine protein will be obtained within 14 days 
prior to treatment initiation then Day 1 of each Cycle. During long term follow up, the type and frequency of laboratory monitoring should be done 
per standard of care. 
 
 
 


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5: Tumor response assessment will consist of evaluation by MRI (preferred) or CT (triple phase CT scan with a liver protocol) of abdomen and 
pelvis at screening then every 3 months and CT scan of the chest every 6 months (imaging selected for each subject should remain the same 
throughout the study) while subjects are on treatment. If tumor assessments are available for subjects who have not yet experienced progressive 
disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented in the eCRF.  Brain or Bone scans should 
be performed ONLY if clinically indicated at investigator’s discretion. CT/MRI image scans may be submitted for central analysis once funding is 
available. Images will be de-identified prior to sending to a central location. Window of ± 7 days for radiology imaging is allowed. Disease 
assessment per RECIST 1.1 and mRECIST will be done based on radiology imaging performed (abdomen/pelvis ± chest CT/MRI) at the disease 
assessment timepoints previously described. These results will be captured in the EDC system.  
 
6: Details regarding treatment administration can be found in Section 5. 
 
7: Archival tissue from a biopsy obtained in the last 6 months is required. Archival tissue will be identified at screening and shipped by the day of 
TARE treatment. If archival tissue is not available, the subject is not eligible. A biopsy will be obtained at progression. If a patient discontinues 
study due to progression, the progression sample may be collected at the D30 safety visit. This biopsy is required. Any leftover samples after 
protocol specified testing complete will be banked for future unspecified cancer related research after subject consent obtained. 
 
8: Whole blood, plasma, serum and buffy coat samples will be collected (1) after consent, during screening or day of TARE treatment prior to 
procedure, (2) prior to treatment C1D1, (3) prior to treatment C5D1, (4) and at progression (may be performed at the D30 safety visit for those 
subjects discontinuing study treatment due to progression). All blood samples are required. Any leftover samples after protocol specified testing 
complete will be banked for future unspecified cancer related research after subject consent obtained. 
 
9: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons and 
should be performed 30 days (± 7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 2 or serious AE (SAE) at this visit 
will continue to be monitored by a member of the study team until the event is resolved, stabilized, determined to be irreversible by the site 
investigator or a new anti-cancer treatment starts, whichever occurs earlier.  
 
10: Long Term Follow Up: Subjects who discontinue for reasons other than progressive disease, will have tumor response assessment consisting 
of evaluation by MRI (preferred) or CT (triple phase CT scan with a liver protocol) of abdomen and pelvis every 3 months and CT scan of the 
chest every 6 months (imaging selected for each subject should remain the same throughout the study) for up to 3 years until progression, initiating 
a new cancer treatment, withdrawing consent or becoming lost to follow-up. The scan interval may be reset if scans were done sooner for clinical 
reasons. This imaging may be done locally. Once disease progression is documented, subjects will be followed for survival every 6 months for 5 
years from the time of documented progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
Information regarding scans and lab results should be obtained if available. A window of ± 14 days will be applied to follow up.  
 
 
 


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11: The EORTC fit-for-purpose instrument will be completed after consent, during screening or day of TARE treatment prior to procedure, C1D1, 
every 4 cycles thereafter starting with Cycle 4 and at the D30 safety visit. The instrument should be completed prior to administration of study 
drug and prior to any other study assessment(s) at the clinical site. Study personnel should review the instrument for completeness before the 
patient leaves the investigational site. The PRO instrument may be completed at the investigational site or be administered via telephone calls. 
 
12: All banking samples are optional. Whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. Serum and plasma for banking 
are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Safety Follow up visit. Submission of unstained slides for banking from an 
archived FFPE tumor block (if available). See CLM for collection, labeling, and shipping instructions. Subjects will also be consented for optional 
storage of any remaining tissue/blood samples after protocol-specified studies are complete. These samples will be stored for future unspecified 
cancer-related research and are considered “banking samples”. 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please see the Correlative Laboratory Manual (CLM) for additional details regarding correlatives 
for this study. 
 
8.1 
Tissue 
We propose examination of the role of immunoscore and PD-L1 expression in the prediction of 
improved clinical outcome in patients receiving Y-90 TARE and bevacizumab plus atezolizumab 
treatment. Immunoscore and PD-L1 expression in addition to other protein biomarkers will be 
measured in HCC biopsies. In addition, immune-inhibitory proteins including B7H3, B7H4, 
indoleamine 2,3-dioxygenase (IDO), and arginase will be evaluated as predictors of effectiveness 
of Y-90 TARE and bevacizumab plus atezolizumab combination therapy and mechanisms of 
resistance to the study treatment.   
 
8.1.1 Archival Tissue 
Archival tissue obtained in the last 6 months is required. Archival tissue will be identified at 
screening and shipped by the day of TARE treatment. If archival tissue is unavailable, the 
subject is not eligible. 
 
8.1.2 Fresh Tissue 
A biopsy will be obtained at progression for subjects on Arm B (experimental Arm). This sample 
is required. 
 
8.2 
Peripheral Blood Samples 
Peripheral blood samples will be collected to study methylation patterns, germline testing, buffy 
coat and circulating tumor DNA. Whole blood, serum, plasma and buffy coat will be collected. 
All blood samples are required. 
 
8.2.1 Whole Blood 
Whole blood samples will be collected (1) after consent, during screening or day of TARE 
treatment prior to procedure, (2) 4 weeks post TARE during safety follow up visit (Arm A) or 
prior to Cycle 1 Day 1 (Arm B), (3) 12 weeks post TARE (Arm A) or prior to Cycle 5 Day 1 
(Arm B) and (4) at progression (may be performed at the D30 safety visit for those subjects 
discontinuing study treatment due to progression). Whole blood samples will support germline 
and methylation pattern testing.  
 
8.2.2 Plasma 
Plasma samples will be collected (1) ) after consent, during screening or day of TARE treatment 
prior to procedure, (2) 4 weeks post TARE during safety follow up visit (Arm A) or prior to 
Cycle 1 Day 1 (Arm B), (3) 12 weeks post TARE (Arm A) or prior to Cycle 5 Day 1 (Arm B) 
and (4) at progression (may be performed at the D30 safety visit for those subjects discontinuing 
study treatment due to progression). Plasma samples will support circulating tumor DNA 
analysis. 
 
 
 


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8.3 
Genetic Testing 
Participants will be given information as part of the informed consent process that samples will 
be used for research purposes that will include genetic testing. The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may 
or may not already be aware. In the case where an incidental genetic finding is identified, the 
sponsor investigator of this project will be notified. Possible decisions for handling incidental 
findings may include notification of the participant (and provider); recommendation for genetic 
counseling, which may or may not include genetic testing (e.g., if the finding was not done in a 
CLIA certified laboratory); or, neither. In general, a member of the participant’s treating team 
will be given the information to help with notification. In all cases, the current policy of 
Georgetown University and local/participating site IRBs, as applicable, will be followed. Any 
additional approvals that may be required prior to participant notification will be secured in 
advance. 
 
8.4 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN) will manage the banked 
samples. Samples will be coded and banked indefinitely in the Hoosier Cancer Research 
Network Biorepository and used for future unspecified cancer-related research.  
 
8.5 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified cancer 
related research. HCRN will manage the banked samples. Samples will be coded and banked 
indefinitely in the HCRN Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to 
treatment on Cycle 1 Day 1 and at the 30-day Safety Follow-up visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to 
treatment on Cycle 1 Day 1 and at the 30-day Safety Follow-up visit. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin 
fixed paraffin embedded tumor sample.  
 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions. 
 
8.6 
Confidentiality of Biospecimens 
Samples will be identified by the subject’s study number assigned at the time of registration to 
the trial. Any material issued to collaborating researchers will be anonymized and only identified 
by the subject’s study number. 
 
 
 


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9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Measurability of Tumor Lesions at baseline 
 
9.1.1 RECIST 1.1 measurable lesions at baseline 
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis diameter for lymph node lesions with IV contrast 
enhanced CT or MRI and that is suitable for accurate repeated measurements. Please see 
additional mRECIST guidance below on measurability of intrahepatic HCC lesions and portal 
hepatis lymph nodes. 
 
The short axis is defined as the longest in-plane axis perpendicular to long axis 
 
9.1.2 mRECIST measurable lesions at baseline 
Typical and atypical intrahepatic, and extrahepatic measurable HCC lesions are defined as 
follows: 
 Typical measurable intrahepatic lesions by mRECIST are liver lesions that show typical 
features of HCC on IV contrast-enhanced CT or MRI scans, ie, hypervascularity in the 
arterial phase with wash-out in the portal or the late venous phase, and the viable, non-
necrotic portion (arterial phase IV contrast-enhancing) can be accurately measured at 
baseline as ≥10 mm in the longest diameter. 
 Atypical measurable intrahepatic lesions are liver lesions that do not show typical 
features of HCC on contrast-enhanced CT or MRI studies (ie, lack hypervascularity in the 
arterial phase with wash-out in the portal or late venous phase), and are well delineated, 
can be considered measurable lesions if the entire tumor measured in the portal venous 
phase is ≥10 mm in the longest diameter. Well-delineated atypical intrahepatic lesions are 
measured as RECIST 1.1 non-nodal lesions, with the entire tumor dimension (whether 
necrotic or viable) included in the measurement (similar to a RECIST 1.1 measure of a 
non-nodal lesion). 
 Extrahepatic measurable lesions include all other lesions thought to be part of the HCC 
burden, and are considered to be measurable lesions if ≥10 mm in the long axis diameter 
for non-nodal lesions or ≥15 mm in the short axis diameter for lymph node lesions as per 
standard RECIST 1.1 criteria where the entire tumor dimension is measured in the 
delayed phase of IV contrast-enhancement. One exception exists for mRECIST: lymph 
nodes detected at the porta hepatis can be considered malignant and measurable if the 
lymph node short axis diameter is at least 20 mm. 
 
9.1.3 Non-measurable lesions at baseline 
 Truly non-measurable lesions include the following: 
o Bone lesions (see exception below for soft tissue component) 
o Leptomeningeal disease 
o Ascites, pleural, or pericardial effusion 
o Inflammatory breast disease 
o Lymphangitic involvement of skin or lung 
 All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline3). 


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 Previously irradiated lesions 
 Brain metastasis 
 
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not 
be recorded or followed as NTLs. 
 
Localized post-radiation changes which affect lesion sizes may occur. Therefore, lesions that 
have been previously irradiated are typically considered non-measurable and as NTL at baseline 
and followed up as part of the NTL assessment. 
 
9.1.4 Special considerations regarding lesion measurability at baseline 
 Bone lesions 
o Bone scan, PET scan or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
o Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. 
o Blastic bone lesions are considered non-measurable. 
 Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same patient, these should be selected over cystic 
lesions as TLs. 
 
9.1.5 Special considerations for mRECIST in HCC regarding lesion measurability at 
baseline 
 Infiltrative type and diffuse type liver HCC where the lesions are ill-defined (poorly 
demarcated) and not suitable for repeat measurements will be considered non- 
measurable. 
 Portal vein thrombosis. Malignant portal vein thrombosis should be considered a 
nonmeasurable lesion due to the difficulty in performing consistent measurements of the 
malignant thrombus during the course of the treatment. Measurements of the extent of 
the malignant thrombus may be impaired by the possible presence of a bland component 
of the thrombosis. 
 Porta hepatis lymph node. Lymph nodes detected at the porta hepatis can be considered 
as malignant if the lymph node short axis diameter is at least 20 mm. Evidence of 
reactive lymph nodes at the porta hepatis, in fact, is a common finding in patients with 
cirrhosis regardless of the presence of an HCC. The short axis diameter of the node is 
used to judge if a node is involved by solid tumor. 
 
9.1.6 RECIST 1.1 Target Lesion selection at baseline 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
identified as TLs at baseline. TLs should be selected on the basis of their size (longest diameter 
for non-nodal lesions or short axis diameter for nodal lesions), but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 


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occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected. 
 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph node locations as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ. 
 
The site and location of each TL should be documented as well as the longest axis diameter for 
non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline the sum of the diameters for all TL will be calculated and 
reported as the baseline sum of diameters. At follow-up visits the sum of diameters for all TL 
will be calculated and reported as the follow-up sum of diameters. 
 
9.1.7 mRECIST Target Lesion selection at baseline 
As in RECIST 1.1, mRECIST allows a maximum of 5 measurable lesions, with a maximum of 2 
lesions per organ, identified as TLs at baseline. In HCC, liver lesions should be prioritized as 
TLs over measurable lesions in other organs. Up to 2 HCC liver lesions may be chosen as 
mRECIST TLs at baseline, and these lesions can include typical or atypical, well-delineated, 
measurable intrahepatic lesions (described above). Preference as choice of liver TL should be 
given to typical as opposed to atypical intrahepatic target lesions if both are present. An 
infiltrative-type HCC liver lesion should be considered as a NTL when the mass shows ill-
defined borders and therefore does not appear to be suitable for accurate and repeat 
measurements. 
 
HCC lesions previously treated with locoregional or systemic treatments may or may not be 
considered as suitable to be selected as target lesions for mRECIST. If the lesion shows a well-
delineated area of viable tumor (IV contrast enhancement in the arterial phase with later 
washout) that is at least 10mm in longest diameter, then it can be selected as a target lesion. In 
contrast, if the lesion is poorly demarcated or exhibits atypical enhancement as a result of the 
previous intervention, then it cannot be selected as a TL for mRECIST. 
 
9.1.8 Special cases for Target Lesion assessment at baseline 
 For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 
 When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non- nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter. 
 If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
 
 
 


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9.1.9 RECIST 1.1 Non-Target Lesion selection at baseline 
All other lesions, including non-measurable lesions and surplus measurable lesions not recorded 
as TLs should be identified as NTLs at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 
9.1.10 mRECIST Non-Target Lesion selection at baseline 
NTL selection at baseline is fundamentally identical between RECIST 1.1 and mRECIST with a 
few exceptions on intrahepatic HCC lesions: Infiltrative-type HCC should be considered as an 
NTL when the mass shows ill-defined borders and therefore does not appear to be suitable for 
accurate and repeat measurements. HCC lesions previously treated with locoregional or systemic 
treatments may or may not be considered as suitable to be selected as target lesions for 
mRECIST: If the lesion shows a well-delineated area of viable tumor (contrast enhancement in 
the arterial phase) that is at least 10 mm in longest diameter, then it can be selected as a target 
lesion. In contrast, if the lesion is poorly demarcated or exhibits atypical enhancement as a result 
of the previous intervention, then it cannot be selected as a TL for mRECIST and should be 
considered as an NTL. 
 
9.2 
Evaluation of tumor response and progression 
 
9.2.1 RECIST 1.1 Target Lesion assessment at follow-up 
This section defines the criteria used to determine objective tumor visit response for RECIST 
1.1-defined TLs. The imaging modality, location, and scan date of each TL identified previously 
at baseline should be documented at follow-up visits with the long axis diameter for non-nodal 
lesions or short axis diameter for lymph node lesions. All measurements should be recorded in 
millimeters. The sum of the diameters for all TL at each follow-up visit will be compared to the 
baseline sum of diameters (for response or stable disease) or to the smallest prior (nadir) sum of 
diameters (for progression). 
 
9.2.2 Special cases for Target Lesion assessment at follow-up 
 If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL. 
 If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 
 If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter. 
 If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm. 
 If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion. The choice of ‘Too large to measure’ in the case report form will 
trigger an overall visit response of PD. 
 
 


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 When a TL has had an intervention, the following apply: 
o Target Lesion Intervention may include radiotherapy, embolization, excisional 
biopsy, surgery, etc. that is not a part of study treatment and might adversely 
affect the size of that Target lesion 
o If an Intervention on a Target Lesion is ticked in the case report form, the 
diameter of the lesion is still recorded (0mm if no longer present) and is included 
in the sum of diameters. 
o If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that Target lesion. 
o If a Target Lesion has an Intervention, the only Overall Visit Responses allowed 
to be recorded by the Investigator are NE or PD, with PD if the sum of diameters 
exceeds a 20% increase and at least a 5mm absolute increase in the visit sum of 
diameters compared to the previous minimum (nadir) sum of diameters. 
o No visit with a recorded Target Lesion Intervention can be used as the minimum 
(nadir) sum of diameters 
 
9.2.3 mRECIST evaluation of Target Lesions for HCC 
 
Complete response (CR)                Disappearance of any intratumoral arterial enhancement in all  
typical intrahepatic target lesions, and complete disappearance of 
all atypical intrahepatic lesions, and complete disappearance of all 
extrahepatic lesions, and absence of any new unequivocal lesions, 
and any pathological lymph nodes selected as TLs must have a 
reduction in short axis diameter to <10 mm (including porta 
hepatis nodes). 
Partial response (PR)                      A combined decrease of at least 30% in the sum of diameters of 
viable tissue (contrast-enhancement in the arterial phase) for 
typical intrahepatic target lesions, the long axis diameters for 
atypical intrahepatic and all extrahepatic non-nodal target lesions, 
and short axis diameters for extrahepatic nodal lesions, taking as 
reference the baseline sum of diameters of target lesions. 
Stable disease (SD)                         Neither sufficient decrease in sum of diameters to qualify for PR 
nor sufficient increase to qualify for PD 
Progression of disease (PD)           A combined increase of ≥20% in the sum of diameters based on 
the longest diameters of viable (enhancing) tissue in typical 
intrahepatic target lesions, the longest diameter of atypical 
intrahepatic target lesions potentially containing necrotic and 
non-necrotic areas, the longest diameter of all extrahepatic 
non-nodal target lesions, and short axis diameters for extrahepatic 
nodal lesions, taking into reference the smallest previous sum of 
diameters (nadir) including the baseline sum if that is the 
smallest. The sum of diameters must also demonstrate an absolute 
increase of at least 5 mm from nadir. 
Not evaluable (NE)                        Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (eg, missing anatomy, poor image quality) or had a 
lesion intervention at this visit. Note: If the sum of diameters 
without unevaluable TLs meets the PD criteria, PD overrides Not 
Evaluable as a TL response 
 


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The measurement of the longest axis diameter of the viable (arterial enhancing) intrahepatic 
HCC tumor may be challenging in lesions showing partial internal necrosis. The following points 
should be taken into account in such cases: 
 The measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and 
nonenhancing necrotic tissue is the highest. 
 The longest axis diameter of the viable tumor is not necessarily located in the same scan 
plane or vector in which the baseline diameter was measured – a thorough careful 
evaluation of the phased CT or MRI scans is required. 
 The measurement of the viable tumor long axis diameter should not include any major 
intervening areas of necrosis. 
 
9.2.4 RECIST 1.1 Non-Target Lesion assessment at follow-up 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded by 
the Investigator. 
 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or partial 
response in TLs, the overall tumor burden has increased sufficiently to merit unequivocal 
progression by NTLs. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of stable disease (SD) or 
progressive disease (PR) of target disease will therefore be extremely rare. 
 
9.2.5 mRECIST Non-Target Lesion assessment at follow-up 
Assessment of NTLs by mRECIST is virtually identical to RECIST 1.1 with the following 
additional guidance for intrahepatic HCC lesions. This section provides mRECIST definitions of 
the criteria used to determine and record overall response for NTL at the investigational site at 
each follow-up visit 
 
9.2.6 mRECIST evaluation of Non-Target Lesions 
Complete response (CR)                 Disappearance of all extrahepatic non-nodal NTLs, disappearance 
of intratumoral arterial enhancement in typical intrahepatic NTLs, 
complete disappearance of infiltrative intrahepatic NTLs with 
ill-defined borders, and complete disappearance of atypical 
intrahepatic NTLs. All lymph node NTLs must become 
non-pathological in size (<10 mm short axis diameter or <20 mm 
short axis diameter for porta hepatis nodes) to allow CR of NTLs. 
Non CR/non PD                              Persistence of one or more NTL without progression, including 
persistence of intratumoral arterial enhancement in one or more 
typical intrahepatic NTLs. 
Progression (PD)                             Unequivocal progression may be due to an important progression 
in one lesion only or in several or all NTLs, including an 
unequivocal increase in the size of the viable (arterial phase 
enhancing) portion of typical intrahepatic NTLs. 


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Not evaluable (NE)                         Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not evaluable at this visit and the progression 
criteria have not been met. 
 
9.2.7 RECIST 1.1 New Lesion identification at follow-up 
Details including the imaging modality, the date of scan, and the location of any NLs will be 
recorded in the case report form. The presence of 1 or more NLs is assessed as progression. The 
finding of an NL should be unequivocal: ie, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor. If an 
NL is equivocal, for example because of its small size, the treatment and tumor assessments 
should be continued until the previously (pre-existing) new lesion has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the date 
of the initial scan when the NL first appeared. 
 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression. 
 
9.2.8 mRECIST New Lesion identification at follow-up 
The following are considerations using mRECIST in the assessment of tumor progression: 
 A newly detected hepatic nodule will be classified as HCC—and therefore will be 
declared as evidence of progression—when its longest diameter is at least 10mm and 
the nodule shows the typical vascular pattern of HCC on dynamic imaging, that is, 
hypervascularization in the arterial phase with washout in the portal venous or late 
venous phase. 
 Liver lesions larger than 10 mm that do not show a typical vascular pattern (atypical) 
may be diagnosed as HCC by evidence of at least 10-mm-interval growth in 
subsequent scans. 
 For any equivocal new lesion that is later determined to be unequivocal the timepoint 
of progression will be the timepoint the lesion was first noted as equivocal. 
 Any newly-detected focal liver lesion that does not meet the criteria for a new lesion 
should be considered equivocal and not conclusive for disease progression. 
 A lymph node is considered as a “new lesion” and, therefore, indicative of PD if for 
the first time in the study, the short axis diameter increases in size to 10 mm for 
nodes other than porta hepatis nodes or 20 mm for porta hepatis nodes and the 
absolute short axis diameter increase is at least 5 mm relative to nadir for that node. 
 As fluid accumulations (eg, ascites) are common in HCC, an effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans 
should not be considered alone as disease progression by NL, unless a soft tissue mass 
(eg, peritoneal mass) is associated with the fluid accumulation. 
 
9.3 
RECIST 1.1 and mRECIST evaluation of overall visit response at follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs is identical between RECIST 1.1 and mRECIST using the algorithm shown below. 
 


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9.3.1 RECIST 1.1 and mRECIST overall visit response 
 
 
a Non-CR/Non-PD for Overall Response if only non-target lesions (no TLs) are present at baseline. 
Note: An overall assessment of Complete Response (all other disease disappears/reverts to normal) would be 
changed to Partial Response if ascites remains present radiologically. 
 
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline: 
 For subjects with TLs (at baseline): CR, PR, SD, PD, or NE 
 For subjects with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE 
 For subjects with no disease at baseline: NED (no evidence of disease; available as an 
option in the electronic case repot form), PD, or NE 
 
9.3.2 Radiological criteria for scans subsequent to mRECIST-defined progression 
A follow-up scan requested at least 4 weeks after an mRECIST-defined radiological progression 
and no later than the next regularly scheduled imaging visit. The follow-up scans provide 
additional information to the Investigator for patient management and further treatment 
decisions, and since the published RECIST 1.1 and mRECIST criteria (Eisenhauer 2009; 
Lencioni and Llovet 2010) do not provide guidance on how to assess scans acquired after 
(m)RECIST-defined PD, supplemental instructions for Investigators on how to evaluate these 
follow-up scans are provided below. The supplemental criteria are used to distinguish patients 
who are on a trajectory of radiological worsening from those who are stable or improved. In 
order for a scan visit following a prior mRECIST-defined radiologic PD to be classified as 
progressive disease, any of the following criteria must be met: 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Visit Response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non PD or NE 
No 
PR 
SD 
NA 
Non PD or NE 
Non-CR/Non-PD 
No 
No 
SD 
SD (Non-CR/Non-PDa) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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 ≥20% increase and at least a 5-mm increase in the sum of diameters of viable 
(enhancing) tissue in typical intrahepatic target lesions, the longest diameter of atypical 
intrahepatic target lesions potentially containing necrotic and non-necrotic areas, the 
longest diameter of all extrahepatic non-nodal target lesions, and short-axis diameters 
for extrahepatic nodal lesions compared with the previous minimum (nadir) sum of 
diameters at 2 consecutive visits, and a further increase of ≥5 mm in the sum of 
diameters at the follow-up scan timepoint compared with the immediate prior timepoint, 
 significant progression (worsening) of NTLs at the follow-up scan timepoint compared 
with the immediate prior timepoint, 
 significant progression (worsening) of previously new lesions (pre-existing new lesions) 
at the follow-up scan timepoint compared with the immediate prior timepoint, 
 additional brand-new unequivocal lesions at the follow-up scan timepoint 
 
If none of these criteria are met, then the follow-up visit assessment should be one of the 
following: SD, PR, CR, or NE. 
 
10. 
DRUG INFORMATION 
 
10.1 
Atezolizumab (Tecentriq) 
Atezolizumab is a humanized immunoglobulin (IgG1) monoclonal antibody that is produced in 
Chinese hamster ovary (CHO) cells. Atezolizumab targets programmed death-ligand 1 (PD-L1) 
on tumor-infiltrating immune cells (ICs) or tumor cells (TCs) and prevents interaction with the 
programmed death-1 (PD-1) receptor and B7.1 (CD80), both of which function as inhibitory 
receptors expressed on T cells and other immune cells. 
 
10.1.1 Supplier/How Supplied 
Genentech will supply atezolizumab at no charge to subjects participating in this clinical trial.  
 
Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) sterile, preservative-free, 
colorless to slightly yellow solution in a single-dose vial. 
 
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 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.1.2 Preparation  
Visually inspect drug product for particulate matter and discoloration prior to administration, 
whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or 
visible particles are observed. Do not shake the vial. Prepare the solution for infusion as follows: 
 Select the appropriate vial(s) based on the prescribed dose. 
 Withdraw the required volume of atezolizumab from the vial(s). 
 Dilute into a 250 mL polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) 
infusion bag containing 0.9% Sodium Chloride Injection, USP. Infusion lines equipped 
with 0.2 or 0.22 μm in-line filters will be used. 
 Dilute with only 0.9% Sodium Chloride Injection, USP. 
 Mix diluted solution by gentle inversion. Do not shake. 


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This product does not contain a preservative. Administer immediately once prepared. If diluted 
atezolizumab infusion solution is not used immediately, store solution either: 
 At room temperature for no more than 8 hours from the time of preparation. This includes 
room temperature storage of the infusion in the infusion bag and time for administration 
of the infusion, or 
 Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of 
preparation. 
 Do not freeze or shake 
 
10.1.3 Storage and Stability 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from 
light. Do not freeze. Do not shake. 
 
10.1.4 Dispensing 
Atezolizumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Atezolizumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.1.5 Adverse Events 
Refer to the current IB for additional information regarding adverse events. The most common 
adverse events of atezolizumab are fatigue, nausea, cough, dyspnea, decreased appetite, hair loss, 
and diarrhea. Atezolizumab can cause immune mediated side effects such as IRRs and immune-
related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic 
syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, myositis, and 
severe cutaneous adverse reactions.  Immune-mediated reactions may involve any organ system 
and may lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome 
(considered to be potential risks for atezolizumab).   
 
Refer to Appendix A and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.   
 
10.2 
Bevacizumab (Avastin) 
Bevacizumab is a recombinant humanized anti-vascular endothelial growth factor (anti-VEGF) 
monoclonal immunoglobulin G1 (IgG1) antibody. VEGF, a diffusible glycoprotein produced by 
normal and neoplastic cells, is an important regulator of physiologic and pathologic 
angiogenesis. Increased levels of VEGF expression have been found in most human 
malignancies examined to date. 
 
10.2.1 Supplier/How Supplied 
Genentech will supply bevacizumab at no charge to subjects participating in this clinical trial.  
 
Avastin (bevacizumab) injection is a clear to slightly opalescent, colorless to pale brown, sterile 
solution for intravenous infusion supplied as single-dose vials in the following strengths: 


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 100 mg/4 mL: carton of one vial (NDC 50242-060-01); carton of 10 vials (NDC 50242-
060-10). 
 400 mg/16 mL: carton of one vial (NDC 50242-061-01); carton of 10 vials (NDC 50242-
061-10). 
 
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 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.2.2 Preparation  
 Use appropriate aseptic technique. 
 Visually inspect vial for particulate matter and discoloration prior to preparation for 
administration. Discard vial if solution is cloudy, discolored or contains particulate 
matter. 
 Withdraw necessary amount of bevacizumab and dilute in a total volume of 100 mL of 
0.9% Sodium Chloride 
 Injection, USP. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. 
 Discard any unused portion left in a vial, as the product contains no preservatives. 
 Store diluted Avastin solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours. 
 No incompatibilities between bevacizumab and polyvinylchloride or polyolefin bags 
have been observed. 
 
10.2.3 Storage and Stability 
Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect 
from light. Do not freeze or shake the vial or carton. 
 
10.2.4 Dispensing 
Bevacizumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Bevacizumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.2.5 Adverse Events 
Refer to the current IB for additional information regarding adverse events. The most common 
adverse events related to bevacizumab include epistaxis, headache, hypertension, rhinitis, 
proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and 
exfoliative dermatitis. Infusion reactions may occur. Other side effects to note include 
gastrointestinal perforations and fistula, wound healing complications, and thromboembolic 
events. 
 
10.3 
TARE 
TARE treatment will be administered either using Glass or Resin Yttrium-90 containing 
microspheres. The choice on the most appropriate TARE treatment will be made after the 
mapping and will be per the discretion of the local interventional radiologist. All TARE 
treatments are preferred to be delivered in a segmental or subsegmental fashion, if feasible, but 
lobar treatments will be allowed as long as the estimated FLR ≥ 40%. All treatment vessels 


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should undergo contrast enhanced cone beam CT demonstrating complete tumor coverage and 
no non-target enhancement. It is preferred that segmental/subsegmental treatments with Glass 
should target for doses >190 Gy or >1 Gbq. BSA or partition dosing methods are acceptable for 
Resin. Pressure assistance devices, such as antireflux catheters or balloon microcatheters, is 
permitted. Total lung dose should not exceed 30 Gy per session or 50 Gy total.  
 
For glass users, the minimum threshold of 190 Gy MIRD will be used for segmental treatment. 
For resin user, a minimum threshold of 100 – 120 Gy calculated with the partition method will 
be used for segmental treatment. For lobar treatment, the BSA method will be used to determine 
the dosage, or a minimum threshold of 100 Gy will be used for treatment. 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE 
assessment. A copy of the CTCAE v5 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the EDC 
system (Documents and Information Tab). 
 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to atezolizumab 
and bevacizumab (see following guidance), and actions taken. 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Hepatocellular Carcinoma 
that were not present prior to the AE reporting period. 
 Preexisting medical conditions: A preexisting medical condition is one that is present at 
the start of the study. Such conditions should be reported as medical and surgical history. 
A preexisting medical condition should be re-assessed throughout the trial and reported 
as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept that 
the preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
 If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 


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 Diagnosis vs. Signs and Symptoms: NOTE: If known at the time of reporting, a 
diagnosis should be reported rather than individual signs and symptoms (e.g., record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the 
information that is currently available. If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that meets any of the following criteria: 
 Results in death. All deaths that occur during the protocol-specified AE reporting period, 
regardless of attribution, will be reported to the appropriate parties. When recording a 
death, the event or condition that caused or contributed to the fatal outcome should be 
reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. NOTE: Death due to 
disease progression should not be reported as a SAE, unless it is attributable by the site 
investigator to the study drug(s). 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for > 24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events.  
 If a subject is hospitalized to undergo a medical or surgical procedure as a result of an 
AE, the event responsible for the procedure, not the procedure itself, should be reported 
as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass as the SAE. Hospitalizations for 
the following reasons do not require reporting: 
o Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
o Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
o Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
 Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
 Is a congenital anomaly or birth defect in a neonate/infant born to a mother exposed to 
the IMP. 


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 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Adverse Events of Special Interest (AESI) 
The following AEs are considered of special interest:  
 Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
o Treatment-emergent ALT or AST  3  ULN (or  3  baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin  2 
 ULN (of which  35% is direct bilirubin) 
o Treatment-emergent ALT or AST  3  ULN (or  3  baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical jaundice 
 Suspected transmission of an infectious agent by the study treatment, as defined below 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product.  This term applies only when a contamination 
of study treatment is suspected. 
 Systemic lupus erythematosus 
 Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and hemophagocytic lymphohistiocytosis  
 Nephritis 
 Ocular toxicities (e.g. uveitis, retinitis, optic neuritis) 
 Grade  2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis) 
 Vasculitis 
 Autoimmune hemolytic anemia 
 Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 Hemorrhage 
o Any grade CNS bleeding 
o Grade ≥ 2 hemoptysis 
o Other Grade ≥ 3 hemorrhagic event 
 
11.1.4 Expected/Unexpected Adverse Event 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B). 
 


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For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
For patients receiving combination therapy, causality will be assessed individually for 
atezolizumab and bevacizumab per each protocol-mandated therapy. 
 
11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
Yes (definitive, probable, possible, unlikely) 
There is a plausible temporal relationship between the onset of the AE and administration of 
atezolizumab and bevacizumab, and the AE cannot be readily explained by the subject’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of atezolizumab or dose reduction and, if applicable, reappears upon re-
challenge. 
 
No (unrelated) 
Evidence exists that the AE has an etiology other than atezolizumab and bevacizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to atezolizumab 
administration (e.g., cancer diagnosed 2 days after first dose of atezolizumab). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B).  
 
Unexpected adverse events are those not listed in the P.I. or current I.B or not identified.  This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B.  For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy 
 
 


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11.1.6 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (V5 .0 Update current versions) 
will be used for assessing adverse event severity. Below Table should be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
 
Grade
Severity
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated
2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living a
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (V5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as 
performed by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event  
d. Grade 4 and 5 events must be reported as serious adverse events 
 
11.2 
Reporting 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 
 
 


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11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form will be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.3 Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior Atezolizumab and Bevacizumab exposure. 
If the investigator should become aware of the development of cancer or a congenital anomaly in 
a subsequently conceived offspring of a female subject who participated in the study, this should 
be reported as an SAE adequately to Genentech drug Safety during follow up period 
 
11.3 
Special Situation Reports 
 
11.3.1 Pregnancy reports 
If a female subject or female partner of a male study subject becomes pregnant while receiving 
the study drug or within 6 months after the last dose of study drug, a report should be completed 
and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the study drug should be 
reported as an SAE to HCRN within thirty (30) calendar days of the awareness date. 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
 
 
 


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11.3.2 Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to HCRN 
within thirty (30) calendar days. 
 Data related to the Product usage during breastfeeding 
 Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
 In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
 
11.3.3 Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to HCRN within thirty (30) 
calendar days of the awareness date. A Product Complaint is defined as any written or oral 
information received from a complainant that alleges deficiencies related to identity, quality, 
safety, strength, purity, reliability, durability, effectiveness, or performance of a product after it 
has been released and distributed to the commercial market or clinical trial.  
 
11.4 
HCRN Requirements for Reporting SAEs to Genentech 
HCRN will report all protocol-defined Adverse Events (AEs)/SAEs, AEs of Special Interest 
(AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with 
or without an AE) originating from the Study for the Product to Genentech within 1 business 
day of receipt of the SAE Submission Form from a site. Follow-up information will be provided 
to Genentech as it is received from site.   
 
Genentech Drug Safety at: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be called at: 
PCHotlineNumber:(800)334-0290   
 
11.5 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.6 
HCRN Responsibilities to FDA 
This protocol is IND exempt per FDA communication 5/7/2020. HCRN will continue to 
facilitate compliance of applicable requirements for the sponsor-investigator in relation to this 
study. This includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, 
and pertinent sections of the Public Health Service Act and FDAAA. 
 
 
 


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11.7 
IND Safety Reports Unrelated to this Trial 
Genentech will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is an open-label, multi-center, randomized phase II study of combination therapy with Y-90 
TARE, bevacizumab, and atezolizumab in patients with advanced HCC. Patients will be 
randomized 1:1 to receive TARE with or without atezolizumab + bevacizumab. Stratification 
factors include AFP level (high is defined as ≥ 400; low as < 400) and presence or absence of 
vascular invasion.  
 
12.3 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
PFS is defined as the time from randomization to the first occurrence of disease progression or 
death from any cause (whichever occurs first) according to mRECIST. Patients without disease 
progression (and did not die) at the time of analysis will be censored at the last disease 
assessment date. Patients with no post-baseline disease assessment will be censored at the 
randomization date.  
 
12.2.2 Definition of Secondary Endpoints 
 Safety and tolerability will be measured on the basis of toxicities experienced graded by 
CTCAE v5. 
 PFS is defined as the time from randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs first) according to RECIST v1.1.  
 TTP is defined as the time from randomization to the first occurrence of disease 
progression according to RECIST v1.1 and mRECIST. Patients without disease 
progression (including death) will be censored at the last disease assessment date. 
Patients who have no post-baseline disease assessment will be censored at randomization 
date.  
 ORR is defined as a complete or partial response according to RECIST v1.1 and 
mRECIST. 
 OS is defined as the time from randomization to death from any cause. Patients alive at 
the time of analysis will be censored at the time of last contact. Patients without post-
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 Change in physical functioning, role functioning, social functioning, and global health 
status/quality of life from the EORTC fit-for-purpose instrument is defined as change 
from baseline (first treatment cycle) at each follow up timepoint, i.e. each subsequent 
treatment cycle, safety follow up visit, and long-term follow up.  
 
12.3 
Sample Size and Accrual 
The first 10 subjects randomized to Arm B and receives Y-90 radioembolization followed by two 
cycles of the combination of bevacizumab and atezolizumab will make up the safety lead in. If 
there are no Grade ≥ 3 unexpected toxicities possibly, probably or definitely related to the TARE 
plus bevacizumab and atezolizumab combination, the study will continue enrollment to meet the 
primary study endpoint. The estimated median PFS for patients receiving segment TARE (Arm 
A) is 9 months. It is hypothesized that the addition of combined bevacizumab and atezolizumab 
(Arm B) will improve the median PFS from 9 months (control arm receiving segment Y-90) to 
15 months (bevacizumab plus atezolizumab following Y-90 TARE). Assuming a hazard ratio of 
0.6 (median PFS of 9 months in Arm A and 15 months in Arm B) and an exponential distribution 
for PFS in each treatment arm, a total of 97 events (53 in the control group, 44 in experimental 
arm) are needed to detect a statistically significant difference using a 1-sided alpha of 0.05 with 
80% power. With an expected accrual rate of 10 patients per month and 24 months of follow up 
after last patient in, a total of 118 patients will be needed for evaluation, consider about 8% drop 
out rate which will lead to 128 patients to be enrolled during the randomized phase of the study.  
 
12.4 
Assessment of Safety 
All randomized patients who receive TARE and any amount of bevacizumab and atezolizumab 
will be included in the safety analysis for Arm B. All randomized patients who receive TARE 
will be included in the safety analysis for Arm A. Patients will be grouped according to the 
actual treatment received and patients who received any amount of atezolizumab and 
bevacizumab will be assigned to Arm B (experimental arm) for safety analysis even if it’s given 
in error.  
 
12.5 
Assessment of Efficacy 
Analysis of efficacy will be based on treatment assigned at randomization regardless of actual 
treatment received. All randomized patients will be included in the analysis for PFS, TTP and 
OS. Arm A subjects that received TARE and Arm B subjects that received TARE and any 
amount of bevacizumab and atezolizumab with measurable disease and have their disease re-
evaluated will be evaluable for assessment of objective response.  
 
12.6 
Data Analysis Plans 
 
12.6.1 Analysis Plans for Primary Objective 
The primary objective of this study is to evaluate the PFS per RECIST v1.1 for patients with 
HCC receiving Y-90 TARE therapy with the combination of bevacizumab and atezolizumab 
compared with those receiving Y-90 TARE therapy alone.  
 
The stratified log-rank will be used as the primary analysis to compare PFS between the two 
treatment arms. Kaplan-Meier methodology will be used to estimate the PFS for both treatment 


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groups. Stratified Cox proportional hazard model will be fit to estimate the hazard ratio and 95% 
confidence intervals (CI). Unstratified analysis will also be conducted.  
 
12.6.2 Analysis Plans for Secondary Objectives 
Patients’ toxicity data will be tabulated according to their grades and attribution by groups. TTP 
and OS will be analyzed using similar methods as for PFS (primary endpoint). ORR will be 
estimated and presented with its 95% confidence interval.   
The PRO instrument is a reduced version of the EORTC QLQ-C30. The instrument includes 
only questions related to the physical, emotional, and social function domains, as well as overall 
health-related quality of life. The purpose of using a limited instrument is two-fold: 1) given the 
nature of the study design and patient population, treatment-related, rather than disease-related 
symptoms will be most likely to impact patient QoL, and we are most interested in measuring the 
impact of treatment on function and QoL, rather than the symptoms themselves; and 2) generally 
we want instruments to be as short as possible to limit patient burden. Completion rates, 
compliance rates, and reasons for missing data will be summarized for each of the EORTC fit-
for-purpose instrument measures by treatment arm. Summary statistics (mean, standard 
deviation, median, range, and CIs) of absolute scores and mean changes from baseline scores 
will be conducted for all measures at each assessment timepoint. Previously published minimally 
important differences will be used to identify meaningful change from baseline within each 
treatment group on the functional and disease/treatment related symptoms scales (Osoba et al. 
1998). In the event of incomplete data for any questionnaire subscales, if more than 50% of the 
constituent items are completed, a prorated score will be computed, consistent with the scoring 
manuals and validation papers. For subscales with less than 50% of the items completed, the 
subscale will be considered as missing (Fayers et al. 2001; Chie et al. 2012).  
 
12.6.3 Analysis Plans for Correlative/Exploratory Objectives 
The correlative studies will be exploratory in nature. Fisher’s exact tests, Wilcoxon rank-sum 
tests, log-rank tests, and descriptive statistics will be used as appropriate to explore associations 
between biomarkers and clinical outcomes. 
 
12.6.4 Subgroup Analyses 
In order to assess the consistency of treatment effect with respect to the primary endpoint across 
prognostic subsets, subgroup analysis will be conducted, including, but not limited to the 
following variables: 
 Presence or absence of vascular invasion 
 AFP level (high is defined as ≥ 400; low as < 400) 
 Prior TACE treatment (Yes vs No) 
 lobar Y-90 TARE vs. segmental TARE 
 
Unstratified analysis results will be presented for subgroup analyses due to the potentially 
limited number of patients in each subgroup. 
 
12.7 
Interim Analysis 
The safety cohort of 10 subjects randomized to Arm B (TARE plus bevacizumab plus 
atezolizumab) will be assessed for safety after two cycles. Accrual will be halted during this 
review. Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to the TARE 


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plus bevacizumab plus atezolizumab will be reviewed (specifically, toxicities beyond those from 
TARE or the combination of bevacizumab and atezolizumab treatment when used independent to 
each other). If there are no Grade ≥ 3 unexpected toxicities; possibly, probably or definitely 
related to TARE in combination with bevacizumab and atezolizumab the combination will be 
deemed safe and accrual will resume. The decision to resume accrual will be made by the DSMC 
and sponsor-investigator. Each toxicity meeting the outlined criteria will be reviewed as a 
separate event.  
 
Toxicities will be graded based on the CTCAE criteria v5. Adverse events will be 
recorded/reported as outlined in Section 11 regardless of the way in which the information was 
obtained (email, virtual visit, in person). Adverse event information will be provided to the 
sponsor-investigator on a weekly basis. Adverse event information will be provided to the 
sponsor-investigator on a weekly basis. If at any time an AE meeting the criteria outlined above 
occurs, accrual will be halted until the sponsor-investigator or designee reviews the event and 
determines that accrual can resume. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Georgetown Lombardi Comprehensive 
Cancer Center’s DSMP.  
 
HCRN oversight activities include: 
 Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
 Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
 Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to Georgetown Lombardi Comprehensive Cancer Center Cancer Center’s 
DSMP. 
 
13.2 
Georgetown Lombardi Comprehensive Cancer Center Data Safety Monitoring 
Committee 
HCRN will provide the following for the Georgetown Lombardi Comprehensive Cancer Center 
DSMC to review: 
 Adverse event summary report 
 Audit results if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The Georgetown Lombardi Comprehensive Cancer Center DSMC will review study data every 
quarter for the first six months, if no significant safety concerns are noted, the review will then 
be performed semiannually.  Documentation of DSMC reviews will be provided to sponsor-
investigator and HCRN.  Issues of immediate concern by the DSMC will be brought to the 


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attention of the sponsor-investigator and other regulatory bodies as appropriate.  The sponsor-
investigator will work with HCRN to address the DSMC’s concerns.   
 
13.3 
Data Quality Oversight Activities by HCRN 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may be performed as necessary. During onsite 
monitoring visits, source documents will be reviewed for verification of agreement with data 
entered into the EDC system.  It is important for the site investigator and their relevant personnel 
to be available for a sufficient amount of time during the monitoring visits or audit, if applicable. 
The site investigator and institution guarantee access to source documents by HCRN or its 
designee. 
 
The trial site may also be subject to quality assurance audit by Genentech or its designee as well 
as inspection by appropriate regulatory agencies.  
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system  by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 


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document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Genentech, IRB, or government agencies, like the FDA, 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require. Progress reports and notifications of serious and unexpected adverse events will be 
provided to the IRB according to local regulations and guidelines. 
 


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15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 


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Flamm S4, Atassi R1, Atassi B1, Sato K1, Benson AB2, Mulcahy MF2, Abouchaleh N1, Asadi 
AA1, Desai K1, Thornburg B1, Vouche M1, Habib A1, Caicedo J3, Miller FH5, Yaghmai V5, 
Kallini JR1, Mouli S1, Lewandowski RJ1,2,3. Institutional decision to adopt Y90 as primary 
treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. 
Hepatology. 2018 Oct;68(4):1429-1440. doi: 10.1002/hep.29691. Epub 2018 Jan 29. 
 
Sangro B, Carpanese L, Cianni R, et al. Survival after Ytrium-90 resin microsphere 
radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a 
European evaluation. Hepatology 2011;54:868-78. 
 
Siegel AB, Cohen EI, Ocean A, et al. PhaseII trial evaluating the clinical and biologic effects of 
bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992-8.  
 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.  
 
Spina JC1, Hume I1, Pelaez A1, Peralta O1, Quadrelli M1, Garcia Monaco R1. Expected and 
Unexpected Imaging Findings after 90Y Transarterial Radioembolization for Liver Tumors. 
Radiographics. 2019 Mar-Apr;39(2):578-595. doi: 10.1148/rg.2019180095. 
 
Tomozawa Y1, Jahangiri Y1, Pathak P1, Kolbeck KJ1, Schenning RC1, Kaufman JA1, Farsad 
K2. Long-Term Toxicity after Transarterial Radioembolization with Yttrium-90 Using Resin 
Microspheres for Neuroendocrine Tumor Liver Metastases. J Vasc Interv Radiol. 2018 
Jun;29(6):858-865. doi: 10.1016/j.jvir.2018.02.002. Epub 2018 Apr 30. 
 


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Vauthey JN, Chaoui A, Do KA, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, Hicks M, 
Alsfasser G, Lauwers G, Hawkins IF, et al. Standardized measurement of the future liver 
remnant prior to extended liver resection: methodology and clinical associations. Surgery. 
2000;127:512–519. 
 
Vilgrain V1, Pereira H2, Assenat E3, Guiu B3, Ilonca AD4, Pageaux GP3, Sibert A5, Bouattour 
M5, Lebtahi R5, Allaham W5, Barraud H6, Laurent V6, Mathias E6, Bronowicki JP6, Tasu JP7, 
Perdrisot R7, Silvain C7, Gerolami R8, Mundler O9, Seitz JF8, Vidal V9, Aubé C10, Oberti F10, 
Couturier O10, Brenot-Rossi I11, Raoul JL11, Sarran A11, Costentin C12, Itti E12, Luciani A13, 
Adam R14, Lewin M14, Samuel D14, Ronot M15, Dinut A2, Castera L15, Chatellier G16; 
SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin 
microspheres compared with sorafenib in locally advanced and inoperable hepatocellular 
carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017 
Dec;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6. Epub 2017 Oct 26. 
 
Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory 
checkpoints on CD8+ T cells in tumors. J Exp Med 2015;212:139-48.  
 
Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances 
antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Comm 2016;7:1-8.  
 
Zhang X1, Wang K1, Wang M2, Yang G3, Ye X2, Wu M1, Cheng S1.Transarterial 
chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular 
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2017 Apr 25;8(17):29416-29427. doi: 10.18632/oncotarget.15075. 
 
Jacky Chow, Nicholas C. Hoffend, Radiation induces dynamic changes to the T cell repertoire in 
renal cell carcinoma patients PNAS September 22, 2020 117 (38) 23721-23729; first published 
September 8, 2020; https://doi.org/10.1073/pnas.2001933117 
 


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APPENDIX A: 
Risks Associated with Atezolizumab and Guidelines for Management of Adverse Events 
Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
 
Although most immune-related adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune related toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive 
agents.  
 
The investigator should consider the benefit-risk balance a given patient may be experiencing 
prior to further administration of atezolizumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered if the patient is 
deriving benefit and has fully recovered from the immune related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate). 
 
 
 


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PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have computed tomography (CT) scans of the chest 
performed at every tumor assessment.   
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.   
 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For recurrent pneumonitis, treat as a Grade 3 or 4 event 
Pulmonary event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or 
equivalent.   
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator.
 
 
 


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HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.   
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
 
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Consider patient referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.  
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
LFT = liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
 
 


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Event
Management
In patients with HCC 
AST/ALT is within normal limits at 
baseline and increases to  
 3ULN to  10ULN  
 
or 
 
AST/ALT is  ULN to  3ULN at 
baseline and increases to 
  5ULN to  10 ULN 
 
or 
 
AST/ALT is  3ULN to 5ULN at 
baseline and increases to  
8ULN to 10ULN 
 Monitor LFTs more frequently until return to 
baseline values.  
 Withhold atezolizumab for up to 12 weeks after 
event onset. a 
 
Events of  5 days' duration:  
 Consider initiating treatment with 12 mg/kg/day 
prednisone or equivalent. 
 If event resolves to baseline, resume 
atezolizumab. b 
 If event does not resolve to baseline while 
withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical 
Monitor. c 
AST or ALT increases to 10ULN or 
total bilirubin increases to  3ULN 
 
 Permanently discontinue atezolizumab and 
contact Medical Monitor. c 
 Consider patient referral to GI specialist for 
evaluation and liver biopsy to establish etiology 
of hepatic injury.  
 Initiate treatment with 12 mg/kg/day prednisone 
or equivalent. 
 If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to baseline, taper corticosteroids 
over 1 month.
Table 43 
Management Guidelines for Hepatic Events (cont.) 
CTCAE  Common Terminology Criteria for Adverse Events; GIgastrointestinal; LFT  liver 
function test; NCI  National Cancer Institute; ULNupper limit of normal. 
Note:  Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
a 
Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor. 
b 
If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 


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GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab.  All events 
of diarrhea or colitis should be thoroughly evaluated for other more common etiologies.  For 
events of significant duration or magnitude or associated with signs of systemic inflammation or 
acute-phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia):  Perform 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five specimens 
for standard paraffin block to check for inflammation and lymphocytic infiltrates to confirm 
colitis diagnosis.  
 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist >5 days, initiate treatment with 12 
mg/kg/day oral prednisone or equivalent.  
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist for evaluation and confirmation biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).  


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ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.   
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present.  
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] 
levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly.
Symptomatic 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
 Permanently discontinue atezolizumab. c
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not stable 


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Event 
Management 
on replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab. c
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Initiate treatment with insulin if needed. 
 Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose levels are 
stable.
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
 Permanently discontinue atezolizumab c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated.
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate).  
 
 
 
 


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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).   
 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event.
Ocular event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab c
Ocular event, Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).  
 
 
 


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IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a 
patient who reports a recent history of GI illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.  All patients with 
possible myocarditis should be urgently evaluated by performing cardiac enzyme assessment, an 
ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per institutional 
guidelines.  A cardiologist should be consulted.  An endomyocardial biopsy may be considered 
to enable a definitive diagnosis and appropriate treatment, if clinically indicated. Patients with 
signs and symptoms of myocarditis, in the absence of an identified alternate etiology, should be 
treated according to the guidelines below. 
 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade 1 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a  
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
 Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. a 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c
Immune-related 
myocarditis, Grade 3-
4 
 Permanently discontinue atezolizumab. c 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. a,b 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length 
of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event.  Patients can be re-challenged with atezolizumab only after approval has been 
documented by the investigator (or an appropriate delegate).
 


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INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release cyndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, antipyretics and/or analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction [29]. CRS has been well 
documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager 
antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 
[30, 31], including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in Table 7.   
 
Table 7 
Management Guidelines for Infusion-Related Reactions and Cytokine Release 
Syndrome 
Event
Management
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate 
may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment,c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS.
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
 Immediately interrupt atezolizumab infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 


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Hypoxia 
requiring low-
flow oxygend 
by nasal cannula 
or blow-by 
appropriate). Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose 
of atezolizumab may be administered. For subsequent infusions, consider 
administration of oral premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact 
Medical Monitor.
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)  
and/or 
Hypoxia 
requiring high-
flow oxygend 
by nasal cannula, 
face mask, non-
rebreather mask, 
or venturi mask 
 Permanently discontinue atezolizumab.f 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus and vasopressor as needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring in the 
ICU is recommended. Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Hospitalize patient until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 4, that is, admit patient to ICU and 
initiate hemodynamic monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator.
Grade 4a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia 
requiring oxygen 
by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
 Permanently discontinue atezolizumab.f 
 Administer symptomatic treatment.c 
 Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other organ 
function closely. Manage constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e For patients who are refractory to anti-cytokine 
therapy, experimental treatmentsg may be considered at the discretion of the 
investigator.


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mechanical 
ventilation)
  Hospitalize patient until complete resolution of symptoms. 
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive airway 
pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway pressure; 
CRS= cytokine-release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related 
reaction; MAS= macrophage activation syndrome.
Note: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI 
CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, 
CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities 
associated with CRS should not influence overall CRS grading.  
b. Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop 
CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade). In this case, the grade is driven by 
the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may 
be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen 
delivered at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, 
and the role of such treatment in the setting of antibody-associated CRS has not been established. 
f. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). For 
subsequent infusions, administer oral premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and 
extending the infusion time may also be considered after considering the benefit-risk ratio. 
g. Refer to Riegler et al. [32] for information on experimental treatments for CRS.
 
 
 


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PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.   
 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase elevation, 
Grade 1 
 Continue atezolizumab 
 Monitor amylase and lipase prior to dosing 
Amylase and/or lipase elevation, 
Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as Grade 3.
Amylase and/or lipase elevation, 
Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c
Immune-related pancreatitis, 
Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c
Immune-related pancreatitis, 
Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length 
of the extended period of time must be determined by the investigator.


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Event 
Management 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event.  Patients can be re-challenged with atezolizumab only after approval has been 
documented by the investigator (or an appropriate delegate). 
 
DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.   
 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, Grade 1   Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic event, Grade 2   Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic event, Grade 3   Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve within 
4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c
Dermatologic event, Grade 4 
 Permanently discontinue atezolizumab. c 
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
 Follow the applicable treatment and management guidelines above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 


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a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 
 
 
 


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NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.   
 
Management Guidelines for Neurologic Disorders 
Event
Management
Immune-related neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology.
Immune-related neuropathy, 
Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology. 
 Initiate treatment as per institutional guidelines. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c
Immune-related neuropathy, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c  
 Initiate treatment as per institutional guidelines.
Myasthenia gravis and 
Guillain-Barré syndrome 
(any grade) 
 Permanently discontinue atezolizumab. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 
 
 
 


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IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines below. 
 
Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
 Permanently discontinue atezolizumab. a 
 Refer patient to neurologist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).
 
 
 


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IMMUNE-RELATED NEPHRITIS 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, 
should be monitored throughout study treatment. Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as nonsteroidal anti-inflammatory drugs). Refer the 
patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. If no alternative cause of acute kidney injury is 
identified, patients with signs and symptoms of acute kidney injury, in the absence of an 
identified alternate etiology, should be treated according to the management guidelines for 
immune-related renal events in the table below. 
 
Management Guidelines for Renal Events 
 
Event 
Management 
Renal event, 
Grade 1 
 
Continue atezolizumab. 
 
Monitor kidney function, including creatinine, closely until values 
resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to renal specialist. 
 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Renal event, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab. 
 
Refer patient to renal specialist and consider renal biopsy. 
 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.  
a. Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the sponsor-investigator. 
b. If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c. Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 


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atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the sponsor-investigator. 
 
 
 
 
 


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IMMUNE-RELATED MYOSITIS 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features and is confirmed with a muscle biopsy.  
 
Management Guidelines for Immune-Related Myositis  
Event 
Management 
Immune-related myositis, Grade 1 
 
Continue atezolizumab 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional guidelines 
Immune-related myositis, Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event 
onseta and contact site investigator. 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional guidelines 
 
Consider treatment with corticosteroid equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent 
 
If event resolves to Grade 1 or better, resume 
atezolizumab.b 
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the sponsor-investigator. c
Immune-related myositis, Grade 3 
 
Withhold atezolizumab for up to 12 weeks after event 
onseta and contact site investigator. 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional guidelines 
 
Respiratory support may be required in more severe cases 
 
Initiate treatment with corticosteroid equivalent to 1-2 
mg/kg/day IV methylprednisolone or higher dose bolus if 
subject is severely compromised (eg, cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 
If event resolves to Grade 1 or better, resume 
atezolizumab.b 
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact HCRN. c 
 
For recurrent events, treat as a Grade 4 event


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Immune-related myositis, Grade 4 
 
Permanently discontinue atezolizumab and contact site 
investigator.c 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional guidelines. 
Respiratory support may be required in more severe cases 
 
Initiate treatment with corticosteroid equivalent to 1-2 
mg/kg/day IV methylprednisolone or higher dose bolus if 
subject is severely compromised (eg, cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month.
IV, intravenous 
a Atezolizumab may be withheld for a period of time (ie, > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the sponsor-
investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully 
recovered from the immune-related event. Subjects can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the sponsor-
investigator. 
 
 
 
 
 
 


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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).   
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
o 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
o 
Platelet count  100  109/L (100,000/L) 
o 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L (150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L (181,000/L) 
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 1. 
 


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Table 1 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
 
References 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resouce on the Internet]. 2014 [updated 29 October 2018; 
cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-features-
and-diagnosis-of-hemophagocytic-lymphohistiocytosis. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819. 
 
 
 


Clinical Study Protocol 
HCRN GI19-405 
 
Version Date: 02DEC2021 
Confidential 
Page 96 of 98 
APPENDIX B: BEVACIZUMAB SPECIFIC AE MANAGEMENT GUIDELINES 
 
Event 
CTCAE Version 5.0 
Grade
Action to be Taken 
Allergic reactions  
OR  
Infusion-related 
reactions 
OR  
Anaphylaxis 
Grade 1 
Systemic intervention not indicated – 
continue bevacizumab
Grade 2 
Oral intervention indicated – slow infusion 
to 50% or interrupt if clinically indicated 
(re-start infusion at 50% and increase in 
50% increments if well tolerated). Infusion 
can be re-started at the full rate for 
subsequent infusions.
Grade 3 
Bronchospasm (allergy-related 
oedema/angioedema; hypotension); 
hospitalization for clinical sequelae; 
intravenous intervention indicated – 
discontinue bevacizumab
Grade 4 
Life-threatening consequences; urgent 
intervention indicated - discontinue 
bevacizumab
Thromboembolic Event 
(arterial) 
Any Grade 
Discontinue bevacizumab 
Thromboembolic Event 
(Venous) 
Grade 3 
 
Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is 
<2weeks, bevacizumab should be held until 
the full-dose anticoagulation period is over. 
The use of direct oral anticoagulants is not 
recommended. 
If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during full-dose 
anticoagulation IF all of the criteria below 
are met: 
o 
The patient must not have pathological 
conditions that carry high risk of 
bleeding (e.g. tumor involving major 
vessels or other conditions) 
o 
The patient must not have had 
hemorrhagic events > grade 2 while on 
study 
o 
The patient must be on stable dose of 
heparin, low molecular weight heparin, 
or have an in-range INR (usually 2-3) 
on a stable dose of warfarin prior to 
restarting bevacizumab.


Clinical Study Protocol 
HCRN GI19-405 
 
Version Date: 02DEC2021 
Confidential 
Page 97 of 98 
If thromboemboli worsen/recur upon 
resumption of study therapy, discontinue 
bevacizumab
Grade 4 
Discontinue bevacizumab
Hypertension 
[Treat with anti-hypertensive medication as needed.  The goal of BP 
control should be consistent with general medical practice]
 
Grade 1 
(SBP 120-139 mmHg 
or DBP80-89 mm Hg)
Consider increased BP monitoring; start anti-
hypertensive medication if appropriate 
 
Grade 2 asymptomatic
(SBP 140-159 mmHg 
or DBP 90-99 mm 
Hg)
Begin (or modify baseline anti-HTN therapy) 
anti-hypertensive therapy and continue 
bevacizumab 
 
Grade 2 symptomatic 
(SBP 140-159 mmHg 
or DBP 90-99 mm 
Hg) 
Start or adjust anti-hypertensive medication 
 
 
Grade 3 
(≥ SBP 160 mmHg 
or ≥ DBP 100 mmHg
Modify existing anti-HTN therapy (more than 
one drug or more intensive therapy than 
previously indicated. 
 
Hold bevacizumab until symptoms resolve 
AND BP < 160/90mmHg
 
Grade 4 
(e.g. Hypertensive 
crisis or malignant 
hypertension)
Discontinue bevacizumab 
Heart Failure or left 
ventricular dysfunction 
Grade 3
Discontinue bevacizumab
Grade 4 
Discontinue bevacizumab
Proteinuria*
1+ proteinuria 
(≥ ULN - <1.0g/24h)
Continue bevacizumab 
2+ and 3+ proteinuria 
(1.0 - <3.5g/24h) 
2+ - administer bevacizumab and obtain 24-
hour urine protein before next 
administration 
3+ - obtain 24-hour urine protein and 
administer bevacizumab if <2.0 g/24h
4+ proteinuria 
(≥ 3.5g/24h) 
Obtain 24-hour urine protein and administer 
bevacizumab only when <2.0 g/24h 
Nephrotic syndrome
Grade 3 or 4
Discontinue bevacizumab
Hemorrhage (CNS)
Any grade
Discontinue bevacizumab
Hemorrhage 
(haemoptysis) 
Grade 1
Trace hemoptysis; continue bevacizumab
Grade 2 - 4 
 2.5 mL bright red blood per episode; 
discontinue bevacizumab
Hemorrhage (other)
Grade 3 - 4
Discontinue bevacizumab


Clinical Study Protocol 
HCRN GI19-405 
 
Version Date: 02DEC2021 
Confidential 
Page 98 of 98 
RPLS (Reversible Posterior 
Leukoencephalopathy syndrome or PRES 
(Posterior Reversible Encephalopathy 
Syndrome)
Discontinue bevacizumab 
Wound dehiscence requiring medical or 
surgical intervention
Discontinue bevacizumab 
Perforation (GI, or any other organ)
Discontinue bevacizumab
Fistula (GI, pulmonary or any other organ)
Discontinue bevacizumab
Obstruction of GI tract 
G2 requiring medical 
intervention
Hold bevacizumab until complete resolution  
 
G3-4 
Hold bevacizumab until complete resolution. 
 
If surgery is required, patient may restart 
bevacizumab after full recovery from surgery, 
and at investigator’s discretion
Febrile neutropenia 
Grade 3
Continue bevacizumab
Grade 4 
Hold bevacizumab until resolution or return 
to baseline
Platelet count decreased
Grades 1 - 3
Continue bevacizumab
Grade 4 
Hold bevacizumab until resolution or return 
to baseline
Other Unspecified 
bevacizumab-related 
AEs (except controlled 
nausea/vomiting). 
Grade 3 
Hold bevacizumab until symptoms resolve to 
≤ grade 1 or baseline
Grade 4 
Discontinue bevacizumab 
 
Upon consultation with the study 
chair/medical monitor, resumption of 
bevacizumab may be considered if a patient is 
benefiting from therapy, and the G4 toxicity 
is transient, has recovered to  
≤ grade 1 (or baseline) and unlikely to recur 
with retreatment.
*Institutional protocols acceptable