Atezolizumab and Bevacizumab in Combination With TACE for Patients With BCLC B HCC
Phase: PHASE2
Conditions: Hepatocellular Carcinoma, BCLC Stage B Hepatocellular Carcinoma
Sponsor: Yale University

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PROTOCOL
TITLE:
STUDY NUMBER:
VERSION NUMBER:
TEST PRODUCTS:
INDICATION:
INVESTIGATOR:
SUPPORT PROVIDED 
BY:
PROTOCOL DATE:
ATEZOLIZUMAB AND BEVACIZUMAB IN 
COMBINATION WITH TACE FOR PATIENTS WITH 
BCLC B HCC
2000026840           NCT05776875   
4.0
Atezolizumab (RO5541267) 
Bevacizumab
TACE
Treatment of Barcelona Clinic Liver Cancer B 
Hepatocellular Carcinoma
Stacey Stein MD 
333 Cedar St
New Haven CT 06520 
Telephone: (203) 737-1600
Fax: (203) 785-3788
E-mail: stacey.stein@yale.edu
Genentech, Inc.
June 30,2023
Confidentiality Statement:
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I, the undersigned, have read and approve this protocol and agree on its contents. It is confirmed 
that the information and guidance given in this protocol complies with scientific principles, the 
guideline of Good Clinical Practice, the Declaration of Helsinki in the latest relevant version, and 
the applicable legal and regulatory requirements. I agree to conduct the study in compliance with all 
applicable regulations including International Ethical Guidelines for Biomedical Research 
Involving Human Patients (Council for International Organizations of Medical Sciences 2002), 
Guidelines for Good Clinical Practice (GCP) (International Council for Harmonisation [ICH] 
1996), ICH E6 (R2) and concepts that have their origin in the Declaration of Helsinki (World 
Medical Association 1996, 2008 & 2013).
Protocol Title: Atezolizumab and Bevacizumab in Combination with TACE for Patients with 
BCLC B HCC
Protocol Version: 4.0 (2023.06.30)
Printed Name of Principal Investigator: 
Signature of Principal Investigator
Date
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REVISION HISTORY
Revision #
Version Date
1.0
2022.02.02
2.0
2022.06.09
3.0
2022.12.15
4.0
2023.06.30
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Table of Contents
1.
BACKGROUND .......................................................................................................13
1.1.
Background on HCC........................................................................................13
1.2.
Background on Atezolizumab and BevacizumaB combination in HCC.........14
1.3.
Background on TACE in HCC ........................................................................15
1.4.
Background on Combination of Atezolizumab and Bevacizumab with TACE15 
1.5.
Study Rationale and Benefit-Risk Assessment................................................16
2.
OBJECTIVES AND ENDPOINTS ...........................................................................17
2.1.
Primary Objective............................................................................................17
2.2.
Secondary Objectives ......................................................................................17
3.
STUDY DESIGN ......................................................................................................17
3.1.
Trial Schema....................................................................................................18
3.2.
Description of the Study ..................................................................................20
3.3.
End of Study and Length of Study...................................................................21
3.4.
Rationale for Study Design..............................................................................21
3.4.1.
Rationale for Patient Population..................................................................22
3.5.
Patients.............................................................................................................22
3.5.1.
Inclusion Criteria .........................................................................................22
3.5.2.
Exclusion Criteria ........................................................................................24
4.
STUDY TREATMENT.............................................................................................28
4.1.
Study Treatment Formulation, Packaging, and Handling................................28
4.1.1.
Atezolizumab...............................................................................................28
4.1.2.
Bevacizumab................................................................................................28
4.1.3.
TACE...........................................................................................................28
4.2.
Study Treatment Dosage, Administration, and Compliance............................29
4.2.1.
Atezolizumab...............................................................................................29
4.2.1.1. Table 1: Administration of First and Subsequent Atezolizumab Infusions 30 
4.2.2.
Bevacizumab................................................................................................30
4.2.3.
TACE...........................................................................................................31
4.3.
Concomitant Therapy and Additional Restrictions..........................................32
4.3.1.
Permitted Therapy........................................................................................32
4.3.2.
Cautionary Therapy for Atezolizumab-Treated Patients .............................33
4.3.2.1. Corticosteroids and Tumor Necrosis Factor-α Inhibitors ............................33
4.3.2.2. Herbal Therapies..........................................................................................33
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4.3.3.
Prohibited Therapy ......................................................................................33
5.
STUDY ASSESSMENTS .........................................................................................33
5.1.
Medical History, Concomitant Medication, and Demographic Data...............34
5.2.
Physical Examinations.....................................................................................34
5.3.
Vital Signs .......................................................................................................34
5.4.
Tumor And Response Evaluations...................................................................35
5.5.
Laboratory, Biomarker, And Other Biological Samples..................................35
5.6.
Electrocardiograms..........................................................................................36
6.
TREATMENT, PATIENT, AND STUDY DISCONTINUATION ..........................36
6.1.
Study Discontinuation .....................................................................................37
7.
ASSESSMENT OF SAFETY....................................................................................38
7.1.
Safety Plan.......................................................................................................38
7.1.1.
Risks Associated with Atezolizumab...........................................................38
7.1.2.
Risks Associated with Bevacizumab ...........................................................38
7.1.3.
Risks Associated with TACE ......................................................................38
7.2.
Safety Parameters and Definitions...................................................................41
7.2.1.
Adverse Events ............................................................................................41
7.2.2.
Serious Adverse Events ...............................................................................41
7.2.3.
Adverse Events of Special Interest ..............................................................41
7.2.4.
Selected Adverse Events..............................................................................43
7.2.5.
Other Special Situation Reports...................................................................43
7.3.
Methods and Timing for Assessing and Recording Study Variables...............43
7.3.1.
Adverse Event Reporting Period .................................................................43
7.3.2.
Assessment of Adverse Events....................................................................44
7.4.
Procedures for Eliciting, Recording, and Reporting Adverse Events..............45
7.4.1.
Eliciting Adverse Event Information...........................................................45
7.4.2.
Specific Instructions for Recording Adverse Events...................................45
7.4.2.1. Diagnosis versus Signs and Symptoms .......................................................45
7.4.2.2. Deaths ..........................................................................................................45
7.4.2.3. Preexisting Medical Conditions...................................................................45
7.4.2.4. Hospitalizations for Medical or Surgical Procedures ..................................45
7.4.2.5. Assessment of Severity of Adverse Events..................................................46
7.4.2.5.1.
Table 2: Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ...........................................................................46
7.4.2.6. Pregnancies..................................................................................................47
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7.4.2.7. Post-Study Adverse Events..........................................................................47
7.5.
Adverse Event Reporting.................................................................................47
7.5.1.
Adverse Event Reporting to Sponsor Investigator.......................................47
7.5.2.
Sponsor-Investigator Adverse Event Reporting to Genentech ....................48
7.5.3.
MedWatch 3500A Reporting Guidelines ....................................................49
7.5.4.
Reporting to Regulatory Authorities, Ethics Committees and Investigators49 
8.
AGGREGATE REPORTS ........................................................................................50
9.
STATISTICAL CONSIDERATIONS.......................................................................50
8.1.
Determination of Sample Size .....................................................................51
8.2.
Primary Efficacy Variables..........................................................................51
8.3.
Secondary Efficacy Variables......................................................................51
10. INVESTIGATOR REQUIREMENTS ......................................................................51
9.1.
Retention of Records....................................................................................51
9.2.
Study Medical Monitoring Requirements....................................................52
10.2.1. Data and Safety Monitoring Committee (DSMC) .......................................52
10.2.2. Study Site Monitoring..................................................................................52
9.3.
Study Medication Accountability ................................................................53
9.4.
Data Collection ............................................................................................54
11. ETHICAL CONSIDERATIONS...............................................................................54
11.1.
Informed Consent ........................................................................................54
11.2.
Institutional Review Board or Ethics Committee ........................................54
11.3.
Confidentiality .............................................................................................54
12. REFERENCES ..........................................................................................................56
13. LIST OF APPENDICES............................................................................................59
13.1.
Appendix 1: Study Flowchart........................................................................59
13.2.
Appendix 2: Calculation of Creatinine Clearance Using the Cockcroft-Gault 
Formula .........................................................................................................................62
13.3.
Appendix 3: Safety Reporting Fax Cover Sheet..............................................63
13.4.
Appendix 4: FDA Medwatch 3500 Form ........................................................64
13.5.
Appendix 5: Current National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE)................................................................................65
13.6.
Appendix 6: Response Evaluation Criteria in Solid Tumors,
Version 1.1 (RECIST v1.1) ...........................................................................................66
13.7.
Appendix 7: Hepatocellular Carcinoma-Specific Modified RECIST (HCC 
mRECIST) .....................................................................................................................76
13.8.
Appendix 8: Preexisting Autoimmune Diseases and Immune Deficiencies....83
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13.9.
Appendix 9: Anaphylaxis Precautions.............................................................84
13.10.
Appendix 10: Guidelines for Management of Adverse Events Associated with 
Bevacizumab..................................................................................................................85
13.11.
Appendix 11: Overall Guidelines for Management of Patients who Experience 
Adverse Events ..............................................................................................................89
13.12.
Appendix 12: Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab ..................................90
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Protocol Title
Atezolizumab and Bevacizumab in combination with TACE for Patients with 
BCLC B HCC
Phase
II
Objectives
The primary objective of this study is to examine the safety and tolerability 
of the combination of atezolizumab and bevacizumab with TACE.
The secondary objectives are response rate, time to progression, overall 
survival, time to TACE progression (TTTP), and time to untaceable 
progression. Assessment of tumor response will be assessed by both 
RECIST 1.1 and mRECIST for HCC.
Study Design
This is an open-label, single-arm study which will be performed at 2 sites 
examining the safety and tolerability of the combination of atezolizumab 
and bevacizumab with TACE for patients with BCLC B HCC.
TACE will be planned for each patient to be completed in up to 4 
treatments. Any patient who is not a TACE candidate will be excluded from 
the study.
Patients on study will have abdominal MRI or CT scans and CT chest every 
8 weeks for the first year, then every 12 weeks for the second year to 
evaluate for disease progression. If there is progression, patients will be 
taken off of study treatment. All patients will be taken off study treatment at 
the end of two years.
Disease progression will be evaluated by both RECIST 1.1 and mRECIST 
for HCC for the secondary objectives of the study.
Patients will continue study treatment for a total of 24 months from start of 
treatment or until intolerable toxicity or disease progression occur, 
whichever is earlier.
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Key Eligibility Criteria
1.
At least 18 years old
2.
ECOG PS of 0 or 1 within 28 days prior to registration ECOG PS of 
0 or 1 within 28 days prior to registration
3.
No cirrhosis or Child-Pugh A cirrhosis
4.
Diagnosis of HCC either by imaging or biopsy
5.
Evidence of HCC that meets BCLC B criteria
6.
Patients must have adequate hepatic, bone marrow, and renal 
function. All screening labs should be performed within 14 days of 
treatment initiation.
7.
Patients must not have signs of liver failure or history of liver failure
e.g. – encephalopathy or variceal bleeding
8.
Patients who are deemed to be candidates for TACE treatment that 
can be treated in up to 4 sessions
9.
Patients can have hepatitis B, as long as they are on antiviral 
therapy with viral loads less than 500 IU/ml
10. Patients who are positive for HBc, negative for HBsAg, regardless of 
HBs status, and have an undetectable HBV viral load do not require 
HBV antiviral prophylaxis
11. Patients who are not on HBV therapy, but positive for HBsAg and 
have an undetectable viral load are eligible for the study as long as 
they begin anti-viral prophylaxis prior to the start of study treatment
12. Patients can have untreated hepatitis C
13. At least one unidimensional tumor measurable by RECIST v1.1 
criteria
14. Hg ≥ 9 g/dL
15. Creatinine less than 1.5 x ULN
16. Serum bilirubin < 2.5 mg/dl
17. AST < 5X upper limit of normal (ULN)
18. ALT < 5 X ULN
19. Platelet count > 100 x 109/L
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20. Patients must have an EGD within 6 months with no evidence of 
esophageal and/or gastric varices with bleeding or high risk of 
bleeding. Patients with varices must be assessed and treated per 
local standard-of-care prior to enrollment.
21. Ability to comply with the study protocol, in the investigator’s 
judgment
22. Life expectancy  6 months
23. Adequate hematologic and end-organ function, defined by the 
following laboratory test results, obtained within 14 days prior to 
initiation of study treatment:
24. ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating 
factor support
25. Lymphocyte count  0.5  109/L (500/L)
26. Serum albumin  25 g/L (2.5 g/dL)
27. For patients not receiving therapeutic anticoagulation: INR or aPTT
 1.5  ULN
28. For patients receiving therapeutic anticoagulation: stable 
anticoagulant regimen
29. For women of childbearing potential: agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraceptive 
methods, and agreement to refrain from donating eggs, as defined 
below:
30. Women of child-bearing potential must remain abstinent or use 
contraceptive methods with a failure rate of  1% per year during the 
treatment period and for 6 months after the final dose of 
atezolizumab and bevacizumab. Women must refrain from donating 
eggs during this same period.
a.
A woman is considered to be of childbearing potential if she 
is postmenarchal, has not reached a postmenopausal state 
( 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone 
surgical sterilization (removal of ovaries and/or uterus).
b.
Examples of contraceptive methods with a failure rate of
 1% per year include bilateral tubal ligation, male 
sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper 
intrauterine devices.
c.
The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of 
contraception.
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31. For men of childbearing potential: With a female partner of 
childbearing potential or pregnant female partner, men must remain 
abstinent or use a condom during the treatment period to avoid 
exposing the embryo. Men must refrain from donating sperm during 
this same period.
32. The reliability of sexual abstinence should be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle 
of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not 
adequate methods of preventing drug exposure.
33. Patients receiving prophylactic antibiotics (e.g., for prevention of a 
urinary tract infection or chronic obstructive pulmonary disease) are 
eligible.
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Statistical 
Considerations
This study will plan to enroll approximately 24 patients. We will examine 
the rate of grade 3 or higher AEs with the atezolizumab and bevacizumab 
and TACE combination. Based on collected data from the G030140 study 
and the IMbrave 150 study, we assume the rate of grade 3 or higher AEs is 
approximately 55% for the atezolizumab and bevacizumab combination and 
will likely be higher with the addition of TACE.
Safety will be continuously 
monitored using the Bayesian Predictive Probability approach (Lee, 2008). 
The predictive probability (PP) of concluding that the toxicity rate is higher 
than 70% by the end of the trial based on toxicity data in the current stage 
will be continuously updated. A high PP indicates that the treatment is 
likely to be overly toxic. We will access safety after 6 patients have 
completed at least 1 TACE and 2 cycles of systemic therapy and then 
quarterly thereafter. The PI and Study Statistician will be responsible for 
review. We recommend halting enrollment on the trial for a safety analysis 
whenever there is sufficient evidence that the true toxicity rate is 
significantly greater than .70 (PP >0.80).
This study is not powered for hypothesis testing and analysis will be based 
on descriptive statistics. In general, categorical data will be summarized 
using frequencies and percentages. Binary endpoints such as response 
rate will be estimated with corresponding exact 95% confidence intervals. 
Continuous measures will be summarized using mean, standard deviation, 
interquartile range, and median. Time to event outcomes will be presented 
with Kaplan-Meier curves.
Total Number of 
Subjects
24
Estimated Enrollment 
Period/Estimated Study 
Duration
18-month enrollment period/24-month study duration
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1. BACKGROUND
1.1.
BACKGROUND ON HCC
Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide and the incidence in the 
United States has been increasing over the last several years (Xu, 2018). In addition to 
Hepatitis B, hepatitis C, and alcohol use, which are well known causes of cirrhosis and 
HCC, the incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise in the US. 
The incidence of HCC secondary to NAFLD is expected to increase and become the 
leading cause of HCC in the US (Younossi, 2019). There is a strong unmet need for 
patients with HCC given that the 5-year survival is only 18% (Jemal, 2017).
Patients with HCC who are candidates for liver transplant or surgical resection can be 
offered curative intent therapy. Also, patients with a single small tumor may be 
candidates for curative therapy with radiofrequency ablation. The Barcelona Clinic Liver 
Clinic B (BCLC B) patients, who have intermediate-stage tumors, are often candidates for 
transarterial therapies. A systematic review of transarterial chemoembolization (TACE) 
examined 101 studies with over 12,000 patients and found an objective response of 
52.5% (Llovet, 2003).
Patients with BCLC C HCC have tumors that are more advanced with either portal 
invasion or extrahepatic spread with a good performance status. These patients are 
typically offered systemic therapy. Since the approval of sorafenib more than a decade 
ago, there has been a role for systemic therapy in HCC, although it was limited to one 
approved treatment with a modest survival benefit (Llovet, 2008). More recently, there 
have been more systemic therapy options for patients, with the approval of other tyrosine 
kinase inhibitors lenvatinib (first line non-inferiority study to sorafenib) (Kudo, 2018), 
regorafenib (second line) (Bruix, 2017), and cabozantinib (second line) (Abou-Alfa, 2018) 
and the VEGF inhibitor ramucirumab (second line for patients with AFP > 400) (Zhu, 
2019).
In addition, there is positive data for immune therapy in HCC with approvals of nivolumab 
(El-Khoueiry, 2017) and pembrolizumab. Nivolumab was approved as a second line 
treatment based on the Checkmate 040 study which showed a response rate of 
approximately 15% (El-Khoueiry, 2017). Based on these positive results, the CheckMate 
459 study enrolled 743 patients with advanced HCC who had not received prior systemic 
therapy. Patients were randomized 1:1 to nivolumab or sorafenib. The primary endpoint 
of overall survival was not met. The median OS was 16.4 months with nivolumab and
14.7 months with sorafenib (p = 0.0752).
Pembrolizumab was initially approved based on the data from the phase 1 KEYNOTE-224 
study (Zhu, 2018), showing a response rate of 17%. This study was followed by the 
KEYNOTE- 240 study, which enrolled patients who had progressed on or were intolerable 
to sorafenib. Patients were randomized 2:1 to pembrolizumab and best supportive care 
or placebo and best supportive care. Co-primary endpoints were OS and PFS. The OS
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was improved (HR 0.78, one sided p = 0.0238) as was the PFS (HR 0.78, one sided p = 
0.0209), but neither met significance per the statistical plan (Finn, 2019).
Given the negative data of these two randomized trials, there is strong interest in ongoing 
studies with combination studies. There are multiple ongoing studies of combination of 
PD-1 and PDL-1 inhibitors with TKIs, CTLA-4 antibodies, and bevacizumab.
There was also a recent approval in March 2020 of the combination of nivolumab and 
ipilimumab for second line treatment based on a small data set from the Checkmate 040 
study. There were 49 patients who received the combination with an overall response 
rate of 33%. Four patients had a complete response, and 12 patients had a partial 
response (Yau, 2019).
1.2.
BACKGROUND ON ATEZOLIZUMAB AND BEVACIZUMAB COMBINATION 
IN HCC
There is strong rationale for the combination of atezolizumab and bevacizumab in multiple 
cancers. Bevacizumab seems to restore anti-cancer immunity by inhibiting VEGF-related 
immunosuppression, promoting T cell tumor infiltration and enabling priming and 
activation of T cell responses against tumor antigens (Chen, 2018). There have been 
multiple studies of the combination in different disease groups and there was recent 
approval for the combination for patients with advanced stage NSCLC (FDA, 2018).
In the phase 1 study (G030140), which enrolled several tumor types, Arm A enrolled 104 
patients with advanced HCC. With a median follow-up of 12·4 months, 37 (36%) of 104 
patients achieved a confirmed response, including 12 (12%) complete responses. For 
these 104 patients, the most common grade 3-4 treatment-related adverse events were 
hypertension (13[13%] and proteinuria 7[7%]). Treatment-related serious events occurred 
in 25 (24%); treatment-related deaths occurred in 3 (3%) patients (Lee et al, 2020).
Based on the initial positive data from Arm A on the phase I study, a phase III study of 
atezolizumab and bevacizumab versus sorafenib, the IMbrave 150 study, was initiated 
(Finn et al, 2020). The study randomized 501 patients with advanced HCC 2:1 to 
atezolizumab and bevacizumab versus sorafenib. The objective response rate for the 
combination was 27.3% by RECIST 1.1 vs 11.9% for sorafenib. Progression free survival 
in the atezolizumab and bevacizumab arm was 6.8 months [95% CI, 5.7 to 8.3] vs 4.3 
months [95% CI, 4.0 to 5.6] in the sorafenib arm. Overall survival (OS) was longer in the 
combination arm, the median OS was not reached in the combination arm and was 13.2 
months in the sorafenib arm. The OS at 6 months was 84.8% in the 
atezolizumab/bevacizumab arm vs 72.2 % in the sorafenib arm. Based on these results, 
the FDA approved the combination in June 2020 for first line systemic therapy in patients 
with advanced HCC.
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1.3.
BACKGROUND ON TACE IN HCC
Transarterial chemoembolization (TACE) is a local therapy for HCC which induces tumor 
necrosis. The liver has a dual blood supply and HCC tumors have blood supplied 
primarily by arterial vascularization compared to the surrounding liver parenchyma. There 
have been randomized controlled trials which have shown benefit of conventional TACE 
(cTACE) compared to best supportive care (BSC). A study from 2002 showed a median 
overall survival of 17.9 months with BSC vs 28.6 months with cTACE (Llovet, 2002).
There was also a meta-analysis that examined studies with cTACE vs BSC which showed 
an improvement in median OS from 16 months with BSC vs 20 months with cTACE 
(Llovet, 2002).
There is also DEB-TACE, which are drug eluting beads (DEB) released with concomitant 
embolization. In 2012, two retrospective studies published results from patients with 
HCC, which showed a median OS 43.8 months and 48 months (Burrel, 2012) (Malagari, 
2012). The most common adverse events for either cTACE or DEB-TACE are consistent 
with a post-embolization syndrome. Patients can develop nausea, vomiting, fever, and 
pain. Patients can have a transient increase in liver enzymes.
There has not been a clear consensus on many issues regarding local therapy for 
patients with HCC including how many local therapies a patient with HCC should receive, 
whether cTACE or DEB-TACE is a better therapy, and which patients with local failure 
should receive retreatment with TACE (Raoul, 2019). Most centers rely on 
multidisciplinary discussion at tumor boards to make decisions on a case-by-case basis.
1.4.
BACKGROUND ON COMBINATION OF ATEZOLIZUMAB AND 
BEVACIZUMAB WITH TACE
There has been a longstanding interest in offering patients who are candidates for local 
therapy a combination of local and systemic therapy. The SPACE study was a global 
placebo-controlled randomized phase 2 trial of TACE + placebo vs TACE + sorafenib with 
a primary endpoint of time to progression (Lencioni, 2016). Patients first received 
sorafenib or placebo for 2-7 days before TACE performed using DEB-TACE. Additional 
DEB-TACE was given according to a fixed schedule at cycle 3, 7, and 13 and then every 
six cycles afterwards (4-week cycles). The primary end point of time to progression (TTP) 
was not statistically different between the two groups (169 days for DEB-TACE with 
sorafenib vs 166 days for DEB-TACE with placebo).
The TACE-2 study was a randomized placebo-controlled, phase 3 study of DEB-TACE + 
placebo vs DEB-TACE + sorafenib with a primary endpoint of progression free survival 
(Meyer, 2017). Patients who received placebo were allowed to cross over at time of 
progression. Overall survival and time to progression were secondary endpoints. The 
study was terminated after a planned interim futility analysis. The mPFS was 238 days in 
the DEB-TACE + placebo group vs 235 days (HR 0.99 [CI 0.77-1.27], p = 0.94).
The ECOG 1208 study was a large cooperative group study in the US which also sought 
to examine the role of adding sorafenib vs placebo to TACE treatment. Unfortunately, it
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was not able to accrue to completion and ended early secondary to poor accrual. The 
results of the study have not yet been published.
A phase II study of the combination of bevacizumab and TACE was performed with 25 
patients treated. Patients received TACE and bevacizumab on the same day. The 
incidence of grade 3-4 events with cycle 1 was 21% and with cycles 2-3 was 10%. There 
was one patient who died of a perforated duodenal ulcer. The study was considered safe 
for the combination and there was not an increased incidence of bleeding events with the 
two events occurring on the same day (Buijs, 2013).
In summary, there remains an unmet need for patients with intermediate stage HCC. It is 
known that local tumor ablation can increase tumor immunogenicity by releasing tumor 
associated antigens, potentially increasing the response to immune therapy not just 
locally, but systemically (Slovak, 2017). In addition, there is now positive data with 
immune therapy in advanced HCC, there is renewed interest in the combination of local 
therapy and systemic therapy in BCLC B patients with systemic therapies other than 
sorafenib. Based on this data, we plan to examine the atezolizumab and bevacizumab 
combination with TACE in patients with BCLC B HCC.
1.5.
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients with 
advanced malignancies who have failed standard-of-care therapies. Objective responses 
have been observed across a broad range of malignancies, including NSCLC, urothelial 
carcinoma, RCC, melanoma, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma (see Atezolizumab Investigator's Brochure for detailed 
efficacy results).
Atezolizumab has been generally well tolerated. Adverse events with potentially immune- 
related causes consistent with an immunotherapeutic agent, including rash, influenza-like 
illness endocrinopathies, hepatitis or transaminitis, pneumonitis colitis, and myasthenia 
gravis, have been observed (see Atezolizumab Investigator's Brochure for detailed safety 
results). To date, these events have been manageable with treatment or interruption of 
atezolizumab treatment.
The combination of atezolizumab and bevacizumab in HCC has been well studied in both 
the phase 1 G030140 study and the phase 3 IMBrave150 study with response rates of 
36% and 27% respectively (Lee, 2020; Finn 2020). A phase 2 study of bevacizumab and 
TACE showed that the combination can be safely administered on the same day. Given 
concern for risk of bleeding with bevacizumab, all patients on these two studies had 
recent EGDs and no patients with untreated varices were included. The risk of bleeding 
on both studies were reported as low, and risk of benefit was presented as outweighing 
risk.
This trial will enroll patients with HCC who have BCLC B disease and are not candidates 
for curative treatment but are candidates for TACE. Typically, these patients would be
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treated with local treatment alone, but given the relatively poor prognosis and limited 
treatment options for these patients, this population is considered appropriate for trials of 
novel therapeutic candidates. The benefit-risk ratio for atezolizumab and bevacizumab in 
combination with TACE is expected to be acceptable in this setting. We will continue to 
watch the incidence of bleeding closely. All patients will have had an EGD in the last 6 
months prior to starting treatment.
2. OBJECTIVES AND ENDPOINTS
This is a pilot study designed to evaluate the safety and feasibility of the combination of 
Atezolizumab and Bevacizumab with TACE in patients with liver limited HCC who are 
candidates for TACE.
2.1.
PRIMARY OBJECTIVE
The primary objective of this study is to examine the safety and tolerability of the 
combination of atezolizumab and bevacizumab with TACE.
2.2.
SECONDARY OBJECTIVES
The secondary objectives are response rate, time to progression, time to TACE 
progression (TTTP), and time to untaceable progression. Assessment of tumor response 
will be assessed by both RECIST 1.1 and mRECIST for HCC.
Time to progression will be defined as the time from trial enrollment until objective tumor 
progression by RECIST criteria, it does not include deaths.
Time to TACE progression is defined as the interval of time from the day of the images 
after a TACE procedure to the time or progression, new vascular invasion or extrahepatic 
spread also is counted as progression (Arizumi 2017).
Time to untaceable progression is defined as time to untreatable tumor progression, 
transient deterioration to Child-Pugh C score, or appearance of vascular 
invasion/extrahepatic spread.
3. STUDY DESIGN
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3.1.
Trial Schema
Study Population: ~24 patients with BCLC B HCC will be enrolled in this study
Study Duration: 18-month enrollment period; 24-month study duration
Screening
C1D1
(± 3 days)
C2D1
(± 3 days)
C2D7
C3D1
(± 3 days)
C3D14
C4D1
(± 3 days)
C4D21
C5D1
(± 3 days)
C6D1
(± 3 days)
C6D7
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
Atezolizumab a
xa
xa
xa
xa
xa
xa
xa
xa
Bevacizumab b
xb
xb
TACE c, d
x c, d
x c, d
x c, d
x c, d
Footnotes:
a.     Atezolizumab 1200mg will be administered intravenously on day 1 of every 21-day cycle beginning C1D1 The initial dose of 
atezolizumab will be delivered over 60 ( 15) minutes. Subsequent infusions will be delivered over 30 (10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an 
infusion-associated adverse event with the previous infusion.
b. Bevacizumab 15mg/kg will be administered intravenously on C1D1 and resume on Day 1 of the treatment cycle at least 4 
weeks after the last TACE procedure. Full recovery from the TACE procedure is required prior to re-starting treatment with 
bevacizumab.
c. TACE treatments may occur 1, 2, 3, or 4 times based on the clinical judgement from the investigational radiologist. The first 
TACE procedure must be at least 28 days from the last bevacizumab treatment.
d. TACE treatments occur 4-6 weeks apart when clinically indicated. TACE window is +1 week.
Example Treatment Schedule by Number of TACE Procedures:
TACE Procedures = 4
Earliest possible first TACE Procedure = C2D7 (based on 28 days from last bevacizumab dose) 
Earliest possible re-introduction of Bev = C8D1 (based on TACE every 4 weeks ending C6D7)
Screening
C1D1
(± 3 days)
C2D1
(± 3 days)
C2D7
C3D1
(± 3 days)
C3D14
C4D1
(± 3 days)
C4D21
C5D1
(± 3 days)
C6D1
(± 3 days)
C6D7
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
Atezolizumab
x
x
x
x
x
x
x
x
Bevacizumab
x
x
TACE
x
x
x
x
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TACE Procedures = 3
Earliest possible first TACE Procedure = C2D7 (based on 28 days from last bevacizumab dose) 
Earliest possible re-introduction of Bev = C7D1 (based on TACE every 4 weeks ending C4D21)
Screening
C1D1
(± 3 days)
C2D1
(± 3 days)
C2D7
C3D1
(± 3 days)
C3D14
C4D1
(± 3 days)
C4D21
C5D1
(± 3 days)
C6D1
(± 3 days)
C6D7
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
Atezolizumab
x
x
x
x
x
x
x
x
Bevacizumab
x
x
x
TACE
x
x
x
TACE Procedures = 2
Earliest possible first TACE Procedure = C2D7 (based on 28 days from last bevacizumab dose) 
Earliest possible re-introduction of Bev = C5D1 (based on TACE every 4 weeks ending C3D14)
Screening
C1D1
(± 3 days)
C2D1
(± 3 days)
C2D7
C3D1
(± 3 days)
C3D14
C4D1
(± 3 days)
C4D21
C5D1
(± 3 days)
C6D1
(± 3 days)
C6D7
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
Atezolizumab
x
x
x
x
x
x
x
x
Bevacizumab
x
x
x
x
x
TACE
x
x
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TACE Procedures = 1
Earliest possible first TACE Procedure = C2D7 (based on 28 days from last bevacizumab dose) 
Earliest possible re-introduction of Bev = C4D1 (based on TACE every 4 weeks ending C2D7)
Screening
C1D1
(± 3 days)
C2D1
(± 3 days)
C2D7
C3D1
(± 3 days)
C3D14
C4D1
(± 3 days)
C4D21
C5D1
(± 3 days)
C6D1
(± 3 days)
C6D7
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
Atezolizumab
x
x
x
x
x
x
x
x
Bevacizumab
x
x
x
x
x
x
TACE
x
3.2.
DESCRIPTION OF THE STUDY
THIS IS A SINGLE ARM PILOT/FEASABILITY STUDY. THE STUDY CONSISTS OF A 
SCREENING PERIOD (DAY -28 TO DAY -1), A TREATMENT PERIOD, AND A 
TREATMENT DISCONTINUATION VISIT.
The atezolizumab and bevacizumab combination will be given every 21 days, 
atezolizumab 1200 mg and bevacizumab 15 mg/kg will be administered intravenously on 
a Q3 week schedule.
Subjects will start the combination of bevacizumab and atezolizumab followed by TACE 
treatment 4 weeks +1 week or up to 5 weeks after study drugs. Full recovery from the 
TACE procedure is required prior to further 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 TACE procedure.
The number of TACE procedures performed will be 1-4 based on the evaluation of the 
interventional radiologist. TACE will be administered every 4-6 weeks, up to 4 TACEs 
are allowed on study, at the discretion of the treating interventional radiologist. Given the 
interest in caution of TACE procedure with bevacizumab, there will need to be a 4-week 
interval between TACE and  bevacizumab, 4 weeks before TACE and 4 weeks after 
TACE. Therefore, around TACE procedures, there will be a longer interval between 
atezolizumab and bevacizumab cycles. So, during  the cycles that have a TACE 
procedure, there will be at least 8 weeks but no more than 12 weeks between cycles. 
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Subjects will have repeat imaging every 8 weeks for the first year and then every 
12 weeks after the first year. Safety assessments will occur at every treatment visit.
Subjects who are tolerating therapy and have not had progression of disease can 
remain on therapy for up to 2 years.
This study will enroll 24 subjects over an 18-month period, with 1-2 subjects enrolled 
each  month. Efficacy will be assessed by imaging, either MRI or CT.
Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg 
on Day 1 of each 21-day cycle (longer cycle when TACE is administered) until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, and clinical status (e.g., 
symptomatic deterioration such as pain secondary to disease).
Bevacizumab will be administered by intravenous (IV) infusion at a dose of 15 mg/kg on 
day 1 of each 21-day cycle, with holding around each TACE administration so that 
administration is not within four weeks before or after TACE. Treatment will be given until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, and clinical status.
3.3.
END OF STUDY AND LENGTH OF STUDY
The end of study is defined as the date that the last patient, last visit occurs, or the date at 
which the last data point required for statistical analysis, or safety follow-up is received 
from the last patient, whichever occurs later. The end of the study is expected to occur 
approximately 6 months after the last patient enrolls on the study. In addition, the 
Investigator may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 24 months.
3.4.
RATIONALE FOR STUDY DESIGN
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of 
each 21-day cycle), which is the approved dosage for atezolizumab, as outlined in the 
prescribing information. Anti-tumor activity has been observed across doses ranging from 
1 mg/kg to 20 mg/kg Q3W. In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached and no DLTs were observed at any dose. The fixed dose 
of 1200 mg Q3W (equivalent to an average body weight-based dose of 15 mg/kg Q3W) 
was selected on the basis of both nonclinical studies (Deng et al. 2016) and available 
clinical pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).
The atezolizumab and bevacizumab combination dosage and schedule is based on both 
the phase 1 G030140 study and the phase 3 IMbrave studies showing the safety and 
efficacy of this regimen. The schedule of TACE is based on a standard schedule of this 
procedure. The schedule of separating bevacizumab infusion from TACE procedure by 4 
weeks is out of concern for bleeding risk.
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3.4.1. Rationale for Patient Population
The phase 1 and phase 3 data of the combination of atezolizumab and bevacizumab has 
shown safety and efficacy in patients with advanced HCC who are no longer candidates 
for local therapy. The purpose of this study is to examine the role of this regimen in 
combination with TACE for patients with HCC who would standardly be treated with TACE 
alone.
3.5.
PATIENTS
Approximately 24 patients with BCLC B HCC will be enrolled in this study. Eligibility 
criteria are to be assessed within 28 days of treatment start unless otherwise noted.
3.5.1. Inclusion Criteria
1.
At least 18 years old
2.
ECOG PS of 0 or 1 within 28 days prior to registration ECOG PS of 0 or 1 within 28 days 
prior to registration
3.
No cirrhosis or Child-Pugh A cirrhosis
4.
Diagnosis of HCC either by imaging or biopsy
5.
Evidence of HCC that meets BCLC B criteria
6.
Patients must have adequate hepatic, bone marrow, and renal function. All screening labs 
should be performed within 14 days of treatment initiation.
7.
Patients must be candidates for TACE treatment that can be treated in up to 4 sessions
8.
Patients who are positive for HBc, regardless of HBs status, and have an undetectable 
HBV viral load do not require HBV antiviral prophylaxis
9.
Patients who are not on HBV therapy, but positive for HBsAg and have an undetectable 
viral load are eligible for the study as long as they begin anti-viral prophylaxis prior to the 
start of study treatment
10. Patients can have untreated hepatitis C
11. At least one unidimensional tumor measurable by RECIST v1.1 criteria
12. Hg ≥ 9 g/dL
13. Creatinine less than 1.5 x ULN
14. Serum bilirubin < 2.5 mg/dl
15. AST < 5X upper limit of normal (ULN)
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16. ALT < 5 X ULN
17. Platelet count > 100 x 109/L
18. Patients must have an EGD within 6 months with no evidence of esophageal and/or gastric 
varices with bleeding or high risk of bleeding. Patients with varices must be assessed and 
treated per local standard-of-care prior to enrollment.
19. Ability to comply with the study protocol, in the investigator’s judgment
20. Life expectancy  6 months
21. Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
22. ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor support
23. Lymphocyte count  0.5  109/L (500/L)
24. Serum albumin  25 g/L (2.5 g/dL)
25. For patients not receiving therapeutic anticoagulation: INR or aPTT  1.5  ULN
26. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen allowed 
for both Atezo and Avastin. Please note the most current guidelines for Avastin are: 
Exclusionary: Current or recent ( 10 days prior to initiation of study treatment) use of 
aspirin ( 325 mg/day), or clopidogrel ( 75 mg/day) Allowed: Note: The use of full-dose 
oral or parenteral anticoagulants for therapeutic purpose is permitted as long as the INR 
and/or aPTT is within therapeutic limits (according to institution standards) within 7 days 
prior to initiation of study treatment and the patient has been on a stable dose of 
anticoagulants for  2 weeks prior to initiation of study treatment. Prophylactic use of 
anticoagulants is allowed. However, the use of direct oral anticoagulant therapies such as 
dabigatran (Pradaxa) and rivaroxaban (Xarelto) is not recommended due to bleeding 
risk.
27. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below. Women of child-bearing potential must remain abstinent 
or use contraceptive methods with a failure rate of  1% per year during the treatment 
period and for 6 months after the final dose of atezolizumab and bevacizumab. Women 
must refrain from donating eggs during this same period.
a. A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
b. Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
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c. The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not adequate methods of contraception.
28. For men of childbearing potential: With a female partner of childbearing potential or 
pregnant female partner, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the final dose of atezolizumab and bevacizumab to 
avoid exposing the embryo. Men must refrain from donating sperm during this same 
period.
29. The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
adequate methods of preventing drug exposure.
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic 
obstructive pulmonary disease) are eligible
3.5.2. Exclusion Criteria
1.
Patients must not have signs of liver failure or history of liver failure e.g. – encephalopathy 
or variceal bleeding
2.
Uncontrolled hepatitis B infection with viral load >500 IU/ml
3.
History of hypertensive crisis or hypertensive encephalopathy
4.
Patients who are candidates for curative intent therapy (transplant, resection, or thermal 
ablation) or liver transplant
5.
Patients who are on the transplant list
6.
Ascites requiring therapeutic paracentesis in the last 12 months
7.
Episode of hepatic encephalopathy in the last 12 months
8.
Extrahepatic spread: borderline portal lymph nodes deemed to be of indeterminate nature 
and measuring less than 2 cm are allowed
9.
Prior local or systemic therapy for HCC or prior TACE, excluding prior use of RFA
10. Patients cannot have known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
11. Occlusion of the hepatic artery or main portal vein
12. Pregnant or lactating, or intending to become pregnant during the study
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13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
other recombinant human antibodies
14. Known history of HIV infection. No HIV testing is required.
15. Active or history of autoimmune disease or immune deficiency, 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 (see Appendix 8 for a more comprehensive list of autoimmune diseases and 
immune deficiencies), with the following exceptions:
a.
Patients with a history of autoimmune-related hypothyroidism who are on thyroid- 
replacement hormone are eligible for the study.
b.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
c.
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:
i.
Rash must cover  10% of body surface area
ii.
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
iii.
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
16. History of leptomeningeal disease
17. Active tuberculosis
18. Uncontrolled tumor-related pain
a.
Patients requiring pain medication must be on a stable regimen at study entry.
19. Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium  12 
mg/dL or corrected serum calcium  ULN)
20. Signs or symptoms of significant infection within 2 weeks prior to Day 1
21. Severe infection within 4 weeks prior to initiation of study treatment, including but not 
limited hospitalization for complications of infection, bacteremia, or severe pneumonia.
22. Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, 
Day 1
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23. Significant cardiovascular disease, (such as New York Heart Association cardiac disease 
Class II or greater, myocardial infarction, or cerebrovascular accident) within 3 months 
prior to prior to Day 1, unstable arrhythmias, or unstable angina
24. Patients with a known left ventricular ejection fraction (LVEF)  40% will be excluded. 
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF  50% must be on a stable medical regimen that is optimized in the 
opinion of the treating physician, in consultation with a cardiologist if appropriate.
25. History of stroke, prolonged reversible ischemic neurological deficit or transient ischemic 
attack within 6 months prior to Day 1
26. Major surgical procedure within 28 days prior to Day 1 or anticipation of need for a major 
surgical procedure during the course of the study
27. 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.
28. Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study
29. Malignancies within 2 years prior to study start, with the exception of those with a 
negligible risk of metastasis or death (e.g., expected 5-year OS  90%) treated with 
expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer, localized prostate cancer treated surgically with 
curative intent, ductal carcinoma in situ treated surgically with curative intent)
30. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
a.
Patients with indwelling catheters (e.g., PleurX) are allowed.
31. Inadequately controlled arterial hypertension (defined as systolic blood pressure [BP] 150 
mmHg and/or diastolic BP  100 mmHg), based on an average of  3 BP readings on  2 
sessions. Anti-hypertensive therapy to achieve these parameters is allowable
32. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1
33. History of hemoptysis ( 2.5 mL of bright red blood per episode) within 1 month prior to 
Day 1
34. Evidence of bleeding diathesis or significant coagulopathy
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35. 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
36. Current or recent ( 10 days prior to initiation of study treatment) use of aspirin ( 325 
mg/day), or clopidogrel ( 75 mg/day)
Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purpose is 
permitted as long as the INR and/or aPTT is within therapeutic limits (according to 
institution standards) within 7 days prior to initiation of study treatment and the patient 
has been on a stable dose of anticoagulants for  2 weeks prior to initiation of study 
treatment. Prophylactic use of anticoagulants is allowed. However, the use of direct oral 
anticoagulant therapies such as dabigatran (Pradaxa) and rivaroxaban (Xarelto) is not 
recommended due to bleeding risk.
37. Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 3 days of treatment start
38. Proteinuria, as demonstrated by urine dipstick or  1.0 g of protein in a 24-hour urine 
collection. All patients with  2+ protein on dipstick urinalysis at baseline must undergo a 
24-hour urine collection for protein.
39. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (occasional use for the 
symptomatic relief of medical conditions such as headache or fever is allowed)
40. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan. History of radiation 
pneumonitis in the radiation field (fibrosis) is permitted.
41. Prior allogeneic stem cell or solid organ transplantation
42. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications
43. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
44. 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
45. Treatment with investigational therapy within 28 days prior to initiation of study treatment
46. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation
47. Known allergy or hypersensitivity to any component of the bevacizumab or atezolizumab 
formulation
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48. History of Grade  4 venous thromboembolism
49. History of abdominal fistula, GI perforation, intra-abdominal abscess, or active GI bleeding 
within 6 months prior to randomization
50. Serious, non-healing wound, active ulcer, or untreated bone fracture
4. STUDY TREATMENT
The investigational medicinal products (IMPs) for this study are atezolizumab and 
bevacizumab. TACE is considered a non-investigational medicinal product (NIMP)
4.1.
Study Treatment Formulation, Packaging, and Handling
4.1.1. Atezolizumab
The atezolizumab 1200 mg drug product will be supplied in a single-use, 20-mL USP/Ph. 
Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, preservative-free clear liquid 
solution intended for IV administration. The vial is designed to deliver 20 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of 
the entire 20-mL volume.
For information on the formulation and handling of atezolizumab, see the Atezolizumab 
Investigator's Brochure.
4.1.2. Bevacizumab
Bevacizumab will be supplied by Genentech, Inc. For information on the formulation and 
handling of bevacizumab, see the pharmacy manual and the Bevacizumab Investigator's 
Brochure.
4.1.3. TACE
Doxorubicin is a marketed chemotherapy drug that will be used during TACE for this study. 
It will be administered as an emulsion with Lipiodol, which is a lipophilic iodinated contrast 
medium made up of a mixture of ethyl esters of carnation oil fatty acids.
An experienced interventional radiologist will be administering cTACE. Lipiodol 10 mL is 
usually administered. Only doxorubicin is mixed in pharmacy (50mg in 2mL sterile water). 
After administered, embolization completed with 250-355 micron polyvinyl alcohol (PVA) 
particles until near stasis or stasis is achieved.
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4.2.
STUDY TREATMENT DOSAGE, ADMINISTRATION, AND COMPLIANCE
Any overdose or incorrect administration of any of the study treatments should be noted in 
the patient’s medical records and reported to the Sponsor Investigator. Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded in the patient’s medical records.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Appendix 10, 11, 12.
4.2.1. Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by 
the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status Atezolizumab will be administered 
first, followed by bevacizumab with a minimum of 5 minutes between dosing. The 
schedule will change on cycles when TACE is being administered, then there will be at 
least 4 weeks separating infusions from TACE.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. For anaphylaxis precautions, see Appendix 9.
Atezolizumab infusions will be administered per the instructions outlined in Table 1.
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4.2.1.1.
Table 1: Administration of First and Subsequent Atezolizumab 
Infusions
First Infusion
Subsequent Infusions
●
No premedication is needed prior to the 
atezolizumab infusion.
●
Vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) should be measured 
within 60 minutes prior to the infusion.
●
Atezolizumab should be infused over 60 ( 15) 
minutes.
●
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the infusion.
●
Patients should be informed about the possibility of 
delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such 
symptoms.
●
If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, antipyretics, 
and/or analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.
●
Vital signs should be measured within 
60 minutes prior to the infusion.
●
Atezolizumab should be infused over 30 ( 10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 ( 15) 
minutes if the patient experienced an infusion- 
related reaction with any previous infusion.
●
If the patient experienced an infusion-related 
reaction with any previous infusion or if clinically 
indicated, vital signs should be measured during 
the infusion and at 30 ( 10) minutes after the 
infusion.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 9.
No dose modification for atezolizumab is allowed.
4.2.2. Bevacizumab
Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3-week cycle. 
The infusion will start at least 5 minutes after the atezolizumab infusion finishes. The 
initial dose will be delivered over 90 minutes (+/- 10 minutes). 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 and 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
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associated adverse event with the 60-minute infusion, all subsequent doses should be 
given over 90 minutes (+/- 10 minutes). Also, 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).
4.2.3. TACE
TACE will be administered by injection through a transfemorally or transradially placed 
catheter into the hepatic artery. Hepatic angiography will be performed to determine the 
vascular anatomy of the liver and feeding arteries to HCCs. As there are frequent arterial 
anomalies in the blood supply to the liver, the interventionalist must be familiar with those 
anomalies. Advanced intraprocedural imaging (e.g., cone beam CT) will be used to map 
the intratumoral vascular supply.
The interventionalist will then insert the catheter selectively into the artery supplying only 
segment/subsegment that contains the HCCs. The doxorubicin/lipiodol emulsion will then 
be delivered to the HCCs with sparing as much of the other non-targeted liver as possible. 
This is an excellent way of delivering high doses of chemotherapy (doxorubicin) to the 
tumor without any chance of damaging the normal liver.
TACE administration will be performed in an angiography suite with a standard 
angiographic technique. Administration into the target vessel will occur via a 
microcatheter. Lipiodol will act as the contrast medium to visualize and monitor the status 
of flow to the treating tumor and feeding vessel under fluoroscopy.
The end point of the procedure is achieved when either 1) the entire amount of 
chemotherapeutic: lipiodol emulsion is administered or 2) the emulsion is seen within 
secondary or tertiary portal venules. If forward flow is visualized after the emulsion is 
administered, PVA particles are administered to achieve stasis or near stasis. This 
includes slowing of flow with pruning of the tumor-feeding branches (the “tree-in-winter” 
appearance) or transit time of contrast in the feeding artery takes 4 heartbeats. Once slow 
vessel flow is detected, no further injection will be performed. Treat the tumor vascularity 
until stasis or near stasis is achieved.
Post-Procedure Care
a) Post-arteriography bedrest with monitoring of vital signs and pulses per institutional 
protocol.
b) Patient can be discharged as soon as they demonstrate adequate oral intake or liquids, 
and no longer require parenteral narcotics or antiemetics. (Average length of stay is 1 
day).
c) Fevers <103.0 are normal in the first week and do not require cultures.
d) Discharge medications:
i. Antibiotics per institutional protocol if felt to be medically necessary by treating 
physicians.
ii. Tylenol #3 (or narcotic) PRN for pain
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iii. Nausea medications PRN
e) Patient returns in approximately 4-6 weeks for repeat treatment (up to 4) based on 
anatomy and tumor burden (remaining lobe of the liver or retreat same territory if 
incompletely embolized).
4.3.
Concomitant Therapy and Additional Restrictions
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the- 
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study treatment to the treatment discontinuation visit. All such medications should be 
reported to the investigator and recorded in the patient’s medical records.
4.3.1. Permitted Therapy
Patients are permitted to use the following therapies during the study:
●
Oral contraceptives
●
Hormone-replacement therapy
●
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose 
or low-molecular-weight heparin)
●
Vaccinations (such as. influenza, SARS-CoV-2)
o (Live, attenuated vaccines are not permitted)
●
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
●
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 (including preexisting conditions) 
with supportive therapies other than those defined as cautionary or prohibited 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 Appendix 
9.
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4.3.2. Cautionary Therapy for Atezolizumab-Treated Patients
4.3.2.1.
Corticosteroids and Tumor Necrosis Factor-α Inhibitors
Systemic corticosteroids and TNF-á inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab. Therefore, in situations in which 
systemic corticosteroids or TNF-á inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered. If the alternatives are not feasible, 
systemic corticosteroids and TNF-á 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 
Appendix 12).
4.3.2.2.
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 (see 
Section 4.3.3) may be used during the study at the discretion of the investigator.
4.3.3.
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:
●
Concomitant therapy, outside of those given a part of this protocol, intended for the 
treatment of cancer (including, but not limited to, chemotherapy, immunotherapy, 
radiotherapy), whether health authorityapproved or experimental, is prohibited 
during study treatment, until disease progression is documented, and the patient has 
discontinued study treatment
●
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.
●
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 6 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 drug elimination half-lives (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 atezolizumab.
5. STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities must be performed and documented for each patient. Patients will be closely 
monitored for safety and tolerability throughout the study. Patients should be assessed
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for toxicity prior to dose with each study drug; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. Local laboratory tests are 
done on the day of each treatment, before the cycle atezolizumab, bevacizumab, and 
TACE. There is a lab window of 48 hours before treatment.
Written informed consent for participation in the study must be obtained before performing 
any study-related procedures (including screening evaluations). Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
5.1.
Medical History, Concomitant Medication, and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking
history, and use of alcohol and drugs of abuse, will be recorded at baseline. In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to 
initiation of study treatment will be recorded. At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
5.2.
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems. Any abnormality identified at baseline should be recorded in the 
patient’s medical records.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in patient notes. New or worsened clinically significant abnormalities 
should be recorded as adverse events in the patient’s medical records.
5.3.
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, and temperature.
Vital signs should be measured within 60 minutes prior to each infusion at every cycle. 
and, if clinically indicated, during or after the infusion. In addition, vital signs should be
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measured at other specified timepoints as outlined in the schedule of activities (see 
Appendix 1).
5.4.
Tumor And Response Evaluations
Patients will undergo tumor assessments at baseline, every 8 weeks for the first
12 months following treatment initiation, and every 12 weeks thereafter, regardless of 
dose delays, until radiographic disease progression per RECIST v1.1 or (loss of clinical 
benefit as determined by the investigator (see Section 3.2 for details). Thus, tumor 
assessments are to continue according to schedule in patients who discontinue treatment 
for reasons other than disease progression or loss of clinical benefit, even if they start 
new anti-cancer therapy. At the investigator’s discretion, tumor assessments may be 
repeated at any time if progressive disease is suspected.
All measurable and evaluable lesions should be assessed and documented at screening. 
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening.
Screening assessments must include an MRI of the abdomen, or CT of the abdomen, and 
a CT of the chest (an MRI of the abdomen is preferred). At the investigator's discretion, 
other methods of assessment of measurable disease as per RECIST v1.1 may be used.
All measurable and evaluable lesions identified at baseline should be re-assessed at each 
subsequent tumor evaluation. The same radiographic procedures used to assess disease 
sites at screening should be used for subsequent tumor assessments (e.g., the same 
contrast protocol for CT scans).
Overall response at a single timepoint will be assessed by the investigator using RECIST 
v1.1 (see Appendix 6 prior to treatment administration at each cycle.
5.5.
Laboratory, Biomarker, And Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:
o
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet 
count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells)
o
Chemistry panel): bicarbonate or total carbon dioxide, sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, 
and AST
o
Coagulation: INR, and aPTT
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o
Thyroid function testing: thyroid-stimulating hormone, free triiodothyronine 
(T3) (or total T3 for sites where free T3 is not performed), and free thyroxine 
(also known as T4)
o
HBV serology: HBsAg, total HBcAb, and (if HBsAg test is negative and total 
HBcAb test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.
o
HCV serology: HCV antibody and (if HCV antibody test is positive) HCV 
RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test must 
also be performed to determine if the patient has an HCV infection.
o
Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening. Urine pregnancy tests will be performed at specified subsequent 
visits. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
o
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); 
dipstick permitted
5.6.
Electrocardiograms
An ECG is required at screening and when clinically indicated. Lead placement should be 
as consistent as possible. ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Any morphologic waveform changes or other ECG abnormalities must be 
documented in the patient’s medical records.
6. TREATMENT, PATIENT, AND STUDY DISCONTINUATION
Patients must permanently discontinue study treatment atezolizumab and bevacizumab if 
they experience any of the following:
●
Intolerable toxicity related to study treatment, including development of an 
immunemediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event
●
Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment
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●
Investigator determines it is in the best interest of the patient
●
Use of another non-protocol anti-cancer therapy
●
Pregnancy
o
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease) (see Section 3.2 for details)
The primary reason for study treatment discontinuation should be documented in the 
patient’s medical records. Patients who discontinue study treatment prematurely will not 
be replaced.
Patients will return to the clinic for a treatment discontinuation visit  30 days after the last 
dose of study treatment. The visit at which response assessment shows progressive 
disease may be used as the treatment discontinuation visit. Patients who discontinue 
study treatment for any reason other than progressive disease or loss of clinical benefit 
will continue to undergo tumor response assessments and PRO assessments as outlined 
in the schedule of activities (see Appendix 1).
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following:
●
Withdrawal of consent
●
Study termination or site closure
●
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented in the 
patient’s medical records. If a patient request to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
6.1.
Study Discontinuation
The Investigator has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following:
●
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients
●
Patient enrollment is unsatisfactory
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7. ASSESSMENT OF SAFETY
7.1.
Safety Plan
The safety plan for patients in this study is based on clinical experience with atezolizumab 
and bevacizumab in completed and ongoing studies. The anticipated important safety 
risks are outlined below (see Section 7.1.)
Measures will be taken to ensure the safety of patients participating in this study, including 
the use of stringent inclusion and exclusion criteria and close monitoring of patients during 
the study. Administration of atezolizumab and bevacizumab and TACE will be performed 
in a monitored setting in which there is immediate access to trained personnel and 
adequate equipment and medicine to manage potentially serious reactions. Guidelines 
for managing patients who experience anticipated adverse events, including treatment 
interruption or discontinuation, are provided in Appendix 10, 11, 12).
Refer to Sections 
7.37.5 for details on safety reporting (e.g., adverse events, pregnancies) during the 
study.
7.1.1. Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following: IRRs and 
immunerelated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis,  
meningoencephalitis, myocarditis, pericardial disorders, 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. Refer to Appendix 12 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab.
7.1.2. Risks Associated with Bevacizumab
Bevacizumab has been associated with common risks such as the following: 
hypertension, proteinuria, epistaxis, dry skin. More serious risks include bleeding, 
impaired surgical wound healing, arterial thrombotic events, and gastrointestinal 
perforation. Refer to the Bevacizumab Investigator’s Brochure for a detailed description 
of anticipated safety risks for bevacizumab.
7.1.3. Risks Associated with TACE
TACE has been associated with infusion-associated symptoms, which can be severe. 
There is also a risk of post-TACE syndrome where patients can have fever, 
nausea/vomiting, and pain. There is also a risk of bleeding. This is risk of bleeding comes 
mostly from groin access, not the TACE administration itself. Refer to the following 
publications: Bajwa et. al. 2020, Kishore et. al. 2017, and Kishore et. al. 2017, Labeur 
2019, Marcacuzco 2018 .
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TACE Common Side Effects:

A low-grade temperature (< 102 F) for one week

Nausea and/or vomiting, lethargy, and decreased appetite for several days

Bruising at the puncture site

Some hair loss: this is usually minimal and may be unnoticed by others

Pain in the upper-right abdomen, under the ribs
Doxorubicin is among the most common chemotherapy drugs used for TACE and will be 
used for this study. Doxorubicin will be administered as an emulsion with Lipiodol.
Doxorubicin Side Effects:
CATEGORY
ADVERSE REACTIONS
Cardiac

Cardiogenic shock
Cutaneous

Skin and nail hyperpigmentation

Oncolysis

Rash

Itching

Photosensitivity

Urticaria

Acral erythema

Palmar plantar erythrodysesthesia
Gastrointestinal

Nausea

Mucositis

Stomatitis

Necrotizing colitis

Typhlitis

Gastric erosions

Gastrointestinal tract bleeding

Hematochezia

Esophagitis

Anorexia

Abdominal pain

Dehydration

Diarrhea

Hyperpigmentation of the oral mucosa
Hypersensitivity

Anaphylaxis
Laboratory Abnormalities

Increased ALT, increased AST
Neurological

Peripheral sensory and motor neuropathy

Seizures

Coma
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Ocular

Conjunctivitis

Keratitis

Lacrimation
Vascular

Phlebosclerosis

Phlebitis/thrombophlebitis

Hot flashes

Thromboembolism
Other

Malaise/asthenia

Fever

Chills

Weight gain
Lipiodol Side Effects:
System Organ Class
Adverse Reaction
Endocrine disorders

hypothyroidism

hyperthyroidism

thyroiditis
Eye disorders

retinal vein thrombosis
Gastrointestinal disorders

nausea

vomiting

diarrhea
General disorders and 
administration site conditions

fever

pain

granuloma
Hepatobiliary disorders

hepatic vein thrombosis
Immune system disorders

hypersensitivity

anaphylactic reaction

anaphylactoid reaction
Nervous system disorders

cerebral embolism
Respiratory, thoracic, and 
mediastinal disorders

pulmonary embolism*

dyspnea

cough

acute respiratory distress syndrome
Urinary system disorders

renal insufficiency
* Lipiodol technically can embolize to the lungs, albeit rarely. Occurs when larger doses (e.g., 20 mL 
lipiodol administered during a single session).
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7.2.
Safety Parameters and Definitions
Safety assessments will consist of monitoring and reporting adverse events and serious 
adverse events per protocol. This includes all events of death and any study-specific 
issue of concern.
7.2.1. Adverse Events
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal 
product (IMP) or other protocol-imposed intervention, regardless of attribution.
This includes the following:
●
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with the atezolizumab, 
bevacizumab, and TACE combination that were not present prior to the AE reporting 
period.
●
Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations).
●
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention.
●
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.
7.2.2. Serious Adverse Events
An AE should be classified as an SAE if any of the following criteria are met:
●
It results in death (i.e., the AE actually causes or leads to death).
●
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.).
●
It requires or prolongs inpatient hospitalization.
●
It 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).
●
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP.
●
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above).
7.2.3. Adverse Events of Special Interest
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific 
to the product, for which ongoing monitoring and rapid communication by the Investigator
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to the Sponsor-Investigator is required. Such an event might require further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial Sponsor-Investigator to other parties (e.g., Regulatory 
Authorities) may also be warranted.
The following AEs are considered of special interest and must be reported to the Sponsor 
Investigator expeditiously, irrespective of regulatory seriousness criteria:
●
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:
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)
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
●
Data related to a suspected transmission of an infectious agent by the study treatment, 
as defined below
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.
Atezolizumab Events of Special Interest to be reported to the PI as SAEs:
●
Systemic lupus erythematosus
●
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, macrophage activating syndrome, 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)
●
Myelitis
●
Facial paresis
There are no Bevacizumab-specific AESIs.
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7.2.4. Selected Adverse Events
Additional data collection or analysis will be performed for selected adverse events.
Selected Adverse Events for this study are:
• Hemorrhage
– Any grade CNS bleeding
– Grade  2 hemoptysis
– Other Grade  3 hemorrhagic event
Note: Selected adverse events should not be confused with adverse events of special 
interest (see Section 7.2.3)
7.2.5. Other Special Situation Reports
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech:

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
Product Complaints

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.
7.3.
Methods and Timing for Assessing and Recording Study Variables
7.3.1. Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient's medical record.
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported.
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special interest
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will continue to be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.
7.3.2. Assessment of Adverse Events
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 bevacizumab and atezolizumab (see following guidance), and actions 
taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline:
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 and bevacizumab or with similar treatments; 
and/or the AE abates or resolves upon discontinuation of atezolizumab and bevacizumab 
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 and bevacizumab administration (e.g., cancer diagnosed 2 days after first 
dose of atezolizumab and bevacizumab).
Expected adverse events are those adverse events that are listed or characterized in the 
current Investigator Brochure (I.B) for both atezolizumab and bevacizumab.
Unexpected adverse events are those not listed in current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the I.B. only referred to elevated hepatic enzymes or hepatitis.
In addition, adverse events thought to be TACE procedure will be reported as an adverse 
event of the study.  These will include any bleeding related events.
For patients receiving combination therapy (atezolizumab, bevacizumab and/or TACE 
procedure), causality will be assessed individually for each protocol-mandated therapy.
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7.4.
Procedures for Eliciting, Recording, and Reporting Adverse Events
7.4.1. Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints. Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
7.4.2. Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations.
7.4.2.1.
Diagnosis versus Signs and Symptoms
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.
7.4.2.2.
Deaths
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”.
7.4.2.3.
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”).
7.4.2.4.
Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. 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:
●
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions
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●
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study or
●
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study
7.4.2.5.
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE 5 will be used for assessing 
adverse event severity.
Table 2 should be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE.
7.4.2.5.1. Table 2:
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
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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
7.4.2.6.
Pregnancies
If a female subject or female partner of male study subject becomes pregnant while 
receiving atezolizumab and bevacizumab or within 6 months after the last dose of 
atezolizumab and bevacizumab, a report should be completed and expeditiously 
submitted to Sponsor Investigator. 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 to the Sponsor Investigator as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to the 
atezolizumab should be reported to the Sponsor Investigator as an SAE.
7.4.2.7.
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 or TACE 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.
7.5.
Adverse Event Reporting
7.5.1. Adverse Event Reporting to Sponsor Investigator
Please refer to the Manual of Procedures (MOPs) for SAE reporting procedures.
The investigators will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation 
Reports (including pregnancy reports), Selected Adverse Events and Product Complaints 
(with or without an AE) originating from the Study for the Product.
Investigators must report all the above-mentioned single case reports adequately to the 
Sponsor Investigator within the timelines described below. The completed MedWatch
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reporting form should be emailed immediately upon completion to the Sponsor 
Investigator, and designee at the contact information listed in the Manual of Procedures.
It is understood and agreed that the Sponsor Investigator will be responsible for the 
evaluation of AEs, SAEs, AESIs, Special Situation reports (including pregnancy reports), 
Selected Adverse Events and Product Complaints (with or without an AE) originating from 
the study.
These single case reports will be exchanged between the parties as outlined below so 
that regulatory obligations are met.
7.5.2. Sponsor-Investigator Adverse Event Reporting to Genentech
This study has SDEA.
The Sponsor Investigator will be responsible for collecting all protocol-defined Adverse 
Events (AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy 
occurring in the partner of a male study subject), other Special Situation reports, AESIs 
and Product Complaints with an AE where the patient has been exposed to the Product. 
The completed MedWatch form should be sent to the Genentech contact specified below. 
Transmission of these reports (initial and follow-up) will be submitted electronically or by 
fax b the Project Manager as outlined in the Manual of Operations (MOP). Transmission 
of these reports (initial and follow-up) will be either electronically via email or by fax and 
within the timelines specified below:
Fax: 650-238-6067
Email: usds_aereporting-d@gene.com
All Product Complaints without an AE should be called into the phone number below: 
Phone: 800-334-0290 (M-F: 5 am to 5 pm PST)
These single case reports will be exchanged between the parties as outlined below so 
that regulatory obligations are met.
Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within the timelines specified below:
Type of Report
Timelines
Serious Adverse Events
(related and not
related to the Product)
Special Situation Reports ( With or without AE
and pregnancy)
Product Complaints (With or without AE)
AESI
30 calendar days from awareness date
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7.5.3. MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C and D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form:

Protocol number and title description

Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics (Section B.6)

Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication
Follow-up Information
Additional information may be added to a previously submitted report by any of the 
following methods:

Adding to the original MedWatch 3500A report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form

Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report)
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download
Please reference the Manual of Operations (MOP) for additional information.
7.5.4. Reporting to Regulatory Authorities, Ethics Committees and 
Investigators
The Sponsor Investigator, as the Sponsor of the Study, will be responsible for the 
expedited reporting of safety reports originating from the Study to the Regulatory 
Authorities (FDA) where it has filed a clinical trial approval, in compliance with local 
regulations.
Local Investigators be responsible for the expedited reporting of safety reports originating 
from the Study to the Ethics Committees and Institutional Review Boards (IRB), where 
applicable.
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The Sponsor-Investigator will be responsible for the distribution of safety information to its 
own investigators, where relevant, in accordance with local regulations.
Please reference the Manual of Operations (MOP) for additional information.
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
8. AGGREGATE REPORTS
Final Study Report
The study Sponsor Investigator will forward a copy of the Final Study Report to 
Genentech upon completion of the Study Close-Out.
9. STATISTICAL CONSIDERATIONS
We will examine the rate of grade 3 or higher AEs with the TACE combination. Based on 
collected data from the GO and the IMbrave 150 study, we assume the rate of grade 3 or 
higher AEs for the atezolizumab and bevacizumab combination is approximately 55%.
Therefore, with the addition of TACE, the rate of grade 3 or higher AEs will likely be 
higher. Safety will be continuously monitored using the Bayesian Predictive Probability 
approach (Lee, 2008). We will access safety after 6 patients have completed at least 1 
TACE and 2 cycles of systemic therapy and then quarterly thereafter. Safety will be 
reviewed based on AEs, SAEs and lab values. The PI and Study Statistician will be 
responsible for review. We recommend halting enrollment on the trial for a safety analysis 
whenever there is sufficient evidence that the true toxicity rate is significantly greater than
.70 (PP >0.80).
The predictive probability (PP) of concluding that the toxicity rate is 
higher than 70% by the end of the trial based on toxicity data in the current stage will be 
continuously updated. A high PP indicates that the treatment is likely to be overly toxic. If 
the probability of true toxicity rate is higher than .70 (PP >0.80) we will halt accrual and 
conduct a comprehensive safety review.
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This study is not powered for hypothesis testing and analysis will be based on descriptive 
statistics. In general, categorical data will be summarized using frequencies and 
percentages. Binary endpoints such as response rate will be estimated with 
corresponding exact 95% confidence intervals. Continuous measures will be summarized 
using mean, standard deviation, interquartile range, and median. Time to event outcomes 
will be presented with kaplan-meier curves.
8.1.
Determination of Sample Size
This pilot study will plan to enroll approximately 24 patients. This is a sufficient number of 
patients to allow us to assess the safety and tolerability of the combination. This allows 
us to treat patients in a reasonable amount of time (1 year) to know if this is a feasible 
combination to move ahead with in a larger patient population.
8.2.
Primary Efficacy Variables
The primary objective of this study is to examine the safety and tolerability of the 
combination of atezolizumab and bevacizumab with TACE.
8.3.
Secondary Efficacy Variables
The secondary objectives are response rate, time to progression, overall survival, time to 
TACE progression (TTTP), and time to untaceable progression. Assessment of tumor 
response will be assessed by both RECIST 1.1 and mRECIST for HCC.
Time to progression will be defined as the time from trial enrollment until objective tumor 
progression by RECIST criteria, it does not include deaths.
Overall survival will be defined as time from trial enrollment until death from any cause in 
the intent-to-treat population.
Time to TACE progression is defined as the interval of time from the day of the images 
after a TACE procedure to the time or progression, new vascular invasion or extrahepatic 
spread also is counted as progression (Arizumi 2017).
Time to untaceable progression is defined as time to untreatable tumor progression, 
transient deterioration to Child-Pugh C score, or appearance of vascular 
invasion/extrahepatic spread.
10.
INVESTIGATOR REQUIREMENTS
9.1.
Retention of Records
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of clinical 
trials and the distribution of investigational drug, patient records, consent forms, laboratory 
test results, and medication inventory records, must be retained for 2 years after the last 
marketing application approval in an ICH region or after at least 2 years have elapsed 
since formal discontinuation of clinical development of the investigational product. All 
state and local laws for retention of records also apply.
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9.2.
Study Medical Monitoring Requirements
10.2.1. Data and Safety Monitoring Committee (DSMC)
The Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) will 
provide the primary oversight of data and safety monitoring. The Yale DSMC will review 
and monitor compliance, toxicity and deviations from this study. The committee is 
composed of clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about participant safety 
will be addressed with the Principal Investigator.
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided 
to the committee includes: a study narrative by the PI, a summary DSMC report produced 
by OnCore (which includes participant accrual, response, trial status history, SAEs, 
adverse events, deviations and survival); audit results, and monitoring reports, as 
applicable. Other information (e.g., scans, laboratory values, etc.) will be provided upon 
request. Upon completing the review, the DSMC will approve whether the study should 
continue as planned, require modification/ amendment, or be placed on administrative 
hold with accrual temporarily suspended.
Trials being monitored by the YCC DSMC will remain under the YCC DSMC purview until 
a DSMC review has occurred that includes the research activity of the last subject who 
completed the intervention, or until the DSMC feels there are no patient safety concerns 
that require further monitoring. The DSMC will determine the length of continued DSMC 
review.
The DSMC has authority to intervene in the conduct of these studies as necessary to 
ensure the safety of the participants and to maintain the highest quality in the clinical 
research performed at YCC. The DSMC has the authority to require additional monitoring 
and/ or more frequent reporting on study progress and serious adverse events.
10.2.2. Study Site Monitoring
Study site monitoring is necessary to assure adequate protection of the rights of human 
subjects and the safety of all subjects involved in clinical investigations and the quality 
and integrity of the resulting data submitted.
The Sponsor Investigator designated monitoring conducts monitoring visits to ensure that 
clinical investigators and study team members are compliant with the protocol, ICH good 
clinical practice, federal, state and local regulations and institutional policies and 
procedures, that data are of high quality and integrity, and that the facilities and staffing 
are adequate for continued study participation. This will be performed by conducting
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monitoring visits including a site initiation visit, regularly scheduled interim monitoring 
visits and/or remote interim monitoring visits while subjects are on study, and a site close- 
out visit at all participating sites. Following each site visit, a visit report will be generated 
containing information on site activities and a summary of pertinent points and action 
items. The report will be provided with a follow-up letter. Site-specific data status reports 
will be distributed to the site regularly to outline planned, missing or incomplete case 
report forms and any outstanding data queries.
During monitoring visits, the following may be reviewed:
•
Protection of the rights, safety and welfare of subjects through review of 
documentation, adverse events (AEs) and serious adverse events (SAEs) and safety 
procedures
•
Subject eligibility
•
Source verification
•
Protocol compliance
•
Deviations and Non-compliance
•
Investigator Site File
•
GCP compliance
•
If applicable, include: Investigational Drug/ Device Storage and Accountability 
(including quantity and disposal procedures)
•
If applicable, include: Laboratory Facilities
•
If applicable, include: Equipment maintenance and calibration
•
Additional study supplies inventory and assessment
•
Study progress and/or follow-up on issues with Site Principal Investigator (PI) and 
relevant members of the study team
The Sponsor Investigator. and YCCI will define the required study monitoring activities in 
a Study Monitoring Plan.
9.3.
Study Medication Accountability
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech 
requirements.
All unused remaining product at the end of the study should be disposed of at the study 
site according to institutional standard operating procedure. If there is no SOP at the site 
for drug destruction, return study drug with the Inventory of Returned Clinical Material 
form as directed by Genentech.
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9.4.
Data Collection
The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled in the 
study, and that data are recorded on the appropriate forms and in a timely manner. Any 
errors on source data should be lined through, but not obliterated, with the correction 
inserted, initialed, and dated by the study coordinator or PI. All source documents will be 
available for routine monitoring, and inspection by the FDA and the Yale IRB.
11.
ETHICAL CONSIDERATIONS
11.1.
Informed Consent
The informed consent document must be signed by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history for 
each subject shall document that informed consent was obtained prior to participation in 
the study. A copy of the informed consent document must be provided to the subject or 
the subject's legally authorized representative. If applicable, it will be provided in a 
certified translation of the local language.
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time.
11.2.
Institutional Review Board or Ethics Committee
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated.
The study will be conducted in accordance with FDA, applicable national and local health 
authorities, and IRB requirements.
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case, the IRB must be updated at least once a year. The Principal Investigator must also 
keep the IRB informed of any significant AEs per local policy.
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected. This generally refers to SAEs that are 
not already identified in the Investigator’s Brochure and that are considered possibly or 
probably related to the molecule or study drug by the investigator. Some IRBs may have 
other specific AE requirements to which investigators are expected to adhere.
Investigators must immediately forward to their IRB any written safety report provided by 
the sponsor investigator per their local policy.
11.3.
Confidentiality
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the ICF (or separate authorization to use and disclose 
personal health information) signed by the patient or unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes.
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Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech representatives and collaborators, and the IRB/Ethics Committee 
(EC) for each study site, if appropriate.
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12.
REFERENCES
Lee J and Liu D. A Predictive Probability Design for Phase II Cancer Clinical Trials. Clinical 
Trials. 2008; 5(2): 93-106.
Xu J. Trends in Liver Cancer Mortality Among Adults Aged 25 and Over in the United States 200- 
2016. NCHS Data Brief, 2018. Jul; (314): 1-8.
Younossi Z, Stepanova M, Ong JP, et al. Nonalcoholic steatohepatitis is the fastest growing cause 
of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol
Hepatol 2019;17(4):748-755.e3.
Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975- 
2014, featuring survival. J Natl Cancer Inst 2017;109(9).
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatoceullar 
carcinoma: Chemoembolization improves survival. Hepatology 2003; 37-429-42.
Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. New 
England Journal of Medicine 2008; 359: 378-390.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with 
unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lancet 2018;391:1163-1173.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who 
progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, 
phase 3 trial. Lancet 2017;389:56-66.
Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing 
hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
Zhu et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and 
increased alpha-fetoprotein concentrations (REACH-2): a randomized, double-blind, placebo- 
controlled, phase 3 trial. The Lancet Oncology 2019.
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular 
carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and 
expansion trial. Lancet 2017;389:2492-2502.
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular 
carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label 
phase 2 trial. Lancet Oncol 2018;19:940-952.
Finn R, Ryoo BY, Merle P, et al. Results of KEYNOTE-240: phase 3 study of 
pembrolizumab vs BSC for second line therapy in advanced HCC. JCO 2019.
APPROVED BY THE YALE UNIVERSITY IRB 2/15/2024

APPROVED BY THE YALE UNIVERSITY IRB 2/15/2024
)
57
Chen DS and Hurwitz H. Combinations of Bevacizumab with Cancer Immunotherapy. Cancer 
Journal 2018.
FDA. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of 
metastatic non-squamous NSCLC. FDA website (fda.gov), 2018
Lee, M. S., Ryoo, B. Y., Hsu, C. H., Numata, K., Stein, S., Verret, W., ... & Tebbutt, N. (2020). 
Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): 
an open-label, multicentre, phase 1b study. The Lancet Oncology, 21(6), 808-820.
Finn R, Qin S, Ikeda Met al. Atezolizumab plus bevacizumab in unresectable hepatocellular 
carcinoma. N Engl J Med 2020; 382: 1894-905.
Yau T, Kang YK, Kim TY, et al. Nivolumab + Ipilimumab Combination Therapy in Patients with 
Advanced Hepatocellular Carcinoma: Results From CheckMate 040. Presentation at American 
Society of Clinical Oncology congress, May 31-June 4, 2019.
Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus 
symptomatic treatment in patients with unresectable hepatoceullar carcinoma: a randomized 
controlled trial. Lancet 2002; 359: 1734-9.
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatoceullar 
carcinoma: Chemoembolization improves survival. Hepatology 2003; 37-429-42.
Burrel M, Reig M, Forner A, et al. Survival of patients with hepatocellular carcinoma treated by 
transarterial chemoembolization (TACE) using Drug Eluting Beads. Implications for clinical 
practice and trial design. J Hepatol 2012, 56: 1330-5.
Malgari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for 
unresectable hepatoceullar carcinoma: five-year survival anlaysis. Cardiovasc Interv Radiol 
2012; 35: 1119-28.
Raoul J-L, Forner A, Bolondi L, et al. Updated use of TACE for hepatocellular carcinoma 
treatment: How and when to use it based on clinical evidence. Cancer Treatment Reviewes 
72(2019) 28-36.
Lencioni et al, Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate 
stage HCC: The SPACE trial; 2016
Meyer et al, Sorafenib in combination with transarterial chemoembolisation in patients with 
unresectable hepatocellular carcinoma (TACE 2): a randomized placebo-controlled, double-blind, 
phase 3 trial. Lancet Gastroenterology Hepatology 2017 Aug 2 565-575.
Buijs et al, Phase II trial of concurrent bevacizumab and transhepatic arterial chemoembolization 
in patients with unresectable hepatocellular carcinoma. Cancer 2013 March 1; 119(5): 1042-
1049.
Slovak R, Ludwig JM, Gettinger SN, et al. Immuno-thermal ablations – boosting the anticancer 
immune response. Journal of Immunotherapy Cancer. 2017 Oct 17; 5(1): 78.
APPROVED BY THE YALE UNIVERSITY IRB 2/15/2024

APPROVED BY THE YALE UNIVERSITY IRB 2/15/2024
)
58
Lee, Michael S., et al. "Atezolizumab with or without bevacizumab in unresectable hepatocellular 
carcinoma (GO30140): an open-label, multicentre, phase 1b study." The Lancet Oncology 21.6 
(2020): 808-820.
Lee, Michael S., et al. "Atezolizumab with or without bevacizumab in unresectable hepatocellular 
carcinoma (GO30140): an open-label, multicentre, phase 1b study." The Lancet Oncology 21.6 
(2020): 808-820.
Finn, Richard S., et al. "Atezolizumab plus bevacizumab in unresectable hepatocellular 
carcinoma." New England Journal of Medicine 382.20 (2020): 1894-1905.
Finn, Richard S., et al. "Atezolizumab plus bevacizumab in unresectable hepatocellular 
carcinoma." New England Journal of Medicine 382.20 (2020): 1894-1905.
Arizumi T, Ueshima K, Iwanishi M, et al. The Overall Survival of Patinets with Hepatocellular 
Carinoma Correlates with the Newly Defined Time to Progression after Transarterial 
Chemoembolization. Liver Cancer 2017; June; 6(3):  227-235.
Deng, Rong, et al. "Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and 
tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor." MAbs. 
Vol. 8. No. 3. Taylor & Francis, 2016
Labeur T, Takkenberg R, Klumpen HJ, et al. Reason of Discontinuation after Transarterial 
Chemoembolization Influences Survival in Patients with Hepatocellular Carcinoma.
CardioVascular and Interventional Radiology 2019, Volume 42, Issue 2 230-238.
Marcacuzco Q, Nutu OA, San Roman Manso R, et al. Complications of transarterial 
chemoembolization (TACE) in the treatment of liver tumors. Cir Esp 2018. Nov; 96(9) 56067.
Bajwa, Raazi, David C. Madoff, and Sirish A. Kishore. "Embolotherapy for Hepatic Oncology: 
Current Perspectives and Future Directions." Digestive disease interventions 4.2 (2020): 134.
Kishore, Sirish A., Raazi Bajwa, and David C. Madoff. "Embolotherapeutic strategies for 
hepatocellular carcinoma: 2020 update." Cancers 12.4 (2020): 791.
Kishore, Sirish, Tamir Friedman, and David C. Madoff. "Update on embolization therapies for 
hepatocellular carcinoma." Current oncology reports 19.6 (2017): 40.
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Protocol v 3.0 (2022.012.13)
13.
LIST OF APPENDICES
13.1. Appendix 1:
Study Flowchart
Screening a
C1D1
(± 3 days)
C2D1
(± 3 days)
TACE Procedure #1
C3D1
(± 3 days)
TACE Procedure #2
C4D1
(± 3 days)
TACE Procedure #3
C5D1
(± 3 days)
C6D1
(± 3 days)
TACE Procedure #4
C7D1
(± 3 days)
C8D1 +
(± 3 days)
Treatment 
Discontinuation
Long Term Follow 
Up – Every 3 
Months
Day
-28-0
1
22
28
43
56
64
84
85
106
112
127
148
≤ 30 post 
last dose b
Every 90
day ± 7 
days
Informed consent
x c
Demographic data
x
Medical history and baseline 
conditions
x
Vital signs d
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
Height
x
Complete physical examination e
x
Limited physical examination f
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
x
Child Pugh
X
X
X
X
X
X
X
X
X
ECG (12-lead) g
x
Hematology h
x n
x o
x o
x
x o
x
x o
x
x o
x o
x
x o
x o
Pregnancy test i
x j
x
x
x
x
x
x
x
x
x
Coagulation (INR, aPTT)
x j
X
X
X
X
X
X
X
x
TSH, free T3 (or total T3), free 
T4 m
x j
x m
x m
x m
x m
x m
x m
x m
x m
x
Viral serology n
x j
Urinalysis o
x j
x p
x p
x p
x p
x p
x p
x p
x p
Chemistry l
x k
x
x
x
x
x
x
x
x
x
Tumor response assessments q
x q
x q
x q
x q
x q
x q
x q
x q
x q
Concomitant medications
x r
x
x
x
x
x
x
x
x
x
Atezolizumab
x s
x s
x s
x s
x s
x s
x s
x s
Bevacizumab
x t
x t
x t
x t
x t
x t
TACE
x u
x u
x u
x u
Adverse events
x
x
x
x
x
x
x
x
x
x
x v

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HBcAb  hepatitis B core antibody; HBsAb  hepatitis B surface antibody; HBsAg  hepatitis B surface antigen; NA  not applicable; 
PK  pharmacokinetic; T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone; WES  whole exome sequencing. 
Notes: On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded in the patient’s medical 
records (except in the case of an adverse event).
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 7 days prior to Day 1 may be 
used; such tests do not need to be repeated for screening. Screening laboratory assessments that were performed within 3 days prior to 
Day 1 of Cycle 1, do not have to be repeated.
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the last 
dose of study treatment. The visit at which response assessment shows progressive disease may be used as the treatment discontinuation 
visit.
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 
days before initiation of study treatment.
d Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
Record abnormalities observed at baseline in the patient’s medical records. At subsequent visits, record new or worsened clinically 
significant abnormalities in the patient’s medical records. For the first infusion, vital signs should be measured within 60 minutes prior to the 
infusion and, if clinically indicated, every 15 ( 5) minutes during and 30 ( 10) minutes after the infusion. For subsequent infusions, vital 
signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous 
infusion, during and 30 ( 10) minutes after the infusion.
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Record abnormalities observed at baseline in the patient’s medical records. At 
subsequent visits, record new or worsened clinically significant abnormalities in the patient’s medical records.
f    Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. Record new or 
worsened clinically significant abnormalities in the patient’s medical records.
g ECG recordings will be obtained during screening and as clinically indicated at other timepoints. Patients should be resting in a supine 
position for at least 10 minutes prior to ECG recording.
h Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
i All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study treatment. (Urine 
pregnancy tests will be performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.)
j     Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
k If screening laboratory assessments were performed within 3 days prior to Day 1 of Cycle 1, they do not have to be repeated.

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l
Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, bicarbonate, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, LDH. There is a lab window of 48 hours before 
treatment.
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter. NOTE-frequency of thyroid testing should be every fourth cycle for 21-day cycle.
n At screening, patients will be tested for HBsAg, HBsAb, total HBcAb, and HCV antibody. If a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test should be performed. If a patient has a positive HCV antibody test at screening, 
an HCV RNA test must also be performed to determine if the patient has an active HCV infection.
o Includes pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted.
p Urinalysis should be performed prior to each treatment with bevacizumab during study treatment.
q Imaging will be every 8 weeks for the first year on treatment and then imaging will be every 12 weeks for the second year. There is a 1- 
week window allowed for imaging.
All measurable and evaluable lesions should be assessed and documented at screening. Tumor assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be repeated at screening. 
Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of the chest, abdomen, pelvis. A spiral CT scan of 
the chest may be obtained but is not a requirement. If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or 
impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, should be performed. At 
the investigator’s discretion, other methods of assessment of measurable disease as per RECIST v1.1 may be used.
r Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment until the treatment discontinuation visit.
s Atezolizumab 1200mg will be administered intravenously on day 1 of every 21-day cycle beginning C1D1
t    Bevacizumab 15mg/kg will be administered intravenously on C1D1 and resume on Day 1 the treatment cycle at least 4 weeks after the last 
TACE procedure. Full recovery from the TACE procedure is required prior to re-starting treatment with Bev.
Bevacizumab will ONLY resume when it has been at least 4 weeks after the last TACE procedure and all TACE related effects are 
resolved.
u TACE treatments may occur 1, 2, 3, or 4 times based on the clinical judgement from the investigational radiologist. The first TACE 
procedure must be at least 28 days from the last Bevacizumab treatment. TACE treatments occur 4-6 weeks apart. Bevacizumab should be 
resumed at the first Atezolizumab administration that occurs at least 28 days from the last TACE procedure.
v  After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (unless the 
patient withdraws consent, or the Investigator terminates the study). If a patient requests to be withdrawn from follow-up, this request must 
be documented in the source documents and signed by the investigator. If the patient withdraws from study, the study staff may use a 
public information source (e.g., county records) to obtain information about survival status only.

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13.2. Appendix 2: Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula
Creatinine Clearance (men)  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72
Creatinine Clearance (women)  0.85  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72
Source: Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum creatinine (editorial). Nephron 
1992;62:249.

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13.3. Appendix 3: Safety Reporting Fax Cover Sheet
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH
AE / SAE FAX No: (650) 238-6067
Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
[DD] / [MON] / [YY]
Follow-up Report Date
[DD] / [MON] / [YY]
Subject Initials
(Enter a dash if patient has 
no middle name)
[ ] - [ ] - [ ]
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET
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13.4. Appendix 4: FDA Medwatch 3500 Form
This form is included in the study start-up zip file to be sent to sites via email.
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13.5. Appendix 5: Current National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE)
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
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13.6. Appendix 6: Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST V1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with 
slight modifications from the original publication and the addition of explanatory 
text as needed for clarity. 1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. All measurable and non-measurable 
lesions should be assessed at screening and at subsequent protocol-specified 
tumor assessment timepoints. Additional assessments may be performed as 
clinically indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size as 
follows:
●
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (CT/MRI scan slice thickness/interval  5 mm)
●
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)
●
20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must 
be  15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be  5 mm). At baseline and follow-up, only the short 
axis will be measured and followed. Additional information on lymph node 
measurement is provided below (see "Identification of Target and Non-Target 
Lesions" and "Calculation of Sum of Diameters").
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.
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DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter  10 
mm or pathological lymph nodes with short axis  10 mm but  15 mm) as well as 
truly non-measurable lesions. Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, peritoneal spread, and 
abdominal mass/abdominal organomegaly identified by physical examination that 
is not measurable by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy 
require particular comment, as outlined below.
Bone Lesions:
●
Technetium-99m bone scans, sodium fluoride positron emission tomography 
scans, and plain films are not considered adequate imaging techniques for 
measuring 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 that can be evaluated by cross-sectional 
imaging techniques such as CT or MRI can be considered 
measurable lesions if the soft tissue component meets the 
definition of measurability described above.
●
Blastic bone lesions are non-measurable.
Cystic Lesions:
●
Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts.
●
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions.
Lesions with Prior Local Treatment:
●
Tumor lesions situated in a previously irradiated area or in an area subjected 
to other loco-regional therapy are usually not considered measurable unless 
there has been demonstrated progression in the lesion.
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment.
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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study. 
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and
 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. In this guideline, the definition of 
measurability of lesions on CT scan is based on the assumption that CT slice 
thickness is  5 mm. When CT scans have slice thickness of  5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI 
is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as 
to whether a non-contrast CT or MRI (without IV contrast) will be used to 
evaluate the patient at baseline and during the study should be guided by the 
tumor type under investigation and the anatomic location of the disease. For 
patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non- 
enhanced) will be performed should also be based on the tumor type and the 
anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible. Each case should be discussed 
with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that 
point forward. Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality, since 
the same lesion may appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, CYTOLOGY, 
HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology 
cannot be utilized for objective tumor evaluation.
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ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and use this as a comparator for 
subsequent measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. This means that, for instances in 
which patients have only one or two organ sites involved, a maximum of two 
lesions (one site) and four lesions (two sites), respectively, will be recorded.
Other lesions (albeit measurable) in those organs will be considered non-target 
lesions.
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition 
should lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. As noted above, 
pathological nodes that are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of  15 mm by CT scan.
Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor. Lymph node size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT, this is almost 
always the axial plane; for MRI, the plane of acquisition may be axial, sagittal, or 
coronal). The smaller of these measures is the short axis. For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 
mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes 
(those with short axis  10 mm but  15 mm) should be considered non-target 
lesions. Nodes that have a short axis of  10 mm are considered non- 
pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are 
not required. It is possible to record multiple non-target lesions involving the 
same organ as a single item on the Case Report Form (CRF) (e.g., "multiple 
enlarged pelvic lymph nodes" or "multiple liver metastases").
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CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis 
for lymph node lesions) will be calculated for all target lesions at baseline and at 
each subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the node regresses to  10 mm during the study. 
Thus, when lymph nodes are included as target lesions, the sum of diameters 
may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of  10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded 
at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes that are recorded as target lesions at baseline become so faint on 
CT scan that the radiologist may not feel comfortable assigning an exact 
measurement and may report them as being too small to measure. When this 
occurs, it is important that a value be recorded on the CRF, as follows:
●
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.
●
If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned and "too small to 
measure" should be ticked. (Note: It is less likely that this rule will be used 
for lymph nodes since they usually have a definable size when normal and 
are frequently surrounded by fat such as in the retroperitoneum; however, if 
a lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned in this circumstance 
as well and "too small to measure" should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, 
that should be recorded, even if it is  5 mm, and in that case "too small to 
measure" should not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the 
fragmented portions should be added together to calculate the sum of diameters. 
Similarly, as lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion. 
If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximum longest 
diameter for the coalesced lesion.
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EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant 
lymph node non-target lesions should be monitored for reduction to  10 mm in 
short axis. Non-target lesions should be noted at baseline and should be 
identified as "present" or "absent" and (in rare cases) may be noted as "indicative 
of progression" at subsequent evaluations. In addition, if a lymph node lesion 
shrinks to a non-malignant size (short axis  10 mm), this should be captured on 
the CRF as part of the assessment of non-target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target 
lesions are provided below:
●
Complete response (CR): Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to  10 
mm.
●
Partial response (PR): At least a 30% decrease in the sum of diameters of 
all target lesions, taking as reference the baseline sum of diameters, in the 
absence of CR
●
Progressive disease (PD): At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum of diameters on study 
(including baseline)
In addition to the relative increase of 20%, the sum of diameters must 
also demonstrate an absolute increase of  5 mm.
●
Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below. While some non-target lesions may 
actually be measurable, they need not be measured and instead should be 
assessed only qualitatively at the timepoints specified in the schedule of 
activities.
●
CR: Disappearance of all non-target lesions and (if applicable) normalization 
of tumor marker level
All lymph nodes must be non-pathological in size ( 10 mm short axis).
●
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits
●
PD: Unequivocal progression of existing non-target lesions
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SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve 
unequivocal progression on the basis of the non-target lesions, there must be an 
overall level of substantial worsening in non-target lesions in a magnitude that, 
even in the presence of SD or PR in target lesions, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest increase in 
the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on 
the basis of change in non-target lesions in the face of SD or PR in target lesions 
will therefore be extremely rare.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; 
therefore, some comments on detection of new lesions are important. There are 
no specific criteria for the identification of new radiographic lesions; however, the 
finding of a new lesion should be unequivocal, that is, not attributable to 
differences in scanning technique, change in imaging modality, or findings 
thought to represent something other than tumor (for example, some "new" bone 
lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the patient’s baseline lesions show PR or CR. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a "new" cystic 
lesion, which it is not.
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression.
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. If 
repeat scans confirm there is definitely a new lesion, progression should be 
declared using the date of the initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at 
baseline.
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Table 1
Criteria for Overall Response at a Single Timepoint: Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient 
is not evaluable at that timepoint. If measurements are made on only a subset of 
target lesions at a timepoint, usually the case is also considered not evaluable at 
that timepoint, unless a convincing argument can be made that the contribution 
of the individual missing lesions would not change the assigned timepoint 
response. This would be most likely to happen in the case of PD. For example, 
if a patient had a baseline sum of 50 mm with three measured lesions and during 
the study only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing 
lesion.
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as "symptomatic deterioration." Every effort should be made to
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document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response; it is a 
reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target lesions as 
shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment. If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression 
was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45: 22847.
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TARGET LESIONS
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions.
NON-TARGET LESIONS
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1. At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (progressive disease [PD]), or 
"present without unequivocal progression" (non-CR/non-PD), as defined by
RECIST v1.1. In addition, any non-target lesions that were categorized as PD at the 
previous timepoint should be evaluated to determine whether there has been any further 
increase in size.
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST v1.1
(e.g., nonlymph node lesions must be  10 mm on the longest diameter; new lymph 
nodes must be  15 mm on the short axis [see note below]). All new lesions 
(measurable or nonmeasurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints.
Up to a maximum of five measurable new lesions total (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint. New lesions that are 
not measurable at first appearance but meet measurability criteria at a subsequent 
timepoint should be measured from that point on, if the maximum number of measurable 
new lesions has not been reached.
All non-measurable new lesions and additional measurable new lesions (in excess of 
five total or two per organ) should be categorized as "absent" or "present." All 
nonmeasurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions should be assessed to determine whether there 
is any increase in size relative to the previous assessment timepoint.
Note regarding new lymph node lesions: If at first appearance the short axis of a lymph 
node lesion is  15 mm, it will be considered a measurable new lesion. If at first 
appearance the short axis of a lymph node lesion is  10 mm and  15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion. If at first appearance the short 
axis of a lymph node is  10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion. A lymph node can subsequently become 
measurable, when the short axis is  15 mm. Measurable new lymph node lesions 
should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to  15 mm (or even  10 mm).
75
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13.7. Appendix 7: Hepatocellular Carcinoma-Specific Modified 
RECIST (HCC mRECIST)
IMAGE ACQUISITION FOR HCC-SPECIFIC MODIFIED RECIST
Optimization of image acquisition protocols and consistency in the use of the same 
protocol throughout follow-up examinations are key for proper application of
HCC-specific modified RECIST (HCC mRECIST; Lencioni et al. 2010).
Patients can be followed with either contrast-enhanced spiral computed tomography 
(CT) preferably with use of multislice scanners or contrast-enhanced dynamic 
magnetic resonance imaging (MRI). The administration of intravenous contrast is 
recommended for all CT or MRI studies if not medically contraindicated. In contrast- 
enhanced studies, it is mandatory to obtain a dual-phase imaging of the liver. Every 
effort should be made to time the contrast administration so that high-quality arterial- 
phase imaging is obtainedthroughout the liver on the first run and that high-quality 
portal venous-phase imaging is obtained throughout the liver on the second run.
Delayed imaging obtained in the equilibrium phase may be useful, but it is not 
mandatory and should be done only if it is part of clinical practice.
For multidetector CT scanners that are capable of acquiring very thin slices, it is 
mandatory to use contiguous slices for image read and interpretation, to avoid 
missingsmall lesions. For example, the analysis of contiguous slices with 
traditional 5-mm thickness and 5-mm reconstruction interval is acceptable; 
however, the analysis of 2.5-mm thickness slices at 5 mm intervals is not 
acceptable.
ASSESSMENT OF TUMOR LESIONS
TARGET LESIONS
The measurement of the longest viable tumor diameter for the assessment of 
responseaccording to HCC mRECIST can be applied only on typical lesions. 
Conversely, for non-enhancing atypical lesions, as well as for any extrahepatic 
neoplastic niches, the
measurements of the longest overall tumor diameter as per conventional RECIST 
shouldprevail. To be selected as a target lesion using HCC mRECIST, an HCC lesion 
should meet all the following criteria:
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•
The lesion is classified as a measurable lesion (i.e., the lesion can be 
accuratelymeasured in at least one dimension as 1 cm or more).
•
The lesion is suitable for repeat measurement.
•
The lesion shows intratumoral arterial enhancement on contrast-enhanced 
CT or MRI. It is important to point out that only well-delineated, arterially 
enhancing lesionscan be selected as target lesions for HCC mRECIST. This 
may not be the case of infiltrative-type HCC. Infiltrative-type HCC should be 
considered as a non-target
lesion when the mass shows ill-defined borders and therefore does not appear to 
besuitable for accurate and repeat measurements.
•
HCC lesions previously treated with locoregional or systemic treatments 
may or maynot be considered as suitable to be selected as target lesions 
for HCC mRECIST: If the lesion shows a well-delineated area of viable 
(contrast enhancement in the arterial phase) tumor that is at least 1 cm in 
longest diameter, then it can be selectedas 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 atarget 
lesion for HCC mRECIST.
Table 1
Target Lesion Selection Criteria
RECIST v1.1
HCC-Specific mRECIST
Measurable
Lesion able to be accurately
Lesion able to be accurately
disease
measured in at least one
measured in at least one
dimension > 1 cm and
dimension > 1 cm and suitable for
suitable for repeat
repeat measurement and lesion
measurement
shows intratumoral arterial
Enhancement
Non-measurable
All other lesions (< 1 cm
All other lesions (< 1 cm lesions and
disease
lesions and truly
truly non measurable lesions) and
non measurable lesions)
lesions exhibiting atypical
Enhancement
Number of lesions
Up to 5 (2 per organ)
Up to 5 (2 per organ)
Measurement
Sum of longest diameters of
Sum of longest diameters of individual
individual lesions
lesions showing arterial enhancement
HCC= hepatocellular carcinoma; mRECIST = modified Response Evaluation Criteria in Solid 
Tumors; RECIST vl.1 =Response Evaluation Criteria in Solid Tumors, Version 1.1.
Defining Treatment Response and Tumor Progression:
•
Complete response: the disappearance of any intratumoral arterial 
enhancement inall target lesions
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•
Partial response: at least a 30% decrease in the sum of the longest 
diameters ofviable (contrast enhancement in the arterial phase) target 
lesions, taking as reference the baseline sum of the diameters of 
target lesions
•
Progressive disease: an increase of at least 20% in the sum of the 
longest diameters of viable (enhancing) target lesions, taking as 
reference the smallest sumof the diameters of viable (enhancing) target 
lesions recorded since the treatment started
•
Stable disease: any cases that do not qualify for either partial 
response or progressive disease
Table 2
Target Lesion Response Definition
RECIST v1.1
HCC-Specific mRECIST
Complete response
Disappearance of all target
Disappearance of any intratumoral
lesions
arterial enhancement in all target
Lesions
Partial response
30% decrease in sum of the
30% decrease in sum of the longest
longest diameters of target
diameters of viable (arterially
lesions compared with baseline
enhancing) target lesions compared
with baseline
Progressive
20% increase in sum of the
20% increase in sum of the longest
disease
longest diameters of target
diameters of viable (arterially
lesions compared with the
enhancing) target lesions compared
smallest sum of longest
with the smallest sum of longest
diameters recorded (nadir)
diameters recorded (nadir)
Stable disease
Neither PR or PD
Neither PR or PD
HCC = hepatocellular carcinoma; mRECIST = modified Response Evaluation Criteria in Solid Tumors; PD= 
progressive disease; PR= partial response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, 
Version 1.1.
NON-TARGET LESIONS
According to HCC mRECIST, tumor necrosis should be taken into account when 
assessing the response of non-target lesions. The disappearance of intratumoral 
arterial enhancement in non-target lesions should be considered equivalent to the 
disappearance of non-target lesions, and therefore, should declare complete 
response of non-target lesions. The persistence of intratumoral arterial 
enhancement in one or more non-target lesions should be considered equivalent 
to persistence of one or more non-target lesions, and therefore, should declare 
incomplete response or stable disease.Special recommendations for the
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assessment of tumor response in non-target lesions in patients with HCC and 
cirrhosis can be made regarding the following points:
•
Portal vein thrombosis. Malignant portal vein thrombosis should be 
considered a non-measurable lesion due to the difficulty in performing 
consistent measurements of the malignant thrombus during the course of 
the treatment. Measurements of theextent of the malignant thrombus 
may be impaired by the possible presence of a bland component of the 
thrombosis.
•
Porta hepatic lymph node. Lymph nodes detected at the portal hepatitis 
can be considered as malignant if the lymph node short axis is at least 20 
mm. Evidence ofreactive lymph nodes at the porta hepatic, in fact, is a 
common finding in patients with cirrhosis regardless of the presence of an 
HCC. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor.
•
Pleural effusion and ascites. The original RECIST publication specifies 
that cytologic confirmation of the neoplastic nature of any effusion that 
appears or worsens during treatment is required when the measurable 
tumor has met criteria for response or stable disease. Under such 
circumstances, the cytologic examination of the fluid collected will 
permit differentiation between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease (if the 
neoplastic origin of the fluid is confirmed).
•
The emergence or the increase in ascites is a common event during the 
course of treatment in a cirrhotic patient, which may be due to worsening 
of the underlying chronic liver disease and be unrelated to cancer 
progression. Other effusions, such as pleural effusion, may also be 
unrelated to cancer progression and be caused by the liver insufficiency. 
Thus, the HCC mRECIST emphasizes that cytopathologic confirmation 
of the neoplastic nature of any effusion (particularly ascites) that appears 
or worsens during treatment is required when the measurable tumor has 
met criteria for response or stable disease. It has to be underlined that 
peritoneal carcinomatosis is a very rare event in HCC.
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Table 3
Non-Target Lesion Response Definition
RECIST v1.1
HCC-Specific mRECIST
Complete response
Disappearance of all non-target
Disappearance of any intratumoral
lesions
arterial enhancement in all
non-target lesions
Progressive disease
Unequivocal increase in size of
Unequivocal increase in size of
non-target lesions, or new
non-target lesions, or new lesions
lesions
meeting specific criteria (see text)
Incomplete response of
Persistence of one or more
Persistence of arterial enhancement
Stable disease
non-target lesions
in one or more non-target lesions
HCC= hepatocellular carcinoma; mRECIST = modified Response Evaluation Criteria in SolidTumors; 
RECIST vl .1 = Response Evaluation Criteria in Solid Tumors, Verison 1.1.
NEW LESIONS
Newly detected hepatic lesions must be 1cm in diameter and show a vascular 
pattern typical of HCC. The appearance of one or more new lesions should declare 
progressivedisease.
OVERALL VISIT RESPONSE
Overall visit response is obtained in a similar fashion as for RECIST1.1 by 
combining theresponse assessment for target lesions, non-target lesions and 
new lesions.
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Table 4
Summary Table
Target Lesions
Response Category
RECIST v1.1
HCC-Specific mRECIST
Complete response
Disappearance of all target
Disappearance of any intratumoral
lesions
arterial enhancement in all target
Lesions
Partial response
:2: 30% decrease in sum of the
:2: 30% decrease in sum of the longest
longest diameters of target
diameters of viable (arterially
lesions compared with baseline
enhancing) target lesions compared
with baseline
Progressive
:2: 20% increase in sum of the
:2: 20% increase in sum of the longest
disease
longest diameters of target
diameters of viable (arterially
lesions compared with the
enhancing) target lesions compared
smallest sum of longest
with the smallest sum of longest
diameters recorded (nadir)
diameters recorded (nadir)
Stable disease
Neither PR or PD
Neither PR or PD
Non-target Lesions
Response Category
RECIST v1.1
HCC-Specific mRECIST
Complete response
Disappearance of all non-target
Disappearance of any intratumoral
lesions
arterial enhancement in all non-target
Lesions
Progressive
Unequivocal increase in size of
Unequivocal increase in size of
disease
non-target lesions, or new lesions
non-target lesions, or new lesions
meeting specific criteria (see text)
Incomplete
Persistence of one or more
Persistence of arterial enhancement in
response of stable
non-target lesions
one or more non-target lesions
disease
mRECIST Recommendations
Pleural effusion and
Cytopathologic confirmation of the neoplastic nature of any effusion that
ascites
appears or worsens during treatment is required to declare PD.
Portal hepatis
Lymph nodes detected at the porta hepatis can be considered malignant if
lymph node
the lymph node short axis is :2: 2 cm.
Portal vein
Malignant portal vein thrombosis should be considered as a
thrombosis
non-measureable lesion and thus included in the non-target lesion group
New lesion
A new lesion can be classified as HCC if its longest diameter is :2: 1 cm and
the enhancement pattern is typical for HCC. A lesion with atypical
radiological pattern can be diagnosed as HCC by evidence of :2: 1 cm
interval growth.
HCC= hepatocellular carcinoma; mRECIST = modified Response Evaluation Criteria in Solid 
Tumors; PD= progressive disease; PR= partial response; RECIST vl.1 =Response Evaluation 
Criteria in Solid Tumors, Version 1.1.
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REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:741220.
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 2017;18:e14352.
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13.8. Appendix 8: Preexisting Autoimmune Diseases and 
Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or 
congenital immune deficiencies or autoimmune disease. Patients with any 
history of immune deficiencies or autoimmune disease listed in the table below 
are excluded from participating in the study. Possible exceptions to this 
exclusion could be patients with a medical history of such entities as atopic 
disease or childhood arthralgias where the clinical suspicion of autoimmune 
disease is low. Patients with a history of autoimmune-related hypothyroidism on 
a stable dose of thyroid replacement hormone may be eligible for this study. In 
addition, transient autoimmune manifestations of an acute infectious disease that 
resolved upon treatment of the infectious agent are not excluded (e.g., acute 
Lyme arthritis).
Autoimmune Diseases and Immune Deficiencies
●Acute disseminated 
encephalomyelitis
●Addison disease
●Ankylosing spondylitis
●Antiphospholipid antibody 
syndrome
●Aplastic anemia
●Autoimmune hemolytic 
anemia
●Autoimmune hepatitis
●Autoimmune 
hypoparathyroidism
●Autoimmune hypophysitis
●Autoimmune myocarditis
●Autoimmune oophoritis
●Autoimmune orchitis
●Autoimmune 
thrombocytopenic purpura
●Behçet disease
●Bullous pemphigoid
●Chronic fatigue syndrome
●Chronic inflammatory 
demyelinating 
polyneuropathy
●Churg-Strauss syndrome
●Crohn disease
●Dermatomyositis
●Diabetes mellitus type 1
●Dysautonomia
●Epidermolysis bullosa 
acquisita
●Gestational pemphigoid
●Giant cell arteritis
●Goodpasture syndrome
●Graves disease
●Guillain-Barré syndrome
●Hashimoto disease
●IgA nephropathy
●Inflammatory bowel disease
●Interstitial cystitis
●Kawasaki disease
●Lambert-Eaton myasthenia 
syndrome
●Lupus erythematosus
●Lyme disease, chronic
●Meniere syndrome
●Mooren ulcer
●Morphea
●Multiple sclerosis
●Myasthenia gravis
●Neuromyotonia
●Opsoclonus myoclonus 
syndrome
●Optic neuritis
●Ord thyroiditis
●Pemphigus
●Pernicious anemia
●Polyarteritis nodosa
●Polyarthritis
●Polyglandular autoimmune 
syndrome
●Primary biliary cholangitis
●Psoriasis
●Reiter syndrome
●Rheumatoid arthritis
●Sarcoidosis
●Scleroderma
●Sjögren syndrome
●Stiff-Person syndrome
●Takayasu arteritis
●Ulcerative colitis
●Vitiligo
●Vogt-Koyanagi-Harada 
disease
●Wegener granulomatosis
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13.9. Appendix 9: Anaphylaxis Precautions
EQUIPMENT NEEDED
●
Monitoring devices: ECG monitor, blood pressure monitor, oxygen 
saturation monitor, and thermometer
●
Oxygen
●
Epinephrine for intravenous, intramuscular, and endotracheal administration 
in accordance with institutional guidelines
●
Antihistamines
●
Corticosteroids
●
Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance. Maintain an adequate airway.
3.
Ensure that appropriate monitoring is in place, with continuous ECG and 
pulse oximetry monitoring, if possible.
4.
Administer antihistamines, epinephrine, or other medications as required by 
participant status and as directed by the physician in charge.
5.
Continue to observe the participant and document observations.
6.
Draw serum/plasma samples for immunogenicity testing.
7.
Ask participant to return for washout immunogenicity sample if appropriate.
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13.10.
Appendix 10:
Guidelines for Management of 
Adverse Events Associated with Bevacizumab
This appendix provides guidelines for the management of patients who 
experience adverse events associated with bevacizumab. Appendix 12 
describes risks associated with atezolizumab and provides guidelines for 
management of patients who experience atezolizumab-associated IRRs and 
immune-related adverse events (e.g., pulmonary, hepatic, gastrointestinal, 
endocrine, ocular, myocarditis, pancreatic, dermatologic, neurologic, 
meningoencephalitis, renal, myositis, hemophagocytic lymphohistiocytosis, and 
macrophage activation syndrome events).
DOSE MODIFICATIONS
There are no dose modifications for bevacizumab.
MANAGEMENT GUIDELINES
Guidelines for management of patients who experience adverse events 
associated with bevacizumab are provided in Table 1a- Bev.
For cases in which management guidelines are not covered in the protocol 
patients should be managed as deemed appropriate by the investigator 
according to best medical judgment.
Table 1a- Bev
Guidelines for Management of Patients Who Experience 
Adverse Events Associated with Bevacizumab
Event
CTCAE Version 5.0 
Grade
Action to be Taken
Allergic reactions
or
Grade 1
Systemic intervention not indicated – continue 
bevacizumab
Infusion-related reactions
Or
Anaphylaxis
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
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Grade 4
Life-threatening consequences; urgent 
intervention indicated - discontinue 
bevacizumab
Thromboembolic Event 
(arterial)
Any Grade
Discontinue bevacizumab
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:
- The patient must not have pathological 
conditions that carry high risk of 
bleeding (e.g. tumor involving major 
vessels or other conditions)
- The patient must not have had 
hemorrhagic events > grade 2 while on 
study
- 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.
If thromboemboli worsen/recur upon resumption 
of study therapy, discontinue bevacizumab
Thromboembolic Event 
(Venous)
Grade 4
Discontinue bevacizumab
[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
Hypertension
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
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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
Grade 3
Discontinue bevacizumab
Heart Failure or left ventricular 
dysfunction
Grade 4
Discontinue bevacizumab
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
Proteinuria*
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
Haemorrhage (CNS)
Any grade
Discontinue bevacizumab
Grade 1
Trace haemoptysis; continue bevacizumab
Haemorrhage (haemoptysis)
Grade 2 - 4
 2.5 mL bright red blood per episode; discontinue 
bevacizumab
Haemorrhage (other)
Grade 3 - 4
Discontinue bevacizumab
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
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Appendix 10:Guidelines for Management of Adverse Events Associated with Bevacizumab
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
Grade 3
Continue bevacizumab
Febrile neutropenia
Grade 4
Hold bevacizumab until resolution or return to 
baseline
Grades 1 - 3
Continue bevacizumab
Platelet count decreased
Grade 4
Hold bevacizumab until resolution or return to 
baseline
Grade 3
Hold bevacizumab until symptoms resolve to
≤ grade 1 or baseline
Other Unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting).
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.
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13.11.
Appendix 11:
Overall Guidelines for Management 
of Patients who Experience Adverse Events
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab or bevacizumab in this 
study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment. If corticosteroids are initiated 
for treatment of the toxicity, they must be tapered over 1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
If atezolizumab is withheld for  12 weeks after event onset, the patient will be 
discontinued from atezolizumab. However, atezolizumab may be withheld for
12 weeks to allow for patients to taper off corticosteroids prior to resuming 
treatment. Atezolizumab can be resumed after being withheld for  12 weeks if 
the treating physician agrees that the patient is likely to derive clinical benefit. 
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., 
surgical procedures). The investigator will determine the acceptable length of 
treatment interruption.
Bevacizumab treatment may be temporarily suspended in patients experiencing 
a grade 3 or 4 toxicity considered to be related to this drug. Bevacizumab can be 
restarted when the toxicity decreases to a grade 2 or below toxicity.
MANAGEMENT GUIDELINES
Guidelines for management of patients who experience specific adverse events 
are provided in Table 1a- Bev and Table 1b-Atezo.
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13.12.
Appendix 12:
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).
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment. If corticosteroids are initiated 
for treatment of the toxicity, they must be tapered over 1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
If atezolizumab is withheld for  12 weeks after event onset, the patient will be 
discontinued from atezolizumab. However, atezolizumab may be withheld for
12 weeks to allow for patients to taper off corticosteroids prior to resuming 
treatment. Atezolizumab can be resumed after being withheld for  12 weeks if 
the patient is likely to derive clinical benefit. The decision to rechallenge 
patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator. Atezolizumab treatment may 
be suspended for reasons other than toxicity (e.g., surgical procedures). The 
acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator.
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Adverse Events Associated with Atezolizumab
MANAGEMENT GUIDELINES
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 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 are provided in Table 1b- Atezo.
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Appendix 12 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Table 1b- Atezo
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 Grade 1 pneumonitis, consider withholding atezolizumab.
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 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
●
For recurrent events, or events with no improvement after 48– 
72 hours of corticosteroids, 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 corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone.
●
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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or appropriate delegate).
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Adverse Events Associated with Atezolizumab
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab. Patients eligible for study treatment must have adequate liver 
function, as manifested by measurements of total bilirubin and hepatic 
transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in Table 2.
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.
Table 2
Management Guidelines for Hepatic Events
Event
Management
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

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Monitor LFTs more frequently until return to baseline 
values.

For events of  5 days' duration, consider initiating 
treatment with corticosteroids equivalent to
12 mg/kg/day oral prednisone.

If event resolves to baseline or to Grade 1 or better, 
resume atezolizumab. b

If event does not resolve to baseline or to Grade 1 or 
better while withholding atezolizumab, permanently 
discontinue atezolizumab. c
AST or ALT increases to
10  ULN or total bilirubin 
increases to  3  ULN

Permanently discontinue atezolizumab. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of 
hepatic injury.

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 baseline, taper corticosteroids over
 1 month.
LFT  liver function test.
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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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of 
atezolizumab. Management guidelines for diarrhea or colitis are provided in 
Table 3.
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.
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Adverse Events Associated with Atezolizumab
Table 3
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 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
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 corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone 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
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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge patients 
with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).
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Adverse Events Associated with Atezolizumab
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or colitis, 
Grade 4
●
Permanently discontinue atezolizumab. c
●
Refer patient to GI specialist for evaluation and confirmation biopsy.
●
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone 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 the equivalent of
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab. Management guidelines for 
endocrine events are provided in Table 4.
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.
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Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
,Grade 1
●
Continue atezolizumab.
●
Initiate treatment with thyroid replacement hormone.
●
Monitor TSH closely.
Symptomatic 
hypothyroidism
, Grade 2
●
Consider withhold atezolizumab.
●
Initiate treatment with thyroid replacement hormone.
●
Monitor TSH closely.
●
Consider patient referral to endocrinologist.
●
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Hypothyroidism,
Grade 3 or 4
●
Withhold atezolizumab.
●
Initiate treatment with thyroid replacement hormone.
●
Monitor TSH closely.
●
Refer patient to endocrinologist.
●
Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status).
●
Resume atezolizumab when symptoms are controlled, and 
thyroid function is improving.
●
Permanently discontinue atezolizumab. c
 
Hyperthyroidis
m, Grade 1
TSH  0.1 mU/L and  0.5 mU/L:
●
Continue atezolizumab.
●
Monitor TSH every 4 weeks.
●
Consider patient referral to endocrinologist.
TSH  0.1 mU/L:
●
Follow guidelines for symptomatic hyperthyroidism.
●
Consider patient referral to endocrinologist.
Hyperthyroidis
m, Grade 2
●
Consider 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.
●
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Hyperthyroidism,
Grade 3 or 4
●
Withhold atezolizumab.
●
Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed.
●
Refer patient to endocrinologist.
●
Resume atezolizumab when symptoms are controlled, and 
thyroid function is improving.
●
Permanently discontinue atezolizumab. c
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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the 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-mediated event. The decision to 
rechallenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).
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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Hyperglycemia, Grade 1
or 2
●
Continue atezolizumab.
●
Investigate for diabetes. If patient has Type 1 diabetes, treat as 
a Grade 3 event. If patient does not have Type 1 diabetes, treat 
as per institutional guidelines.
●
Monitor for glucose control.
Hyperglycemia, Grade 3
or 4
●
Withhold atezolizumab.
●
Initiate treatment with insulin.
●
Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines.
●
Monitor for glucose control.
●
Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge patients 
with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).
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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by 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 are provided in Table 5.
Table 5
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 corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.
●
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 the equivalent of
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
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IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab. Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging 
abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise 
tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis (see section on pericardial disorders 
below) and should be managed accordingly. Immune-mediated myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly 
viral, e.g., in a patient who reports a recent history of gastrointestinal 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 in Table 6.
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IMMUNE-MEDIATED PERICARDIAL DISORDERS
Immune-mediated pericarditis should be suspected in any patient presenting with 
chest pain and may be associated with immune-mediated myocarditis (see 
section on myocarditis above).
Immune-mediated pericardial effusion and cardiac tamponade should be 
suspected in any patient presenting with chest pain associated with dyspnea or 
hemodynamic instability.
Patients should be evaluated for other causes of pericardial disorders such as 
infection (commonly viral), cancer related (metastatic disease or chest 
radiotherapy), cardiac injury related (post myocardial infarction or iatrogenic), and 
autoimmune disorders, and should be managed accordingly.
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI 
as appropriate per institutional guidelines. A cardiologist should be consulted.
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, 
if clinically indicated.
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6. Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the 
etiology and manage accordingly.
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Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-mediated 
myocarditis, Grade 2-4
Immune-mediated 
pericardial disorders, 
Grades 2-4
●
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 corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone 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.
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
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 medication with 
antihistamines, antipyretics and/or analgesics (e.g., acetaminophen).
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.
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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 (Lee et al. 2019). . 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 (Rotz et al. 2017; Adashek and 
Feldman 2019) , 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. For subsequent cycles, IRRs should be managed according to 
institutional guidelines.
Severe COVID-19 appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and 
Martin 2020). If a patient develops suspected CRS during the study, a 
differential diagnosis should include COVID-19, which should be confirmed or 
refuted through assessment of exposure history, appropriate laboratory testing, 
and clinical or radiologic evaluations per investigator judgment. If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or 
institutional guidelines.
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
●Immediately interrupt atezolizumab infusion.
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Feverb with
hypotension not
requiring
vasopressors
and/or
Hypoxia requiring
low-flow oxygend
by nasal cannula
or blow-by
●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 
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 as described in this appendix.
●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 
the sponsor-investigator.
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
Feverb with
hypotension
requiring multiple
vasopressors
●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
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(excluding 
vasopressin) 
and/or
Hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP,
BiPAP, intubation 
and mechanical 
ventilation)
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.
●
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.
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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; CTCAE  Common Terminology Criteria for Adverse Events; 
eCRF  electronic Case Report Form; HLH  hemophagocytic lymphohistiocytosis;
ICU  intensive care unit; IRR  infusion-related reaction; MAS  macrophage activation 
syndrome; NCCN  National Cancer Comprehensive Network; NCI  National Cancer Institute.
Note: These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE v5.0 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    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to rechallenge patients 
with atezolizumab should be based on investigator's assessment of benefitrisk and 
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 assessing the benefitrisk ratio.
f    Refer to Riegler et al. (2019).
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 workup should include an evaluation for ductal 
obstruction, as well as serum amylase and lipase tests. Management guidelines 
for pancreatic events, including pancreatitis, are provided in Table 8.
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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
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 a Grade 3 event.
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 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

For recurrent events, permanently discontinue atezolizumab. c
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 the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the 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-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
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Event
Management
Immune-mediated 
pancreatitis, Grade 2 or 3
●Withhold atezolizumab for up to 12 weeks after event onset. a
●Refer patient to GI specialist.
●Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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-mediated 
pancreatitis, Grade 4
●Permanently discontinue atezolizumab. c
●Refer patient to GI specialist.
●Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 the equivalent of
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
DERMATOLOGIC EVENTS
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Treatment-emergent rash has been associated with atezolizumab. The majority 
of cases of rash were mild in severity and self limiting, 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 are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
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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.
●Initiate treatment with topical corticosteroids.
●Consider treatment with higher-potency topical corticosteroids if event 
does not improve.
●If unresponsive to topical corticosteroids, consider oral prednisone
0.5 mg/kg/day.
Dermatologic 
event, Grade 3
●Withhold atezolizumab for up to 12 weeks after event onset. a
●Refer patient to dermatologist.
●Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, 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-Johnso 
n 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.
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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the 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.
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c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).
NEUROLOGIC DISORDERS
Myasthenia gravis, Guillain-Barré syndrome,immune-mediated myelitis and 
immunemediated facial paresis, have been observed with singleagent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or 
motor neuropathy. Diagnostic workup is essential for an accurate 
characterization to differentiate between alternative etiologies. Management 
guidelines for neurologic disorders are provided in Table 10.
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Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, Grade 
1
●
Continue atezolizumab.
●
Investigate etiology.
Immune-mediated 
neuropathy, Grade 
2
●
Withhold atezolizumab for up to 12 weeks after event onset. a
●
Investigate etiology and refer patient to neurologist.
●
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-mediated 
neuropathy, Grade 
3 or 4
●
Permanently discontinue atezolizumab. c
●
Refer patient to neurologist.
●
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 corticosteroids equivalent to 12 mg/kg/day oral 
or IV prednisone.
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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).
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IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab. Immune-mediated 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 in 
Table 11.
Table 11 Management Guidelines for Immune-Mediated 
Meningoencephalitis
Event
Management
Immune-mediated 
meningoencephalitis, all 
grades
●
Permanently discontinue atezolizumab. a
●
Refer patient to neurologist.
●
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone 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-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).
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RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab. Eligible patients must have adequate renal function. 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 non-steroidal 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.
Patients with signs and symptoms of nephritis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 12.
Table 12 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.
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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 the equivalent of
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
IMMUNE-MEDIATED 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.
Patients with possible myositis should be referred to a rheumatologist or 
neurologist. Patients with possible myositis should be monitored for signs of 
myocarditis.
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1
●
Continue atezolizumab.
●
Refer patient to rheumatologist or neurologist.
●
Initiate treatment as per institutional guidelines.
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Immune-mediated 
myositis, Grade 2
●
Withhold atezolizumab for up to 12 weeks after event onset a..
●
Refer patient to rheumatologist or neurologist.
●
Initiate treatment as per institutional guidelines.
●
Consider treatment with corticosteroids 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. c
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 based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk
and documented by the investigator (or an appropriate delegate).
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Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated 
myositis, Grade 3
●
Withhold atezolizumab for up to 12 weeks after event onset a.
●
Refer patient to rheumatologist or neurologist.
●
Initiate treatment as per institutional guidelines.
●
Respiratory support may be required in more severe cases.
●
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., 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. c
●
For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4
●
Permanently discontinue atezolizumab. c
●
Refer patient to rheumatologist or neurologist.
●
Initiate treatment as per institutional guidelines.
●
Respiratory support may be required in more severe cases.
●
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., 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.
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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 the equivalent of
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 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-mediated event. The decision to rechallenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).
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) which are considered to be potential risks for atezolizumab.
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:
– Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks 
old)
– Platelet count  100  109/L (100,000/L)
– 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
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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 14.
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH or 
MAS
●
Permanently discontinue atezolizumab.
●
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, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours after, initiate 
treatment as appropriate according to published guidelines (La Rosée 
2015; Schram and Berliner 2015; La Rosée et al. 2019).
●
.
●
If event resolves to Grade 1 or better, taper corticosteroids over
 1 month.
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome.
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Appendix 12 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
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.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
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.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for 
hepatocellularcarcinoma. Semin Liver Dis 2010;30:52- 60.
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