A Phase IIIB, Single Arm, Multicenter Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase IIIB, Single-Arm, Multicenter Study of Atezolizumab 
(Tecentriq) in Combination With Bevacizumab to Investigate Safety 
and Efficacy in Patients With Unresectable Hepatocellular Carcinoma 
Not Previously Treated With Systemic Therapy - Amethista 
NCT Number: 
NCT04487067 
Document Date: 
Protocol Version 5: 11-Jan-2024 
 
 
 

FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially unpublished data, is the property of Roche 
S.p.A. (or under its control), and therefore provided to you in confidence as an investigator, 
potential investigator or consultant, for review by you, your staff and an applicable Independent 
Ethics Committee. It is understood that this information will not be disclosed to others without 
written authorization from Roche except to the extent necessary to obtain informed consent from 
those persons to whom the drug may be administered. 
 
 
 
Atezolizumab—RocheS.p.A. 
Protocol ML42243, Version 5 
PROTOCOL 
TITLE: 
A PHASE IIIB, SINGLE ARM, MULTICENTER 
STUDY OF ATEZOLIZUMAB (TECENTRIQ) IN 
COMBINATION 
WITH 
BEVACIZUMAB 
TO 
INVESTIGATE 
SAFETY 
AND 
EFFICACY 
IN 
PATIENTS 
WITH 
UNRESECTABLE 
HEPATOCELLULAR 
CARCINOMA 
NOT 
PREVIOUSLY 
TREATED 
WITH 
SYSTEMIC 
THERAPY - AMETHISTA 
PROTOCOL NUMBER: ML42243 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-001973-66 
IND NUMBER: 
N/A 
 
 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
MEDICAL MONITOR: 
  
SPONSOR: 
Roche S.p.A. 
DATE FINAL: 
See electronic signature and date stamp on the 
final page of this document. 

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Version 
Date Final 
5 
See electronic signature and date stamp on the 
final page of this document. 
4 
See electronic signature and date stamp on the 
final page of the document. 
3 
See electronic date stamp on title page 
2 
See electronic date stamp on title page 
1 
19 May 2020 

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PROTOCOL AMENDMENT, VERSION 5.0: 
RATIONALE 
Protocol ML42243 has primarily been amended to update safety language following the 
release of the Atezolizumab Investigator’s Brochure Version 20. Changes to the protocol, 
along with a rationale for each change, are summarized below: 
● 
The Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 20 (Appendix 6). 
Additional minor changes have been made to improve clarity and consistency. Substantive 
new information appears in italics. This amendment represents cumulative changes to the 
original protocol. 
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 7 
PROTOCOL SYNOPSIS ...................................................................................... 8 
1. 
BACKGROUND .......................................................................................... 30 
1.1 
Background on HEPATOCELLULAR 
CARCINOMA ......................................................................... 30 
1.2 
CURRENT SYSTEMIC Treatment for 
ADVANCED HEPATOCELLULAR CARCINOMA .................. 30 
1.3 
Background on Atezolizumab ................................................ 32 
1.4 
Background on BEVACIZUMAB ............................................ 32 
1.5 
OVERVIEW OF CLINICAL DEVELOPMENT 
PROGRAM IN HEPATOCELLULAR 
CARCINOMA ......................................................................... 33 
1.6 
Study Rationale and Benefit-Risk Assessment ...................... 36 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 41 
2.1 
PRIMARY OBJECTIVE ......................................................... 41 
2.2 
SECONDARY OBJECTIVES ................................................. 42 
2.3 
EXPLORATORY OBJECTIVES ............................................ 43 
3. 
STUDY DESIGN ......................................................................................... 44 
3.1 
Description of the Study......................................................... 44 
3.2 
End of Study and Length of Study ......................................... 46 
3.3 
Rationale for Study Design .................................................... 46 
4. 
MATERIALS AND METHODS .................................................................... 51 
4.1 
Patients .................................................................................. 51 
4.2 
Method of Treatment Assignment and Blinding ..................... 61 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 61 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 66 
4.5 
Study Assessments ............................................................... 69 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ...................................................................... 76 

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5. 
ASSESSMENT OF SAFETY ....................................................................... 79 
5.1 
Safety Plan ............................................................................ 79 
5.2 
Safety Parameters and Definitions ........................................ 80 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 83 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 92 
5.5 
Follow-Up of Patients after Adverse Events .......................... 96 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 96 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees .......................................................... 97 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 97 
6.1 
Determination of Sample Size ............................................... 97 
6.2 
Summaries of Conduct of Study ............................................ 99 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 99 
6.4 
SAFETY Analyses ............................................................... 100 
6.5 
EFFICACY Analyses ........................................................... 102 
6.6 
Biomarker Analyses ............................................................. 103 
6.7 
HEALTHECONOMIC Analysis ............................................ 104 
6.8 
EXPLORATORY Analyses of PRO-CTCAE Data ................ 107 
6.9 
Interim Analyses .................................................................. 107 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 108 
7.1 
Data Quality Assurance ....................................................... 108 
7.2 
Electronic Case Report Forms ............................................. 108 
7.3 
Source Data Documentation ................................................ 109 
7.4 
Use of Computerized Systems ............................................ 109 
7.5 
Retention of Records ........................................................... 109 
8. 
ETHICAL CONSIDERATIONS .................................................................. 110 
8.1 
Compliance with Laws and Regulations .............................. 110 
8.2 
Informed Consent ................................................................ 110 

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8.3 
Institutional Review Board or Ethics Committee .................. 111 
8.4 
Confidentiality ...................................................................... 112 
8.5 
Financial Disclosure ............................................................ 112 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 113 
9.1 
Study Documentation .......................................................... 113 
9.2 
Protocol Deviations .............................................................. 113 
9.3 
Management of Study Quality ............................................. 113 
9.4 
Site Inspections ................................................................... 113 
9.5 
Administrative Structure....................................................... 113 
9.6 
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 114 
9.7 
Protocol Amendments ......................................................... 115 
10. REFERENCES ......................................................................................... 116 
 
 
LIST OF TABLES 
Non è stata trovata alcuna voce dell'indice delle figure. 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 46 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 124 
Appendix 2 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 130 
Appendix 3 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 140 
Appendix 4 
Anaphylaxis Precautions ........................................................... 142 
Appendix 5 
Guidelines for Management of Adverse Events Associated 
with Atezolizumab + Bevacizumab ........................................... 143 
Appendix 6 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 148 
Appendix 7 
NCI-PRO CTCAE ITEMS (Item Library Version 1.0) ................ 191 
 

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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIIB, SINGLE ARM, MULTICENTER 
STUDY OF ATEZOLIZUMAB (TECENTRIQ) IN 
COMBINATION 
WITH 
BEVACIZUMAB 
TO 
INVESTIGATE 
SAFETY 
AND 
EFFICACY 
IN 
PATIENTS 
WITH 
UNRESECTABLE 
HEPATOCELLULAR 
CARCINOMA 
 
NOT 
PREVIOUSLY 
TREATED 
WITH 
SYSTEMIC 
THERAPY – AMETHISTA 
PROTOCOL NUMBER: ML42243 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-001973-66 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
MEDICAL MONITOR: 
 
SPONSOR: 
Roche S.p.A. 
 
 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study Monitor. 

 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IIIB, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB 
(TECENTRIQ) 
IN 
COMBINATION 
WITH 
BEVACIZUMAB TO INVESTIGATE SAFETY AND EFFICACY IN 
PATIENTS 
WITH 
UNRESECTABLE 
HEPATOCELLULAR 
CARCINOMA NOT PREVIOUSLY TREATED WITH SYSTEMIC 
THERAPY – AMETHISTA 
PROTOCOL NUMBER: 
ML42243 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-001973-66  
IND NUMBER: 
N/A 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
PHASE: 
Phase IIIB 
INDICATION: 
Unresectable hepatocellular carcinoma (HCC) 
SPONSOR: 
Roche S.p.A. 
 
Objectives and Endpoints 
 
This study will evaluate the safety and efficacy of atezolizumab in combination with bevacizumab 
in patients with unresectable hepatocellular carcinoma (HCC) who have received no prior 
systemic treatment. In this protocol, "study treatment" refers to the combination of treatments 
assigned to patients as part of this study (i.e., atezolizumab and bevacizumab). 
Specific objectives and corresponding endpoints for the study are outlined below. 
Primary Objective 
Corresponding Endpoint 
To evaluate the safety of 
atezolizumab  bevacizumab in 
terms of bleeding/haemorrhage  
 Incidence of Grade 3-5 NCI CTCAE v.5 
bleeding/haemorrhage  
  
Main Secondary Objective 
Corresponding Endpoint 
To evaluate the efficacy of 
atezolizumab  bevacizumab 
Overall survival (OS), defined as the time from initiation of 
study treatment to death from any cause 
 
 
 
 

 
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Other Secondary Objectives 
Corresponding Endpoints 
To further evaluate the safety of 
atezolizumab + bevacizumab 
 
 
 
 
To further evaluate the efficacy of 
atezolizumab  bevacizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate Patient Reported 
Outcomes (PROs) and to describe 
the patient’s experience while 
receiving atezolizumab + 
bevacizumab 
 Incidence and severity of adverse events (AEs), with 
severity determined according to NCI CTCAE v5.0 
 Vital signs 
 Clinical laboratory test results 
 
 Progression-free survival (PFS), defined as the time from 
initiation of study treatment to the first occurrence of 
disease progression or death from any cause (whichever 
occurs first), as determined by the investigator according 
to RECIST v1.1 
 Objective response rate (ORR), defined as a complete or 
partial response, as determined by the investigator 
according to RECIST v1.1 
 Time to progression (TTP), defined as the time from 
initiation of study treatment to the first occurrence of 
disease progression, as determined by the investigator 
according to RECIST v1.1 
 Duration of response (DOR), defined as the time from the 
first occurrence of a documented objective response to 
disease progression or death from any cause (whichever 
occurs first), as determined by the investigator according 
to RECIST v1.1 
 Post-progression survival (PPS), defined as the time from 
the first occurrence of disease progression as determined 
by the investigator according to RECIST v1.1 to death 
from any cause 
 Number/Rate of patients starting second or further lines  
of treatment 
 
 Patient self-reported symptomatic Adverse Events (AEs) 
using National Cancer Institute's Patient-Reported 
Outcomes Version of the Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) 

 
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Exploratory Efficacy Objectives Corresponding Endpoints 
 To evaluate whether the 
patterns of tumor progression 
(growth versus new lesion, 
intrahepatic versus extrahepatic) 
have a different impact on OS 
and PPS 
 
 
 
 To evaluate if post-study 
treatment have impact on OS  
 
 To evaluate if reason of 
treatment withdrawal has impact 
on OS 
 OS and PPS based on the following patterns of 
progression:  
- >20% increase in tumor size against a known baseline 
lesion (intrahepatic growth [IHG] or extrahepatic growth 
[EHG]) 
- new intrahepatic tumor lesion (NIH)  
- new extrahepatic lesion (NEH) and/or vascular 
invasion 
 OS based on type and duration of each post-study 
treatments 
 
 OS based on the following reasons of treatment 
withdrawal: 
- Progressive disease (PD) vs AEs vs deteriorating liver 
function/clinical conditions 
 
Exploratory Biomarker 
Objective 
Corresponding Endpoint 
 Gut Microbiome evaluation 
 
Relationship between the compositional and functional 
structure of the gut microbiome and antitumour 
responses following atezolizumab and bevacizumab 
 Exploratory Economic 
Objective 
Corresponding Endpoint 
 To identify, quantify and 
valuate health care resources 
consumed for managing 
Grade 3 and 4 AEs related to 
the administration of 
atezolizumab + bevacizumab  
 To assess the cost for 
managing adverse events 
related to the administration of 
atezolizumab + bevacizumab 
 
Relationship between AEs and health care resource 
consumption 
 
 
 
 
 
Cost description of health care resources consumed for 
managing Grade 3 and 4 AEs related to the 
administration of atezolizumab + bevacizumab  
 
AE 
= 
Adverse 
Event; 
DOR  duration 
of 
response; 
EHG 
= 
extrahepatic 
growth; 
HCC  hepatocellular carcinoma; IHG = intrahepatic growth; NCI CTCAE v5.0  National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; NEH = new extrahepatic 
lesion; NIH = new intrahepatic lesion; ORR = Objective Response Rate; OS  overall survival; PD 
= progressive disease; PFS  progression-free survival; PRO = Patient Reported Outcome; PRO-
CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events; PPS = Post-progression Survival; RECIST v1.1  Response Evaluation Criteria in Solid 
Tumors, Version 1.1; PPS=Post Progression Survival; TTP = Time to Progression 

 
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Study Design 
Description of Study 
This is a Phase IIIb, one arm, multicenter, open-label study designed to evaluate the safety and 
efficacy of atezolizumab  bevacizumab in patients with unresectable HCC who have received no 
prior systemic treatment.   
This study will enroll approximately 150 patients in one arm of treatment: 
 Atezolizumab 1200 mg intravenous (IV) infusions Q3W (dosed in 3-week cycles)  bevacizumab 
15 mg/kg IV Q3W (dosed in 3-week cycles)  
Patients treated with atezolizumab   bevacizumab arm who transiently discontinue or withdraw 
from either atezolizumab or bevacizumab may continue on single-agent therapy as long as the 
patients are experiencing clinical benefit in the opinion of the investigator and withdraw after 
discussion with the Medical Monitor (i.e., patients transiently discontinue or withdraw from 
bevacizumab for adverse effects may continue atezolizumab monotherapy and vice versa).  
Patients will receive atezolizumab and/or bevacizumab 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). In the absence of unacceptable toxicity, patients who meet criteria for disease 
progression per RECIST v1.1 while receiving atezolizumab and/or bevacizumab will be permitted 
to continue the study treatment if they meet all of the following criteria: 
 Evidence of clinical benefit, as determined by the investigator following a review of all available 
data; 
 Absence of symptoms and signs (including laboratory values) indicating unequivocal 
progression of disease; 
 Absence of decline in ECOG Performance Status that can be attributed to disease progression; 
 Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease or brain 
metastases) that cannot be managed by protocol-allowed medical interventions. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Laboratory safety assessments will include the 
regular monitoring of haematology and blood chemistry.   
Tumor assessments will be performed at baseline and at regular intervals during study treatment.  
Additional scans will be performed as clinically indicated. Tumor assessments will continue until 
disease progression according to RECIST V1.1, regardless of whether treatment has been 
discontinued (e.g., for toxicity) or until loss of clinical benefit, whichever occurs later. In the absence 
of disease progression, tumor assessments should continue regardless of whether patients start 
new anti-cancer therapy, until consent is withdrawn, death, or the study is terminated by the 
Sponsor, whichever occurs first.   
Following disease progression, patients will be followed for survival and subsequent anti-cancer 
therapies until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor, 
whichever occurs first.   
Patient samples of faeces will be collected for future exploratory biomarker assessments. 

 
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Number of Patients 
This study will enroll approximately a sample of convenience (Lohr 2010) of 150 patients across 
21 Italian sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 Signed Informed Consent Form; 
 Age  18 years at time of signing Informed Consent Form; 
 Ability to comply with the study protocol, in the investigator's judgment; 
 Unresectable HCC with diagnosis confirmed by histology, with a biopsy within 6 months from 
recruitment;  
 Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive 
disease after surgical and /or locoregional therapies; 
 No prior systemic therapy (including systemic investigational agents) for HCC; 
 At least one measurable (per RECIST 1.1) untreated lesion; 
 Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous ethanol 
or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial 
chemoembolization, transarterial embolization, SIRT etc.) are eligible provided the target 
lesion(s) have not been previously treated with local therapy or the target lesion(s) within the 
field of local therapy have subsequently progressed in accordance with RECIST version 1.1; 
 ECOG Performance Status of 0 or 1 within 7 days prior to recruitment; 
 Child-Pugh class A within 7 days prior to recruitment; 
 Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small 
to large) must be assessed. In case of varices at high risk of bleeding (corresponding to medium 
(F2) or large (F3) varices, or F1 varices with cherry red spots or red wale marking) prophylatic 
treatment per local standard of care must be adopted prior to enrollment. Patients who have 
undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat 
the procedure provided they had no varices at high risk of bleeding; 
 Adequate hematologic and end-organ function, defined by the following laboratory test results, 
obtained within 7 days prior to recruitment, unless otherwise specified: 
- 
ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor support; 
- 
Lymphocyte count  0.5  109/L (500/L); 
- 
Platelet (PLT) count  75  109/L (75,000/L) without transfusion;  
- 
Haemoglobin  90 g/L (9 g/dL); 
Patients may be transfused to meet this criterion. 
- 
AST, ALT, and alkaline phosphatase (ALP)  5  upper limit of normal (ULN); 
- 
Total bilirubin   3 ULN;  
- 
Serum creatinine  1.5  ULN or creatinine clearance  50 mL/min (calculated using the 
Cockcroft-Gault formula); 
- 
Serum albumin  28 g/L (2.8 g/dL) without transfusion; 
- 
For patients not receiving therapeutic anticoagulation: INR and aPTT or PTT  1.5 x ULN; 

 
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- 
Urine dipstick for proteinuria  2 (within 7 days prior to initiation of study treatment); 
Patients discovered to have ≥ 2 proteinuria on dipstick urinalysis at baseline should 
undergo a 24-hour urine collection (or an alternative method such as protein: creatinine 
ratio, per local guidance) and must demonstrate  1 g of protein in 24 hours. 
 Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to 
Grade  1 prior to study entry, with the exception of alopecia; 
 Negative HIV test at screening with the following exception: patients with a positive HIV test at 
screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count 
≥200µL, and have an undetectable viral load; 
 In patients with viral HCC, documented virology status of hepatitis, as confirmed by screening 
HBV and HCV serology test;  
 For patients with active hepatitis B virus (HBV):  
HBV DNA  500 IU/mL obtained within 28 days prior to initiation of study treatment, and 
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days 
prior to study entry and willingness to continue treatment for the length of the study; 
 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 must remain abstinent or use contraceptive methods with a failure rate of < 1% 
per year while they are receiving atezolizumab and bevacizumab and for 5 months after 
the final dose of atezolizumab and for 6 months after the final dose of bevacizumab. 
Women must refrain from donating eggs during the same period. 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 is not permanently infertile due to surgery (removal of ovaries, fallopian 
tubes and/or uterus) or another cause as determined by the investigator (e.g., Müllerian 
agenesis). Per this definition, a woman with a tubal ligation is considered to be of 
childbearing potential. 
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. 
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 acceptable methods of contraception; 
 For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of  1% 
per year during the treatment period and for 6 months after the last dose of bevacizumab. 
Men must refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the last dose of bevacizumab to avoid exposing 
the embryo. 

 
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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 acceptable methods of contraception. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 History of leptomeningeal disease or brain metastases; 
 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, with the 
following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the 
study provided all of following conditions are met: 
- 
Rash must cover  10% of body surface area; 
- 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids; 
- 
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; 
 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. 
 Known active tuberculosis; 
 Significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to 
initiation of study treatment, unstable arrhythmia, or unstable angina;  
 History of congenital long QT syndrome or corrected QT interval 500 ms (calculated with use 
of the Fridericia method) at screening; 
 History of uncorrectable electrolyte disorder affecting serum levels of potassium, calcium, 
or magnesium; 
 Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study; 
 History of malignancy other than HCC within 5 years prior to screening, with the exception of 
malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate  90%), such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized 
prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer; 

 
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 Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia or any severe 
infection that in the opinion of the investigator could impact patient’s safety; 
 Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment; 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) or patients receiving rifaximin as 
prevention of encephalopathy are eligible for the study.  
Antibiotics administered within 30 days prior to initiation of study treatment will be collected. 
 Prior allogeneic stem cell or solid organ transplantation; 
 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; 
 Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or 
anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after 
the last dose of atezolizumab; 
 History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion 
proteins; 
 Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or bevacizumab formulation;  
 Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 
at least 5 months after the last dose of atezolizumab and 6 months after the last dose of 
bevacizumab;  
Women of childbearing potential must have a negative serum pregnancy test result within 
14 days prior to initiation of study treatment. 
 Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; 
 Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk 
for bleeding; 
 A prior bleeding event due to oesophageal and/or gastric varices within 6 months prior to 
initiation of study treatment; 
 Clinically evident ascites; 
 At least one clinically evident episode of encephalopathy in the past three months;  
 Co-infection of HBV and HCV; 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV; 
 Co-infection with HBV and hepatitis D viral infection; 
 Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases; 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met: 
- 
Measurable disease, per RECIST v1.1, must be present outside the CNS; 
- 
The patient has no history of intracranial haemorrhage or spinal cord haemorrhage; 

 
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- 
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord); 
- 
There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment; 
- 
The patient has not undergone stereotactic radiotherapy, whole-brain radiotherapy, 
and/or neurosurgical resection within 28 days prior to initiation of study treatment; 
- 
The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.  
- 
If the patient is receiving anti-convulsivant therapy, the dose is considered stable 
Asymptomatic patients with CNS metastases newly detected at screening are eligible for the 
study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan. 
 Uncontrolled tumor-related pain; 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment. Patients should 
be recovered from the effects of radiation. There is no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment. 
 Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently); 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 Clinically significant uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL or corrected serum calcium  ULN); 
 Treatment with investigational therapy within 28 days prior to initiation of study treatment; 
 Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies;  
 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; 
 Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF- 
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic 
immunosuppressive medication during study treatment, with the following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant medication or a one-
time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study. 
 Inadequately 
controlled 
arterial 
hypertension 
(defined 
as 
systolic 
blood 
pressure 
(BP)  150 mmHg and/or diastolic blood pressure  100 mmHg), based on an average of  3 BP 
readings on  2 sessions; 

 
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Anti-hypertensive therapy to achieve these parameters is allowable. 
 Prior history of hypertensive crisis or hypertensive encephalopathy; 
 Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral 
arterial thrombosis) within 6 months prior to initiation of study treatment; 
 History of haemoptysis ( 2.5 mL of bright red blood per episode) within 1 month prior to initiation 
of study treatment; 
 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation); 
 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; 
 Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral 
anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose; 
Prophylactic anticoagulation for the patency of venous access devices is allowed provided 
the activity of the agent results in an INR  1.5  ULN and aPTT or PTT is within normal 
limits within 14 days prior to initiation of study treatment. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is allowed. 
However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa®) 
and rivaroxaban (Xarelto®) is not recommended due to bleeding risk. Benefits and risks 
should be assessed and caution exercised for use of direct oral anticoagulants. The 
investigator should consider switching to other approved anticoagulants due to the risk of 
upper gastrointestinal (GI) bleeding in patients with HCC. 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 3 days prior to the first dose of bevacizumab; 
 
History of gastrointestinal (GI) fistula, GI perforation, or intra-abdominal abscess within 
6 months prior to initiation of study treatment; 
 
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including 
sub-occlusive disease related to the underlying disease or requirement for routine parenteral 
hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment; 
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of 
initial diagnosis may be enrolled if they had received definitive (surgical) treatment for 
symptom resolution. 
 Evidence of abdominal free air that is not explained by paracentesis or recent 
surgical procedure; 
 Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture; 
 Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal 
tumor masses ( 30 mm from the carina) of large volume; 
Patients with vascular invasion of the portal or hepatic veins may be enrolled.   
 History of clinically significant intra-abdominal inflammatory process within 6 months prior to 
initiation of study treatment, including but not limited to complicated active peptic ulcer disease, 
diverticulitis, or colitis; 
 Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation 
of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation 
of study treatment; 

 
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 Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid 
injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, 
transarterial embolization, SIRT etc.) within 28 days prior to initiation of study treatment or non-
recovery from side effects of any such procedure; 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
initiation of study treatment, or abdominal surgery, abdominal interventions or significant 
abdominal traumatic injury within 60 days prior to initiation of study treatment or anticipation of 
need for major surgical procedure during the course of the study or non-recovery from side 
effects of any such procedure; 
 Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID), excluding acetyl 
acetic acid (aspirin) at doses <325 mg/day; 
Occasional use of NSAIDs for the symptomatic relief of medical conditions such as 
headache or fever is allowed. 
End of Study 
The end of study will occur when all enrolled patients have either died, withdrawn consent, are lost 
to follow up, or have been followed for 36 months since the last study patient is enrolled, whichever 
occurs first.  
In addition, the Sponsor may decide to terminate the study at any time. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study is 
approximately 4 years (12 months enrolment). 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Patients will receive treatment as outlined below 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).   
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
Atezolizumab 1200 mg IV on Day 1 
Bevacizumab 15 mg/kg IV on Day 1 
 
Comparator  
Not applicable. 
Non-Investigational Medicinal Products 
Not applicable. 
 
Statistical Methods 
Determination of Sample Size  
This study will enroll approximately a sample of convenience (Lohr 2010) of 150 patients across 
21 Italian sites, possibly according to a competitive enrolment scheme (Kim et al. 2017). 

 
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According to the results of the YO40245 (IMbrave150) trial (Cheng et al. 2019), the expected 
incidence of Grade 3-5 bleeding events is 7.9% (that is, 6.4% incidence of Grade 3-4 bleeding 
events plus 1.5% incidence of Grade 5 bleeding events) during a 10.4 months timespan (that is, 
7.4 months of median treatment duration plus 90 days or 3 months of follow-up). 
Therefore, assuming a fixed rate with respect to time, the overall Grade 3-5 bleeding events rate 
(r) per month is (Miller and Homan 1984; Briggs et al. 2006): 
𝑟= −
[ln(1 −0.079)]
10.4
 
or 0.007913, that, considering a convenience sample (Lohr 2010) of 150 patients and a 12-month 
lasting year (Wilkins 1990), can be converted into an annual probability (one year p) - or incidence 
- of Grade 3-5 bleeding events as follows (Miller and Homan 1984; Briggs et al. 2006): 
𝑜𝑛𝑒 𝑦𝑒𝑎𝑟 𝑝= [1 −exp(−0.007913x12)] 
or 0.090587. 
According to this incidence point estimate and assuming no missing 1-year patient time and that 
each patient can experience only one Grade 3-5 bleeding event per year (that is, ruling out for sake 
of simplicity shared frailty issues, such as multiple occurrence of 3-5 bleeding events experienced 
by the same patient) (Therneau and Grambsch 2000), the expected number (#) of patients with 
Grade 3-5 bleeding event per year out of a convenience sample size (Lohr 2010) of 150 evaluable 
subjects can be calculated as follows: 
# 𝑜𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑏𝑙𝑒𝑒𝑑𝑖𝑛𝑔 𝑒𝑣𝑒𝑛𝑡𝑠 𝑝𝑒𝑟 𝑦𝑒𝑎𝑟= (0.090587x150) 
or about 14 patients with the event per year. 
The achievable precision (width of 95% CI) for the incidence of Grade 3-5 bleeding events related 
to treatment is illustrated separately (Table 9). The sample variance of the binomial distribution is 
conditional on its sample mean (Agresti 2002) and both these statistics enter the formula for 
calculating the standard error of the sample distribution of the mean (Agresti 2002). Therefore, 
given the same sample size, a low incidence of Grade 3-5 bleeding events leads to a small width 
of the 95% CI, whereas a higher incidence of Grade 3-5 bleeding events results in a wider 95% CI.  
In order to investigate the precision of the point estimate for the incidence of Grade 3-5 bleeding 
events under different scenarios, the Clopper-Pearson method (Clopper and Pearson 1934; Agresti 
2002; Fleiss et al. 2003) for calculating incidence 95% CI and the width of 95% CI has been applied. 
Thus, assuming a sample size of 150 patients and the incidence of Grade 3-5 bleeding events 
which lies within the range of 0% - 9.33%, the precision (CI width) could vary from 2.43 to 9.96 
percent points. In particular, considering the incidence of Grade 3-5 bleeding events around 8%, a 

 
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two-sided 95% confidence interval with a width equal to 9.36 percent points will be provided (see 
section 6.1 for details). 
Safety Analysis 
The safety analysis population (SAP) consists of all enrolled patients who had at least one full or 
partial administration of atezolizumab + bevacizumab. 
Primary Analysis 
The incidence of grade 3-5 NCI CTCAE bleeding/haemorrhage events will be calculated for the 
SAP, along with binomial exact (or Clopper-Pearson) (Clopper and Pearson 1934; Agresti 2002; 
Fleiss et al. 2003) 95% (CI). 
Primary analysis 
The overall incidence of Grade 3-5 NCI CTCAE bleeding events will be calculated for the SAP, 
along with Clopper-Pearson (Clopper and Pearson 1934; Agresti 2002; Fleiss et al. 2003) 95% CI. 
No hypothesis testing is intended, as the focus of the statistical analyses is on the precision of the 
obtained estimate of the incidence of this key safety parameter. 
For the primary safety endpoint, that is overall Grade 3-5 bleeding events, in addition to the annual 
probability of experiencing such AEs, the annual and overall bleeding rate (BR) will be calculated 
as follows:  
𝐵𝑅= #𝑒𝑣𝑒𝑛𝑡𝑠/𝑃𝑌 
where #events is the total number of Grade 3-5 bleeding events (including multiple occurrences 
per patient), and PY is the total number of patient-years under observation. The BR point estimate 
will be provided along with 95% CI, assuming a Poisson distribution (Poisson 1837; Agresti 2001; 
Hilbe 2014) for the underlying number of related events. 
Secondary analysis 
Safety will be also assessed through summaries of exposure to study treatment, adverse events, 
deaths, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, dose intensity, number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
Laboratory data with values outside the normal ranges will be identified. In addition, selected 
laboratory data will be summarized by grade with descriptive statistics. 
Descriptive statistics will be used to summarize changes in vital signs. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according to NCI CTCAE 
v5.0. All adverse events, serious adverse events, adverse events leading to death, adverse events 

 
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of special interest, and adverse events leading to study treatment discontinuation that occur on or 
after the first dose of study treatment (i.e., treatment-emergent adverse events) will be summarized 
by mapped term, appropriate thesaurus level, and severity grade. For events of varying severity, 
the highest grade will be used in the summaries. Deaths with causes of death reported during the 
study will be summarized. 
The following events occurring during or after the first dose of study treatment will be summarized 
by NCI CTCAE grade v5.0: 
- All Adverse Events (AEs) 
- 
All severe AEs (Grade 3-4) 
- All treatment related AEs;  
- 
All severe treatment-related AEs (Grade 3 -4) 
- All serious AEs 
- 
All treatment-related serious AEs 
- All immune-mediated AEs 
- 
 All severe immune-mediated AEs (Grade 3-4) 
- All adverse events leading to withdrawal from any component 
- All adverse events leading to withdrawal from atezolizumab 
- All adverse events leading to withdrawal from bevacizumab 
- All Grade 5 AEs 
- 
All treatment related Grade 5 AE 
- All adverse event of special interest (AESIs) of atezolizumab 
- 
All severe AESIs of atezolizumab (Grade 3-4) 
- All adverse event of special interest (AESIs) of bevacizumab  
- 
All severe AESIs of atezolizumab (Grade 3-4) 
- All adverse events leading to dose temporary interruption of any component 
- All adverse events leading to dose temporary interruption of atezolizumab 
- All adverse events leading to dose temporary interruption of bevacizumab 
Multiple occurrences of the same event will be counted once at the maximum severity. 
The following descriptive statistics on the selected items will be reported (Pagano and Gavreau 
2000): 

 
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- 
Continuous and count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Summary statistical tables including number of and patients with adverse events along with 95% 
CI assuming an underlying Poisson distribution (Poisson 1837; Agresti 2001; Hilbe 2014) as well 
as number absolute and relative frequencies of adverse events along with Clopper-Pearson 95% 
CI (Clopper and Pearson 1934; Agresti 2002; Fleiss et al. 2003) will be produced.  
Additional analyses may be performed as indicated. 
Missing values will be classified and managed using the methods outlined in Section 6.7. 
According to its relevance to possible AEs experienced by patients on atezolizumab + 
bevacizumab, a subset of the about 80 items included in the Italian translation of the Item Library 
Version 1.0 of the NCI-PRO-CTCAE™ questionnaire (Appendix 7) (Smith et al. 2016; National 
Cancer Institute, 2017) will be selected by a working group composed of study investigators and 
patient advocates. 
The following descriptive statistics on the selected items (possibly grouping in domains items that 
share common features) (Brazier et al.2017) of the Italian translation of the Item Library Version 
1.0 of the NCI-PRO-CTCAE™ questionnaire version 1.0 of the NCI-PRO-CTCAE™ questionnaire 
will be reported (Pagano and Gavreau 2000): 
- Ordinal count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Missing data for items and patients will be summarized to improve results interpretation (National 
Cancer Institute, 2020). 
Missing values will be classified and managed using the methods outlined in Health economic 
analysis paragraph. 
 
Secondary Analysis 
Efficacy 
Efficacy analysis includes both main and other secondary objectives, 
All baseline summaries and efficacy analyses will be based on the intent-to-treat (ITT) analysis set 
defined as all recruited patients. 
Time-dependent variables OS, PFS, TTP, DOR and PPS will be analyzed using Kaplan-Meier (K-
M) methods and Greenwood’s formula. Medians and the quartiles with 95% confidence interval (CI) 
will be derived from the K-M curves. Kaplan-Meier plots with a 95% CI for OS, PFS, DOR and PPS 
will be prepared. 
ORR will simply be summarised. The ORR will be calculated as the percentage of patients who 
have a CR or PR before any evidence of progression. A 95% CI will be derived for the ORR using 
Wilson score intervals (CIs for a single proportion). 

 
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Following disease progression, patients will be followed-up to evaluate whether the patterns of 
tumor progression (growth versus new lesion, intrahepatic versus extrahepatic) have a different 
impact on OS and PPS. OS and PPS will be described based on the following patterns of 
progression:  
- >20% increase in tumor size against a known baseline lesion (intrahepatic growth [IHG] or 
extrahepatic growth [EHG]) 
- new intrahepatic lesion (NIH)  
- new extrahepatic lesion (NEH) and/or vascular invasion 
To evaluate if post-study treatments have impact on OS following disease progression, patients 
will be followed for anti-cancer therapies and survival with a descriptive analysis.  In details, number 
and rate of patients starting second or further lines of treatment will be described indicating time 
and duration of each post-study treatment. OS based on type and duration of each post-study 
treatment will be described. 
To evaluate if reason of treatment withdrawal has impact on OS, OS based on the following reasons 
of treatment withdrawal will be described: 
- Progressive disease (PD) vs adverse event (AE) vs deteriorating liver function/clinical conditions. 
Missing values will be classified and managed using the methods outlined described above. 
For the primary safety endpoint of grade 3-5 bleeding events, the overall bleeding rate (BR) will be 
calculated in Health economic analysis paragraph. 
- Continuous and count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Health economic analysis 
The health care resources consumed for managing Grade 3 and 4 AE related to the administration 
of atezolizumab + bevacizumab by the sample of convenience (Lohr 2010) of approximately 150 
patients enrolled in 20 Italian clinical sites will be prospectively identified and quantified, using the 
ITT analysis population.  
Following the Italian National Health Service (INHS) viewpoint (Drummond et al. 2015), the 
abovementioned health care resources will be valued and detailed via a partial technique of 
economic evaluation of health care programmes (Drummond et al. 2015), named cost description 
(Drummond et al. 2015). Cost description describes the health care resources cost but neither 
takes their effects on patient’s health state into account, nor informes any choice among different 
health care programmes (Drummond et al. 2015).  
The cost description will focus on the following INHS-funded health care resources (Lazzaro et al. 
2013; Lazzaro et al. 2018; Lazzaro et al. 2019): 
- Laboratory tests; 
- Diagnostic imaging;  
- Instrumental tests; 
- Drugs (posology; number of administrations per diem; length of treatment); 
- Other medications (eg, oxygen therapy); 
- Transfusions (RBC and/or PLTs); 

 
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- Specialist follow-up visits; 
- Hospitalizations: 
✓ day-hospital setting (type of ward; number of accesses); 
✓ inward setting (type of ward; number of episodes; number of days per episode); 
- Emergency room (number of admittances). 
The cost description will be carried out via a three-step approach that encompasses (i) INHS-
funded health care resources identification and (ii) quantification, followed by (iii) their valuation. 
INHS-funded health care resources consumed by patients for managing Grade 3 and Grade 4 AEs 
related to the administration of atezolizumab + bevacizumab will be identified and quantified via the 
Adverse Event eCRF. 
INHS-funded health care resources valuation will be performed via multiplying by an item-specific 
unitary cost the volume of INHS-funded health care resources consumed by patients for managing 
Grade 3 and Grade 4 AEs related to the administration of atezolizumab + bevacizumab. 
Since the cost description will follow the INHS standpoint: 
- Drugs will be valued at consumer price (Lazzaro et al. 2019). 
- For health care services that differ from drugs, INHS tariffs will be used to value health care 
resources consumed for managing Grade 3 and Grade 4 AEs related to the administration of 
atezolizumab + bevacizumab (Ministero della Salute, 2012; Conferenza Permanente per i 
Rapporti tra lo Stato le Regioni e le Province Autonome di Trento e Bolzano, 2019). 
The monetary standards will be consistent with the delivery setting of each health care procedure 
(outpatient; day-hospital; inward). 
It is expected that INHS-funded health care resources consumed by patients for managing Grade 
3 and Grade 4 AEs related to the administration of atezolizumab + bevacizumab (visits, diagnostic 
imaging and tests) will be mostly valued as outpatient procedures via the Italian Ministry of Health 
tariffs in force for outpatient setting (Ministero della Salute, 2012).   
Had any of the abovementioned health care procedures been performed in day-hospital or inpatient 
setting, only the hotel cost for hospital stay (Conferenza Permanente per i Rapporti tra lo Stato le 
Regioni e le Province Autonome di Trento e Bolzano, 2019) will be added to the cost of the health 
care procedure itself calculated according to the Italian Ministry of Health tariffs in force for 
outpatient setting (Ministero della Salute, 2012). 
Emergency room admittance will be valued according to a dedicated INHS tariff (Ministero della 
Salute, 2007). 
As the reference literature on the economic evaluation of health care programmes (Drummond et 
al 2015) requires that the resource costing procedure refers to the same and, preferably, the most 
recent year (imposing a proper inflation rate, when necessary), all costs will be reported in € at 
2020 values. 
The following descriptive statistics concerning INHS-funded health care resources consumption 
(type and volume) and valuation (cost) due to Grade 3 and 4 AEs related to the administration of 
atezolizumab + bevacizumab management will be reported (Pagano and Gavreau 2000): 

 
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- Continuous and count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Both base case statistical analyses and cost description (Drummond et al. 2015) will be performed 
on all the evaluable patients included in the study database (Complete Case Analysis - CCA) (Little 
and Rubin 2002). If the CCA sample will prove to be too limited, an available case analysis (ACA) 
(Little and Rubin 2002) will replace CCA. 
The frequency of missing data will be reported for all analyzed variables and patients.  
Missing data will be diagnosed and classified according to their underlying missing mechanism 
(Missing Completely At Random - MCAR; Missing At Random - MAR; Missing Not At Random - 
MNAR) and pattern (monotonic; generalized; univariate) (Van Buuren et al. 1999; Little and Rubin 
2002; Van Buuren 2018).  
Missing data will be dealt with via one or more multiple imputation regression models and/or other 
statistical methods consistent with their underlying missing mechanism (Van Buuren et al., 1999; 
Little & Rubin 2002; Van Buuren 2018). 
Therefore CCA (or ACA) and fully imputed descriptive statistics for quantitative non-monetary and 
quantitative monetary variables (Anthony and Young 2002) will be presented. 
Non-parametric bootstrap method will be applied to INHS-funded health care sector-related costs 
data for calculating 95% CIs in CCA (or ACA) (Efron and Tibshirani 1993; Desgagné et al. 1998; 
Barber and Thompson 2000). 
Statistical analyses will be supported by Stata/SE software v 16.0 (StataCorp LP, College Station, 
TX, USA). 
In order to carry out the cost description and statistical analyses concerning the abovementioned 
INHS-funded health care resources consumed by patients for managing Grade 3 and Grade 4 AEs 
related to the administration of atezolizumab + bevacizumab, a dedicated excerpt of the original 
database will be provided by the Sponsor of the study. 
According to the YO40245 (IMbrave150), the expected incidence of grade 3-5 bleeding events is 
7.9% (6.4% of Grade 3-4 and 1.5% of Grade 5). 
Interim Analyses   
An interim analysis of safety will be performed at the time of 50 recruited patients, estimated to 
occur at approximately 6 months after first patient in (FPI).   
A second interim analysis will be performed when patients have completed a period of follow-up of 
approximately 10 months. This follow-up period corresponds to that reported in the published 
YO40245 (IMbrave150) trial (Cheng et al. 2019; Finn et al. NEJM 2021), which has been taken into 
consideration in the sample size calculation for this study with regard to the expected incidence of 
Grade 3-5 bleeding events. This second interim analysis will take into account all the efficacy and 
safety endpoints with descriptive purposes. 
 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracyl 
ACA 
Available Case Analysis 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
ATE 
Arterial Thromboembolic Event 
BID 
Bis In Die (twice daily) 
BP 
Blood Pressure 
BR 
Bleeding Rate 
CCA 
Complete Case Analysis 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete Response 
CRC 
Colorectal Carcinoma 
CRO 
Contract Research Organization 
CRS 
Cytokine-release Syndrome 
CT 
Computerized Tomography 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration Of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 

 
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eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGD 
Esophagogastroduodenoscopy 
EHG 
Extrahepatic Growth 
EMA 
European Medicine Agency 
EOC 
Epithelial Ovarian Cancer 
FDA 
Food and Drug Administration 
FPI 
First Patient In 
FTC 
Fallopian Tube Cancer 
GBM 
Glioblastoma Multiforme 
GHS 
Global Health Status 
GI 
Gastrointestinal 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B virus core antibody 
HBsAg 
Hepatitis B virus surface antigen 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLH 
Hemophagocytic Lymphohistiocytosis 
HR 
Hazard Ratio 
HRQoL 
Health-related Quality of Life 
ICH 
International Council for Harmonisation 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IHG 
Intrahepatic Growth 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
INHS 
Italian National Health Service 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
IRR 
Infusion-related Reaction 
ITT 
Intention-to-treat 
IV 
IVIG 
Intravenous 
IntraVenous ImmunoGlobulin 
IxRS 
Interactive Voice/Web Response System 
K-M 
Kaplan Meier 

 
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LDH 
Lactate Dehydrogenase 
LL 
Lower Limit 
LMWH 
Low Molecular Weight Heparin 
MAR 
Missing At Random 
MAS 
Macrophage Activation Syndrome 
MCAR 
Missing Completely At Random 
MNAR 
Missing Not At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
N/A 
Not Applicable 
NAFLD 
Non-alcoholic Fatty Liver Disease 
NCI 
National Cancer Institute 
NCNN 
National Comprehensive Cancer Network 
NCI CTCAE v 5.0 
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 
NE 
Not Evaluable 
NEH 
New Extrahepatic Lesion 
NIH 
New Intrahepatic Lesion 
NSAID 
Non-steroidal Antinflammatory Drug 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-L1 
Programmed Death-ligand 1 
PET 
Positron Emission Tomography 
PF 
Physical Functioning 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PLT 
Platelets 
PPC 
Primary Peritoneal Cancer 
PPS 
Post-progression Survival 
PR 
Partial Response 
PRO 
Patient-reported Outcome 
PTT 
Partial Thromboplastin Time 
Q2W 
Every 2 weeks 

 
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Q3W 
Every 3 weeks 
QLQ-C30 
Quality-of-life Questionnaire for Cancer 
QLQ-HCC18 
HCC disease-specific module 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RF 
Role Functioning 
SAP 
Statistical Analysis Plan 
also Safety Analysis Population 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Stable Disease 
SIRT 
Selective Internal Radiation Therapy 
SITC 
Society for Immunotherapy of Cancer 
T3 
Free Triiodothyronine 
T4 
Free Tyroxine 
TNF-α 
Tumor Necrosis Factor-alpha 
TSH 
Thyroid Stimulating Hormone 
TTD 
TTE 
Time To Deterioration 
TransThoracic Echocardiogram 
TTP 
Time To Progression 
UC 
Urothelial Carcinoma 
UL 
Upper Limit 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
VTE 
Venous Thromboembolism 
WBC 
White Blood Cell 
 
 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HEPATOCELLULAR CARCINOMA 
Liver cancer is the fifth most common cancer, accounting for 7% of all cancers, and the 
second most frequent cause of cancer-related death globally, with 854,000 new cases 
and 810,000 deaths per year. Hepatocellular carcinoma (HCC) represents approximately 
90% of primary liver cancers and thus represents a significant global public health issue. 
On the basis of annual projections, the World Health Organization estimates that in excess 
of 1 million people will die from liver cancer in 2030 (Villanueva 2019). 
The majority of HCCs occur in patients with underlying liver disease, mostly as a result of 
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or alcohol abuse. HBV infection 
accounts for the majority of HCC cases worldwide; however, in Western countries and 
Japan, HCV is the main cause of HCC (Villanueva 2019). Universal HBV vaccination and 
wide implementation of direct-acting antiviral agents against HCV are likely to change the 
etiologic landscape of HCC. However, the incidence of non-alcoholic fatty liver disease 
(NAFLD), which is a risk factor for HCC, is increasing worldwide and NAFLD will soon 
become a leading cause of liver cancer in Western countries (Villanueva 2019). 
1.2 
CURRENT SYSTEMIC TREATMENT FOR ADVANCED 
HEPATOCELLULAR CARCINOMA 
Prior to the approval of sorafenib (Nexavar®), there was no globally approved systemic 
treatment for patients presenting with unresectable advanced or metastatic HCC. 
Doxorubicin was the most widely used cytotoxic agent, and is reported to have an 11% to 
15% response rate (Mok et al. 1999; Zhu 2006; Lind et al. 2007). More aggressive 
combinations of cytotoxic chemotherapy have not been shown to increase OS rates and 
have been associated with considerable toxicity (Yeo et al. 2005). 
Sorafenib, an oral multikinase inhibitor, was first approved in 2007 by the U.S. FDA and 
is currently considered the global standard of care for the first-line treatment of patients 
with advanced HCC. The efficacy of sorafenib has been demonstrated in two large 
multicenter, randomized, double-blind, placebo-controlled Phase III trials: the Sorafenib 
HCC Assessment Randomized Protocol (SHARP) trial and a trial conducted in the Asia-
Pacific region. Both studies demonstrated a survival benefit of sorafenib versus placebo. 
In the SHARP trial, median overall survival (OS) was 10.7 months with sorafenib versus 
7.9 months with placebo (hazard ratio [HR] = 0.69 [95% CI: 0.55, 0.87]); in the Asia Pacific 
trial, median OS was 6.5 months versus 4.2 months (HR = 0.68 [95% CI: 0.50, 0.93]). 
Benefit in median time to radiographic progression was also demonstrated: 5.5 months 
versus 2.8 months in the SHARP trial (HR = 0.58 [95% CI: 0.5, 0.7]) and 2.8 months versus 
1.4 months in the Asia Pacific trial (HR = 0.6 [95% CI: 0.4, 0.8]). 

 
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The objective response rate (per RECIST v1.0) was 2.3% (7 of 299 patients) in the SHARP 
trial and 3.3% (5 of 150 patients) in the Asia Pacific trial. The numerically shorter OS and 
duration of benefit in the Asia-Pacific trial may be largely attributed to the fact that patients 
had more advanced disease at the time of recruitment, and potentially also to the regional 
difference in aetiology and supportive care (Llovet et al. 2008; Cheng et al. 2009). 
Despite the survival benefit reported from these two Phase III studies, the overall benefit-
risk ratio of sorafenib is modest given the known toxicity. Adverse events commonly 
reported across both sorafenib studies included hand-foot skin reaction, diarrhoea, 
hypertension, weight loss, fatigue, anorexia, alopecia, nausea, and rash/desquamation. 
Drug-related adverse events reported were predominantly Grade 1 or 2 in severity. Drug 
discontinuation rate in patients receiving sorafenib was 38% in the SHARP trial compared 
with 20% in the Asia-Pacific trial. The frequency of dose reductions due to adverse events 
was similar between the two studies (26% in SHARP and 30.9% in the Asia-Pacific trial) 
(Llovet et al. 2008; Cheng et al. 2009). 
Despite additional clinical experience with the use of sorafenib, the GIDEON study, which 
evaluated sorafenib in the real-world setting, showed the drug discontinuation rates due 
to adverse events in patients starting at the label recommended dose of 800 mg was 27%, 
indicating that tolerability has not improved. Moreover, GIDEON showed that in real-life 
practice, the starting dose of 800 mg daily (400 mg twice a day [BID]) is halved to 400 mg 
daily in over 22% of patients (Lencioni et al. 2014). 
Since the approval of sorafenib, there have been a number of Phase III trial failures in 
first-line HCC in head-to-head comparisons with sorafenib, including sunitinib, brivanib, 
and linifanib (Cheng et al. 2013; Johnson et al. 2013; Cainap et al. 2015). Recently, 
frontline treatment with lenvatinib, a multi-targeted receptor tyrosine kinase inhibitor, was 
shown to be non-inferior to sorafenib in terms of OS (lenvatinib vs. sorafenib: median OS 
13.6 months vs. 12.3 months; HR = 0.92, 95% CI: 0.79, 1.06) (Kudo et al. 2018) in phase 
III non-inferiority REFLECT trial. In addition, lenvatinib showed statistically significant 
superiority compared to sorafenib in terms of PFS, TTP, and ORR, as determined by the 
local investigator tumor assessments per mRECIST. Of note, patients with ≥50% liver 
involvement, clear invasion of the bile duct, or main portal vein invasion were excluded 
from the trial. Lenvatinib had a generally manageable tolerability profile, with the most 
common treatment-emergent adverse events being hypertension, diarrhoea, decreased 
appetite and decreased weight. The REFLECT led to approval of lenvatinib in Japan, the 
US (July 2018) and EU (October 2018) However, there remains an ongoing high unmet 
medical need for patients with advanced unresectable HCC, requiring further evaluation 
of treatment with novel, more efficacious, and less toxic agents. 

 
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1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed death-
ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, PD-1 and 
B7-1 (also known as CD80), both of which function as inhibitory receptors expressed on 
T cells. Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to 
enhance the magnitude and quality of tumor-specific T-cell responses, resulting in 
improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016). 
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and 
is being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab 
is being studied as a single agent in the advanced cancer and adjuvant therapy settings, 
as well as in combination with chemotherapy, targeted therapy, and cancer 
immunotherapy. 
In EMA countries, Atezolizumab is approved for the treatment of urothelial carcinoma (UC), 
nonsmall cell lung cancer (NSCLC), small-cell lung cancer, and triple-negative breast 
cancer. In May 2020 and in November 2020, atezolizumab in combination with 
bevacizumab was approved by the U.S. Food and Drug Administration (FDA) and by 
European Medicine Agency (EMA) respectively for the treatment of unresectable or 
metastatic HCC in patients who have not received prior systemic therapy. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.4 
BACKGROUND ON BEVACIZUMAB 
Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds 
to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in 
in-vitro and in-vivo assay systems. Bevacizumab contains human framework regions and 
the complementarity-determining regions of a murine antibody that binds to VEGF, and 
has an approximate molecular weight of 149 kD. Bevacizumab is produced in a 
mammalian Chinese hamster ovary cell line. 
Bevacizumab was first granted marketing approval in the United States on 26 February 
2004 (international birth date) in combination with IV 5-fluorouracil (5-FU)-based 
chemotherapy for the first-line treatment of patients with metastatic carcinoma of the colon 
or rectum (CRC). As of November 2016, bevacizumab has been approved for use in over 
a 100 countries worldwide in a variety of indications, including locally recurrent or 
metastatic breast cancer; advanced, metastatic, or recurrent NSCLC; advanced and/or 
metastatic renal cell cancer (RCC); newly diagnosed glioblastoma multiforme (GBM) and 
GBM after relapse or disease progression; persistent, recurrent, or metastatic cervical 

 
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cancer; front-line treatment of epithelial ovarian cancer (EOC), primary peritoneal cancer 
(PPC), or fallopian tube cancer (FTC); and treatment of platinum-sensitive and platinum-
resistant recurrent EOC, PPC, or FTC. 
1.5 
OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM IN 
HEPATOCELLULAR CARCINOMA 
1.5.1 
Atezolizumab Monotherapy 
A comprehensive overview of atezolizumab efficacy across all indications is provided in 
the atezolizumab Investigator's Brochure. This section provides an overview of the 
available efficacy data in patients with HCC treated with atezolizumab as monotherapy. 
To date, atezolizumab as single agent has shown minimal activity in the treatment of HCC 
patients with similar characteristics as those that would be included in this study. 
Safety findings in the HCC cohort are in line with expectations for an HCC population and 
with the atezolizumab safety profile observed in the overall study population across 
multiple tumor types. No new safety signals related to atezolizumab monotherapy were 
observed in the HCC population. 
Study PCD4989g 
Study PCD4989g is a Phase Ia, multicenter, first-in-human, open-label, dose-escalation 
study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion every 3 weeks (Q3W) to patients with locally 
advanced or metastatic solid malignancies or hematologic malignancies. 
The largest cohorts enrolled into this trial consisted of patients with NSCLC, RCC, and 
UC. Expansion cohorts have included patients with CRC, melanoma, NSCLC, pancreatic 
cancer, UC, breast cancer, oesophageal cancer, prostate cancer, small-cell lung cancer, 
malignant lymphoma, multiple myeloma, HCC, and other less common tumor types. 
In the analysis of Study PCD4989g (clinical cut-off date of 31 December 2016) conducted 
in 15 patients with first- and later-line HCC, the median duration of treatment was 2.0 
months (range: 0.7-6.3 months). At the time of the clinical cut-off date, 1 patient remained 
on treatment, 12 patients had discontinued treatment due to disease progression, 1 patient 
discontinued because of an adverse event, and 1 patient was discontinued as per the 
physician's decision. 
Of the 15 response-evaluable patients, none had an objective response (confirmed 
complete response [CR] or partial response [PR] as assessed by investigator per 
Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). Four patients (33.3%) had 
stable disease (SD) < 24 weeks. No patients had SD ≥ 24 weeks. Median progression-

 
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free survival (PFS) per investigator assessment per RECIST v1.1 was 2.3 (95% CI: 1.3, 
3.4) months and median OS was 5.3 (95% CI: 2.4, NE) months. 
Study YO29233 
Study YO29233 is a Phase I, open-label, multicenter study evaluating the 
pharmacokinetics, safety, and preliminary anti-tumor activity of atezolizumab as 
monotherapy in Chinese patients with locally advanced or metastatic gastric cancer, 
nasopharyngeal carcinoma, oesophageal cancer, HCC and other solid tumors, and the 
safety and preliminary anti-tumor activity of atezolizumab in combination with gemcitabine 
and cisplatin in Chinese patients with Stage IV, treatment-naive NSCLC. 
For monotherapy cohorts, atezolizumab is administered as a single agent at a dose of 
1200 mg IV Q3W.  
Based on a clinical cut-off date of 1 April 2018, 21 patients with HCC had received 
atezolizumab monotherapy. At the time of the clinical cut-off date, 7 patients remained on 
treatment (3 first-line HCC patients), while 7 patients had discontinued treatment due to 
disease progression, 2 patients discontinued treatment due to an adverse event, 2 
patients discontinued treatment due to non-compliance with study drug, and 1 patient each 
discontinued treatment due to a protocol deviation, physician decision, and death due to 
progression of disease. 
Of the 21 efficacy-evaluable patients (first-line and second-line or greater), 2 patients 
(9.5% [95% CI: 1.17%, 30.38%]) had a confirmed objective response and 11 patients 
(52.4% [95% CI: 29.78%, 74.29%]) had a best response of SD. Median PFS was 2.8 
months (95% CI: 1.4, 7.8 months) and median OS was 11.1 months (95% CI: 4.7 months, 
NE). 
1.5.2 
Bevacizumab Monotherapy 
A comprehensive overview of bevacizumab efficacy across all indications is provided in 
the bevacizumab Investigator's Brochure. This section provides an overview of the 
available efficacy data in patients with HCC treated with bevacizumab as monotherapy. 
Overall, bevacizumab as a single agent demonstrated minimal activity in HCC, and is 
unlikely to demonstrate a meaningful clinical benefit over current standard of care 
(sorafenib) based on the survival data observed. Bevacizumab monotherapy was 
generally safe and well tolerated in the HCC population, and safety findings were 
consistent with the HCC population and established safety profile of bevacizumab. 
No new safety signals related to bevacizumab monotherapy were observed in this patient 
population. 

 
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Phase II Study of Bevacizumab in Unresectable Hepatocellular Carcinoma 
This study was a Phase II, single centre, single arm trial designed to evaluate the clinical 
and biological effects of bevacizumab in unresectable HCC (Siegel et al. 2008). Adult 
patients with organ-confined HCC, ECOG Performance Status of 0-2, and compensated 
liver function (Child-Pugh class A or B7), received bevacizumab 5 mg/kg or 10 mg/kg 
every 2 weeks (Q2W) until disease progression or treatment-limiting toxicity. 
Of note, patients with extrahepatic disease, tumor invasion of the main portal vein or 
inferior vena cava were excluded. Given the known prognostic value of these factors, the 
study likely enrolled a population with a more favourable prognosis and treatment outcome 
compared with a population that would typically be enrolled in a first-line HCC study. The 
primary objective was to determine whether bevacizumab improved the 6-month PFS rate 
from 40% to at least 60%. Overall, 46 patents were enrolled, including 12 patients who 
received bevacizumab 5 mg/kg and 34 patients who received bevacizumab 10 mg/kg 
Q2W. 
Clinical activity of bevacizumab was observed in patients with non-metastatic HCC. Of the 
46 patients, 6 patients (13%) had objective responses (95% CI: 3%, 23%), and 65% (95% 
CI: 51%, 79%) of patients were progression free at 6 months. Median PFS was 6.9 months 
(95% CI: 6.5, 9.1) and median OS was 12.4 months (95% CI: 9.4, 19.9). 
No significant changes were seen with respect to dose and outcome. The response rates 
for the 5 mg/kg and 10 mg/kg groups were 8.3% and 14.7%, respectively (p = 0.99 by 
Fisher's exact test). Median OS times for patients receiving 5 mg/kg and 10 mg/kg were 
15.1 months and 12.2 months, respectively (p = 0.64 by the log-rank test) (Siegel et al. 
2008). 
Phase II Study of Bevacizumab in Advanced Hepatocellular Carcinoma 
This study was a Phase II, single-centre, single-arm trial designed to evaluate the efficacy, 
safety, and potential biomarkers of activity of bevacizumab in patients with advanced HCC 
(Boige et al. 2012). Patients with histologically confirmed advanced HCC that was not 
amenable to curative-intent therapies (e.g., resection, liver transplantation, or 
percutaneous ablation) received bevacizumab 5 mg/kg or 10 mg/kg Q2W until disease 
progression or unacceptable toxicity. The primary objective was to determine the disease-
control rate at 16 weeks (16W-DCR) defined as the proportion of patients with a CR, PR, 
or SD at 16 weeks after study entry, according to RECIST v1.0. 
Overall, 48 patients were enrolled, of which 25 patients were planned to receive 
bevacizumab 5 mg/kg and 23 patients were planned to receive bevacizumab 10 mg/kg, 
Q2W. Of the 48 patients enrolled, 43 patients received at least one dose of bevacizumab. 

 
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Among the 38 response-evaluable patients, six patients achieved a PR (ITT) objective 
response rate [ORR], 14%; 95% CI: 4%, 24%), median duration of response (DOR) was 
148 days (range, 55-362 days), 18 patients had SD (DCR, 56%), including 12 patients 
who experienced SD for ≥ 16 weeks. The 16W-DCR was 42% (95% CI: 27%, 57%) in the 
overall population, 39% (95% CI: 19%, 59%) in patients treated with 5 mg/kg 
bevacizumab, and 45% (95% CI: 23%, 67%) in those treated at the 10 mg/kg dose. In the 
overall population (n = 43), median PFS was 3 months (95% CI: 2, 4); median OS was 8 
months (95% CI: 4, 9) (Boige et al. 2012). 
1.6 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.6.1 
Rationale for the Combination of Anti-PD-L1 and Anti-VEGF 
Therapy in Hepatocellular Carcinoma 
Strong scientific rationale and emerging clinical data suggest that the combined 
VEGF/PD-L1 blockade may be clinically beneficial in a number of tumor types including 
HCC. 
It is known that HCC is a highly vascularised tumor, and that several proangiogenic factors 
play a role in HCC pathogenesis. For example, in HCC, increased VEGF correlates with 
vascular density, tumor invasiveness and metastasis, and poor prognosis (Boige et al. 
2012; Frenette 2012). The VEGF pathway also plays a crucial role in exerting and 
maintaining 
an 
immunosuppressive 
tumor 
microenvironment 
through 
several 
mechanisms. For instance, VEGF-A has been shown to induce FasL expression on 
endothelial cells, which have the ability to kill effector CD8+ T cells, but not T-reg cells. 
Administration of anti-VEGF-A attenuated tumor endothelial FasL expression and 
produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells, 
which was FasL-dependent, and led to CD8-dependent tumor growth suppression (Motz 
et al. 2014). Furthermore, bevacizumab can restore and/or maintain the antigen 
presentation capacity of dendritic cells, leading to enhanced T-cell infiltration in tumors 
(Oelkrug and Ramage 2014; Wallin et al. 2016). In addition to increased trafficking of T 
cells into tumors (Manning et al. 2007), several publications have illustrated that anti-
VEGF therapies can also reduce frequency of myeloid-derived suppressor cells, decrease 
production of suppressive cytokines, and lower expression of inhibitory checkpoints on 
CD8+ T cells in tumors (Roland et al. 2009; Voron et al. 2015). 
Therefore, the immunomodulatory effect of bevacizumab is expected to increase CD8-
positive T-cell recruitment and relieve intratumoral immunosuppression, thereby boosting 
the effects of atezolizumab. 

 
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1.6.2 
Clinical Data of Atezolizumab in Combination with 
Bevacizumab in Hepatocellular Carcinoma 
The efficacy and safety of atezolizumab + bevacizumab combination therapy as first-line 
treatment of non-resectable or metastatic HCC is currently being assessed in two studies: 
GO30140 and YO40245 (IMbrave150). 
Study GO30140 
Study GO30140 is a Phase Ib, multicenter, open-label study of atezolizumab in 
combination with bevacizumab and/or chemotherapy as first-line therapy in patients with 
various metastatic cancers (Lee et al. 2020). Arms A and F of GO30140 were specific to 
unresectable or advanced HCC. Arm A was designed to evaluate the combination of 
atezolizumab + bevacizumab in 104 patients with locally advanced or metastatic HCC who 
have not received prior systemic therapy. Arm F was later added to the study to compare 
combination treatment with atezolizumab + bevacizumab to atezolizumab alone, in which 
119 patients with locally advanced or metastatic HCC were randomized 1:1 to 
atezolizumab + bevacizumab or atezolizumab monotherapy. Results for Arm A and Arm 
F have been recently presented (Lee et al 2019). 
Arm A 
As of the clinical cut-off date of 14 June 2019, the efficacy data for Arm A showed clinically 
meaningful and durable objective responses. The confirmed objective response rate 
(ORR) based on Independent-Review Facility (IRF) assessment per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) was 35.6% (37 of 104 patients; Table 
1). Among the 37 responders, 12 patients (11.5%) achieved a CR and the remaining 25 
patients (24.0%) achieved a PR. Median DOR was not reached at the time of this analysis. 
Arm F 
At the same clinical cut-off date of 14 June 2019, Arm F met its primary efficacy endpoint 
by demonstrating a statistically significant and clinically meaningful improvement in 
progression-free survival (PFS) with the combination compared to atezolizumab 
monotherapy. 
Median PFS for the combination was 5.6 months compared to 3.4 months for the 
monotherapy resulting in a HR of 0.55 and a stratified p-value of 0.0108 (Table 1). 
These results demonstrate the need for combination therapy rather than checkpoint 
inhibition alone to effectively increase progression free survival in patients with HCC. 

 
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Table 1 
Study GO30140: Overall Efficacy Summary 
Arm 
Median 
Duration of 
Follow-Up  
Key Efficacy Endpoint  
Arm A 
12.4 m  
ORR (95% CI): 35.6% (26.4-45.6%)  
Median DOR: Not reached with 76% ongoing responders  
Arm F 
6.6 m  
Median PFS: 5.6 m (Atezo - Bev) vs. 3.4 m (Atezo) Stratified 
HR (80% CI): 0.55 (0.40-0.74)  
Stratified p-value: 0.0108  
Abbreviations: Atezo = atezolizumab; Bev = bevacizumab; DOR = duration of response; HR = 
hazard ratio; m = month; ORR = objective response rate; PFS = progression-free survival. 
The combination of atezolizumab + bevacizumab was generally well tolerated; no new 
safety signals related to the combination therapy were identified beyond the established 
safety profile for each individual agent. Furthermore, no unexpected adverse events were 
observed. The most common adverse events were proteinuria, decreased appetite, 
fatigue, pyrexia, and rash. 
Study YO40245 (IMbrave150) 
Study YO40245 (IMbrave150) is a Phase III, multicenter, randomized, open-label study 
designed to evaluate the efficacy and safety of atezolizumab + bevacizumab versus 
sorafenib in patients with advanced or metastatic HCC who have received no prior 
systemic treatment (Cheng et al. 2019; Finn et al. 2020). The study enrolled 501 patients 
randomized in a 2:1 ratio to one of the following treatment arms: 
 Arm A (experimental arm): atezolizumab 1200 mg IV every 3 weeks (Q3W) + 
bevacizumab 15 mg/kg IV Q3W (336 patients) 
 Arm B (control arm): sorafenib 400 mg by mouth, twice per day, continuously (165 
patients) 
The co-primary efficacy endpoints were OS and IRF-assessed PFS by RECIST v1.1. 
The last patient was enrolled in April 2019. Based on a clinical cut-off date of 29 August 
2019, the primary analysis of Study YO40245 demonstrated statistically significant and 
clinically meaningful improvements with atezolizumab + bevacizumab compared with 
sorafenib in the co-primary endpoints of OS and IRF-assessed PFS per RECIST v1.1 in 
the ITT population (Table 2) (Cheng et al. 2019). 
 The co-primary endpoint of OS demonstrated a statistically significant and clinically 
meaningful improvement for atezolizumab + bevacizumab over sorafenib. The 
observed OS translated into a reduction in the risk of death by 42% in the atezolizumab 

 
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+ bevacizumab arm compared with sorafenib (HR = 0.58 [95% CI: 0.42, 0.79], p = 
0.0006, median OS: NE vs. 13.24 months). 
OS benefits were generally consistent across predefined subgroups. 
 The co-primary endpoint of IRF-assessed PFS per RECIST v1.1 demonstrated a 
statistically significant and clinically meaningful improvement for atezolizumab + 
bevacizumab over sorafenib (HR = 0.59 [95% CI: 0.47, 0.76]; p = 0.0001; median PFS: 
6.83 vs. 4.27 months). 
These PFS benefits were generally consistent across predefined subgroups. 
Similar to Study GO30140, the safety of the combination was consistent with the known 
safety profile of each agent and no new safety signals were identified. 
Table 2 
Study YO40245: Overall Efficacy Summary 
Co-primary 
Efficacy 
Endpoints 
Median Duration 
of Follow-up 
 
Sorafenib 
(n = 165) 
Atezo + Bev 
(n = 336) 
OS 
8.6 months 
Median (months) 
(95% CI) 
13.2 (10.4, NE) 
NE 
Stratified HR (95% CI) 
0.58 (0.42, 0.79) 
Stratified log-rank p-value 
0.0006 
IRF-PFS 
8.6 months 
Median (months) 
(95% CI) 
4.3 (4.0-5.6) 
6.8 (5.7-8.3) 
Stratified HR (95% CI) 
0.59 (0.47-0.76) 
Stratified log-rank p-value 
<0.0001 
Abbreviations: Atezo = atezolizumab; Bev = bevacizumab; HR = hazard ratio; IRF = Independent 
Review Facility; NE = Not Estimable; OS = Overall Survival; PFS = progression-free survival. 
At a clinical cutoff on 31 August 2020, after 12 months of additional follow up from the 
primary analysis (median follow up 15.6 months), an updated OS analysis was reported. 
This descriptive analysis shows a median OS of 19.2 months in atezo+bev arm vs 13.4 
months in sorafenib arm; HR = 0.66 (95% CI: 0.52, 0.85), confirming the significant and 
consistent clinical benefit of atezo+bev observed in the primary analysis. (Cheng J of 
Hepatology 2022 ). 
1.6.3 
Benefit-risk Assessment 
Atezolizumab has been combined with bevacizumab in patients with a range of different 
tumor types in Phase I-III studies. Overall, the adverse events observed with atezolizumab 
in combination with bevacizumab are consistent with the known risks of each individual 
study treatment across tumor types including HCC (Socinski et al. 2018; Rini et al. 2019). 

 
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This trial will enroll patients with locally advanced or metastatic HCC who have received 
no prior systemic treatment. Given the poor prognosis and limited treatment options for 
these patients, this population is considered amenable for treatment with combined PD-
L1 and VEGF antagonists. 
The benefit-risk profile for atezolizumab in combination with bevacizumab in this patient 
population is expected to be favourable. 
In the setting of the coronavirus 2019 (COVID-19) pandemic, patients with comorbidities, 
including those with cancer, are considered a more vulnerable population, with the 
potential for more severe clinical outcomes from severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection. However, it is unclear whether or how systemic 
cancer therapies such as chemotherapy, targeted therapy, or immunotherapy impact the 
incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses. In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of acute 
(as opposed to chronic) viral infection with lymphocytic choriomeningitis virus (Clone 13) 
(Frebel et al. 2012). However, there are insufficient and inconsistent clinical data to assess 
if outcome from SARS-CoV-2 infection is altered by cancer immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release syndrome 
(CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon 
(IFN)- (Merad and Martin 2020). While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute 
SARS-CoV-2 infection while receiving atezolizumab. At this time, there is insufficient 
evidence for causal association between atezolizumab and an increased risk of severe 
outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2-related interstitial pneumonia. Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary symptoms. 
Given the mechanism of action for atezolizumab and bevacizumab, immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
these two agents. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 

 
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positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021). Given the lack of clinical data, currently no recommendations can be made 
regarding the optimal sequence of COVID-19 vaccination in patients who are receiving 
cancer immunotherapy (SITC 2020). For patients enrolling in this study and receiving 
atezolizumab treatment, a decision to administer the vaccine to a patient should be made 
on an individual basis by the investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive COVID-19 
vaccination include the following: the risk of SARS-CoV-2 infection and potential benefit 
from the vaccine, the general condition of the patient and potential complications 
associated with SARS-CoV-2 infection, underlying disease, and the severity of COVID-19 
outbreak in a given area or region.   
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines. When administered, 
COVID-19 vaccines must be given in accordance with the approved or authorized vaccine 
label.  Receipt of the COVID-19 vaccine is considered a concomitant medication and 
should be documented as such (see Section 4.4.1). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety and efficacy of atezolizumab in combination with 
bevacizumab in patients with unresectable HCC who have received no prior systemic 
treatment.  
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., atezolizumab and bevacizumab). 
Specific objectives and corresponding endpoints for the study are outlined below. 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the safety of atezolizumab  bevacizumab 
in terms of bleeding/haemorrhage on the basis of the following endpoint: 
 
Incidence of Grade 3-5 NCI CTCAE v.5 bleeding/haemorrhage 

 
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2.2 
SECONDARY OBJECTIVES 
2.2.1 
Main Secondary Objective 
The main secondary objective of the study is to evaluate the efficacy of atezolizumab  
bevacizumab on the basis of the following endpoint: 
 
Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause 
2.2.2 
Other Secondary Objectives 
The other secondary objectives of the study are: 
1) To further evaluate the safety of atezolizumab  bevacizumab on the basis of the 
following endpoints: 
 Incidence and severity of adverse events (AEs), with severity determined according 
to NCI CTCAE v5.0 
 Vital signs 
 Clinical laboratory test results 
2) To further evaluate the efficacy of atezolizumab  bevacizumab on the basis of the 
following endpoints: 
 Progression-free survival (PFS), defined as the time from initiation of study 
treatment to the first occurrence of disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to RECIST v1.1 
 Objective response rate (ORR), defined as a complete or partial response, as 
determined by the investigator according to RECIST v1.1 
 Time to progression (TTP), defined as the time from initiation of study treatment to 
the first occurrence of disease progression, as determined by the investigator 
according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1) 
 Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to 
RECIST v1.1 

 
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 Post-progression survival (PPS), defined as the time from the first occurrence of 
disease progression as determined by the investigator according to RECIST v1.1 to 
death from any cause 
3) To evaluate Patient Reported Outcomes (PROs) and to describe the patient’s 
experience while receiving atezolizumab + bevacizumab on the basis of the following 
endpoint: 
 
Patient self-reported symptomatic AEs using National Cancer Institute's Patient-
Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) 
2.3 
EXPLORATORY OBJECTIVES 
2.3.1 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives of the study are: 
1) To evaluate whether the patterns of tumor progression (growth versus new lesion, 
intrahepatic versus extrahepatic) have a different impact on overall survival (OS) and 
PPS on the basis of the following endpoints: 
 OS and PPS based on the following patterns of progression:  
- >20% increase in tumor size against a known baseline lesion (intrahepatic growth 
[IHG] or extrahepatic growth [EHG]) 
- new intrahepatic lesion (NIH)  
- new extrahepatic lesion (NEH) and/or vascular invasion 
2) To evaluate if post-study treatments have impact on OS on the basis of the following 
endpoints: 
 
Number/Rate of patients starting second or further lines of treatment 
 
OS based on type and duration of each post-study treatments 
3) To evaluate if reason of treatment withdrawal has impact on OS on the basis of the 
following endpoint: 
 
OS based on the following reasons of treatment withdrawal: 
- 
Progressive disease (PD) vs adverse event (AE) vs deteriorating liver 
function/clinical conditions 

 
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2.3.2 
Exploratory Biomarker Objective 
The exploratory biomarker objective of the study is: 
 
Gut Microbiome evaluation on the basis of the following endpoint: 
- Relationship between the compositional and functional structure of the gut 
microbiome and antitumour responses following atezolizumab and bevacizumab 
2.3.3 
Exploratory Economic Objectives 
The exploratory economic objectives of the study are: 
1) To identify, quantify and valuate health care resources consumed for managing 
Grade 3 and 4 AEs related to the administration of atezolizumab + bevacizumab on 
the basis of the following endpoint: 
 
Relationship between AEs and health care resource consumption 
2) To assess the cost for managing adverse events related to the administration of 
atezolizumab + bevacizumab on the basis of the following endpoint: 
 
Cost description of health care resources consumed for managing Grade 3 and 4 
AEs related to the administration of atezolizumab + bevacizumab 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase IIIb, one arm, multicenter, open - label study designed to evaluate the 
safety and efficacy of atezolizumab  bevacizumab in patients with unresectable HCC who 
have not received prior systemic treatment.   
This study will enroll a sample of convenience (Lohr 2010) of approximately 150 patients 
in one arm of treatment: 
 Atezolizumab 1200 mg IV infusions Q3W (dosed in 3-week cycles)  bevacizumab 15 
mg/kg Q3W (dosed in 3-week cycles)  
Patients treated with atezolizumab   bevacizumab arm who transiently discontinue or 
withdraw from either atezolizumab or bevacizumab may continue on single-agent therapy 
as long as the patients are experiencing clinical benefit in the opinion of the investigator 
and after discussion with the Medical Monitor (i.e., patients transiently discontinue or 
withdraw from bevacizumab for adverse effects may continue atezolizumab monotherapy 
and vice versa).  

 
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Patients will receive atezolizumab and/or bevacizumab 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). In the absence of unacceptable toxicity, patients who 
meet criteria for disease progression per RECIST v1.1 while receiving atezolizumab 
and/or bevacizumab will be permitted to continue the study treatment if they meet all of 
the following criteria: 
 Evidence of clinical benefit, as determined by the investigator following a review of all 
available data; 
 Absence of symptoms and signs (including laboratory values) indicating unequivocal 
progression of disease; 
 Absence of decline in ECOG Performance Status that can be attributed to disease 
progression; 
 Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease 
or brain metastases) that cannot be managed by protocol-allowed medical 
interventions. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Laboratory safety 
assessments will include the regular monitoring of haematology and blood chemistry.   
Tumor assessments will be performed at baseline and at regular intervals during study 
treatment. Additional scans will be performed as clinically indicated. Tumor assessments 
will continue until disease progression, regardless of whether treatment has been 
discontinued (e.g., for toxicity) or until loss of clinical benefit, whichever occurs later. In the 
absence of disease progression, tumor assessments should continue regardless of 
whether patients start new anti-cancer therapy, until consent is withdrawn, death, or the 
study is terminated by the Sponsor, whichever occurs first.   
Following disease progression, patients will be followed for survival and subsequent anti-
cancer therapies until death, loss to follow-up, withdrawal of consent, or study termination 
by Sponsor, whichever occurs first.   
Patients’ samples of faeces, will be collected for exploratory biomarker assessments. 
Patients who do not meet the criteria for participation in this study (screen failure) cannot 
be re-screened. The investigator will maintain a record of reasons for screen failure (see 
Section 4.5.1). 

 
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2021) trials. In addition, no new safety signals related to the combination therapy were 
identified beyond the established safety profile for each individual agent 
3.3.2 
Rationale for Bevacizumab Dose and Schedule 
Bevacizumab will be administered at a fixed dose of 15 mg/kg Q3W on Day 1 of each 21-
day cycle which is the approved dosage for bevacizumab (Avastin® local labels). 
This dose schedule aligns with the atezolizumab dose schedule highlighted above as the 
dose used in combination with atezolizumab in Study GO30140 and YO40245 
(IMbrave150).  
3.3.3 
Rationale for Patient Population 
This study will enroll patients with unresectable HCC who have not received prior systemic 
treatment. Given the poor prognosis and limited treatment options for these patients, this 
population is considered amenable for treatment with combined PD-L1 and VEGF 
antagonists. 
The broad patient population selected is similar to that enrolled in Study GO30140, the 
initial study testing this combination in first-line HCC patients.  
Although sorafenib and lenvatinib are approved for the first-line treatment of patients with 
advanced HCC, the prognosis of these patients remains poor with a median OS reported 
of 10.7 – 14.7 months for sorafenib (Llovet et al. 2008; Yau et al. 2019) and 13.6 months 
for lenvatinib (Kudo et al. 2018) .  
Therefore, there is a continuing need for more efficacious, better tolerated treatments for 
the first line treatment of patients with unresectable HCC. 
3.3.4 
Rationale for Control Group 
Not applicable. 
3.3.5 
Rationale for Open-Label Study  
The primary objective of this study is to assess the safety profile of atezolizumab + 
bevacizumab in a non-comparative fashion. Thus, as all patients are pre-specified to 
receive active treatment, the study will have an open-label and non-randomized design. 
3.3.6 
Rationale for Primary Safety Endpoint 
In this study, the primary safety end-point is incidence of Grade 3-5 NCI CTCAE v.5 
bleeding/haemorrhage.  
Bevacizumab use has been associated with an increase in the risk of bleeding. Although 
bleeding events involved typically minor epistaxis and other self-limited mucosal bleeding, 
severe (Grade ≥3) bleeding events have also been reported in clinical trials across all 

 
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indications (Leighl et al. 2011). In patients treated with bevacizumab, the overall incidence 
of Grade 3–5 bleeding reactions ranged from 0.4–6.9% (European Medicines Agency 
2017 
SmPC 
Avastin 
https://www.ema.europa.eu/en/documents/product-
information/avastin-epar-product-information en.pdf. 
There 
were 
initial 
concerns 
regarding the bleeding toxicity in evaluating the treatment of bevacizumab in advanced 
HCC, due to the concomitant presence in these patients of cirrhosis, and consecutively 
portal hypertension, oesophageal varices, thrombocytopenia, and coagulopathy. Of note 
upper gastrointestinal bleeding is a common and severe complication in patients with HCC. 
In this setting the drug has been studied both as monotherapy, as well as in combination 
with the epidermal growth factor receptor inhibitor erlotinib and with cytotoxic 
chemotherapy (Siegel et al. 2008, Boige et al. 2012, Zhu et al. 2006, Thomas et al. 2009, 
Hsu et al. 2010, Sun et al. 2011, Kaseb et al. 2012, Yau et al. 2012). Most trials have been 
small, Phase II trials; bevacizumab was given at dose of 5 mg/kg or 10 mg/kg every 2 
weeks, or 7.5 mg/kg every 3 weeks. The treatment seemed to be fairly well tolerated. 
Notably, bleeding/haemorrhage Grade 3-5 incidence was reported up to 11% of patients 
and instances of gastro-intestinal (GI) bleeding were seen in 5-9% of patients (Frenette et 
al. 2012). The cause of GI bleeding was typically esophageal varices and/or portal 
hypertension. One important learning from these studies is that esophageal varices must 
be assessed by upper GI endoscopy and treated as primary prophylaxis with either 
propranolol or banding in all patients with significant varices before starting treatment with 
bevacizumab. This was a requirement in the studies included in clinical development of 
atezolizumab + bevacizumab.  
In the YO40245 (IMbrave150) phase III trial (Cheng et al. 2019), bleeding/haemorrhage 
≥Grade 3 were considered as Adverse Events of Special Interest (AESI) for bevacizumab 
and collected up to 90 days after the end of treatment. In the study with a median treatment 
duration of bevacizumab 6.9 months (range 0-16 months), atezolizumab 7.4 months 
(range 0-16 months) and sorafenib 2.8 months (range 0-16) the bleeding/haemorrhage 
results were as follows (Roche on file data; Finn et al, 2020): 
 
a numerically lower proportion of patients experienced bleeding/hemorrhage in the 
sorafenib arm (17.3%) compared to the Atezo+Bev arm (25.2%) 
 
the AE of hemoptysis was reported with a higher incidence (≥ 2% difference) in the 
sorafenib arm, whereas the AEs of epistaxis, hematuria, gingival bleeding, and 
esophageal varices hemorrhage were reported with a higher incidence (≥ 2% 
difference) in the Atezo+Bev arm) 
 
the majority of bleeding/hemorrhage were of Grade 1-2 intensity 
 
the proportion of patients experiencing Grade 3-4 bleeding (5.7% [sorafenib] vs 
6.4% [Atezo+Bev] was comparable between the two treatments arms (mainly 
gastrointestinal and upper gastrointestinal/varices esophageal bleeding events 

 
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were reported). One Grade 3-4 bleeding event (gastrointestinal haemorrhage) was 
assessed as related to Bev and 3 events (1 gastrointestinal haemorrhage and 2 
upper gastrointestinal haemorrhage events) were assessed as related to Atezo 
and Bev 
 
a similar proportion of patients in the sorafenib (7.7%) and Atezo+Bev arm (9.1%) 
had AESIs of bleeding/hemorrhage that were reported as serious (most frequent 
were gastrointestinal haemorrhage 1.9% vs. 2.4% [Atezo+Bev] and esophageal 
varices hemorrhage (0.6% vs 2.4 % [Atezo+Bev]) 
 
one patient (0.6) in the sorafenib arm and 16 patients (4.9%) in the Atezo+Bev arm 
were withdrawn from study treatment due to AESI of bleeding/hemorrhage  
 
similar proportion of patients in sorafenib (3.8%) and Atezo arm (4.3%) had study 
treatment interruption/study modification due to AESIs of bleeding/haemorrhage 
 
a lower proportion of patients experienced Grade 5 AESIs of bleeding/hemorrhage 
in the sorafenib arm (1 patient, 0.6%) compared to the Atezo+Bev arm (5 patients, 
1.5%). In the sorafenib arm one Grade 5 event of peritoneal haemorrhage was 
reported. In the Atezo+Bev arm, Grade 5 events of gastrointestinal hemorrhage, 
(3 patients with gastrointestinal bleeding, 0.9%), esophageal varices hemorrhage 
and subarachnoid hemorrhage (1 patient each, 0.3%) were reported. Of the 4 
above reported events of upper gastrointestinal haemorrhage (3 gastrointestinal 
hemorrhage and one esophageal varices haemorrhage), three events were 
assessed as unrelated to atezolizumab and bevacizumab, but as related to the 
disease under study, and one event was assessed by the investigator as related 
to both atezolizumab and bevacizumab and also as related to the disease under 
study. The subarachnoid haemorrhage event was assessed as related to both 
bevacizumab and arterial hypertension. 
As above reported, in YO40245 (IMbrave150), incidence of bleeding/haemorrhage Grade 
3-5 was 7.9% (6.4% of Grade 3-4 and 1.5% of Grade 5) with collection up to 90 days after 
end of treatment as AESIs. Even if the results of the trial have shown that the incidence 
of bleeding/haemorrhage Grade 3-5 was consistent with the known safety profile of 
bevacizumab and no new safety signals were identified, additional information collected 
using this endpoint in the same patient population as the above study have the potential 
to reinforce the safety data already available, given the particular attention paid to 
bleeding/haemorrhage toxicity in this setting of patients. 
At data cut off of august 31, 2020 , after a median follow up of 15.6 months , overall there 
were 6 grade 5 bleeding events in the atezolizumab plus bevacizumab arm (5 upper 
gastrointestinal bleeding events [3 gastrointestinal hemorrhage, 2 esophageal varices 
hemorrhage] and 1 subarachnoid hemorrhage) and 1 in the sorafenib arm (peritoneal 

 
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hemorrhage). Only 1 of the 5 upper gastrointestinal bleeding events in the combination 
arm, which occurred within 3 months of the first dose, was considered to be related to the 
study treatment by the investigator. All patients who had grade 5 upper gastrointestinal 
bleeding in the combination arm had macrovascular invasion; 3 had varices at baseline 
and 1 had hypertensive gastropathy. (Cheng J of Hepatology 2022). 
3.3.7 
Rationale for Atezolizumab + Bevacizumab Treatment beyond 
Initial Radiographic Progression 
In studies of immunotherapeutic agents, complete response, partial response, and stable 
disease have each been shown to occur after radiographic evidence of an apparent 
increase in tumor burden. This initial increase in tumor burden caused by immune-cell 
infiltration in the setting of a T-cell response has been termed pseudoprogression (Hales 
et al. 2010). In Study PCD4989g, evidence of tumor growth followed by a response was 
observed in several tumor types. In addition, in some responding patients with 
radiographic evidence of progression, biopsies of new lesions or areas of new growth in 
existing lesions revealed immune cells and no viable cancer cells. Therefore, this study 
will allow all patients to continue their treatment after apparent radiographic progression 
per RECIST v1.1, provided the benefit-risk ratio is judged to be favourable by the 
investigator (see criteria in Section 3.1). Patients should be discontinued for unacceptable 
toxicity or loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, and clinical status (see Section 3.1.1 
for details). 
3.3.8 
Rationale for Gut Microbiome Evaluation  
The microbiome is defined as the collective genomes of microbes within a community, 
whereas the term microbiota refers to the microbes themselves in aggregate.  
The impact of the gut microbiota on response to immune checkpoint blockade was first 
studied in mouse models, with landmark publications in Science in 2015 demonstrating 
that the composition of the gut microbiota could influence the response to immune 
checkpoint inhibitors targeting the cytotoxic T lymphocyte antigen-4 (CTLA-4) and the 
programmed death receptor-1 (PD-1) (Vetizou et al. 2015, Sivan et al. 2015). 
These studies were further supplemented by multiple studies demonstrating a role for the 
gut microbiota in patients on immune checkpoint blockade (Chaput et al., 2017, Frankel 
et al., 2017, Gopalakrishnan et al., 2018, Matson et al., 2018, Routy et al., 2018). In 
patients with non-small-cell lung cancer, renal cell carcinoma, or urothelial cancer, 
antibiotic use actually had a negative impact on response to immune checkpoint blockade. 
A different profile of the gut microbiota was associated with improved response to immune 
checkpoint therapy. Similarly, a so-called “favorable” profile of the gut microbiota has been 
suggested to play a role in the reduction of adverse side effects and the incidence of 
recurrence. The feasibility of manipulating the intestinal microbiota in order to influence 

 
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the response to therapy has recently been demonstrated in a mouse model (Routy et al., 
2018). However, the studies available to date show some discrepancies in defining such 
a “favorable” profile, mainly related to differences in techniques and bioinformatics 
pipelines used to analyse samples, as well as to a series of host confounders, especially 
diet, lifestyle and other geographical influences. 
In this study, the gut microbiome will be evaluated to detect a possible relashionship with 
the response to treatment. Specifically, we aim to reconstruct the temporal dynamics of 
the gut microbiota and identify possible microbial predictors, at a taxonomic and functional 
level, of long-term response vs. recurrence, as well as of the onset and severity of side 
effects. 
3.3.9 
Rationale for Non-standard Clinical Outcome Assessments  
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events. Recent research has shown that clinicians may underreport 
the incidence and severity of symptoms experienced by patients receiving treatment for 
cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; Basch 2010; Quinten 
et al. 2011; Atkinson et al. 2012; Basch et al. 2014). Collecting adverse event information 
directly from patients can provide a better understanding of treatment characteristics and 
their effects. In order to evaluate the tolerability of atezolizumab in combination with 
bevacizumab in HCC, patients will be asked to report on their experience related to 
atezolizumab in combination with bevacizumab treatment-related symptoms selected 
from the validated PRO-CTCAE item bank (see Appendix 7).  These symptoms were 
identified as being salient to patients' experience with current treatment on the basis of 
preliminary safety data, drug class, mode of administration, mechanism of action. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
A sample of convenience (Lohr 2010) of approximately 150 patients with unresectable 
HCC who have not received prior systemic treatment will be enrolled in 21 Italian sites. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 Signed Informed Consent Form; 
 Age  18 years at time of signing Informed Consent Form; 
 Ability to comply with the study protocol, in the investigator's judgment; 
 
Unresectable HCC with diagnosis confirmed by histology , with a biopsy within 6 
months from recruitment;  

 
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 Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies; 
 No prior systemic therapy (including systemic investigational agents) for HCC; 
 At least one measurable (per RECIST 1.1) untreated lesion; 
 Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous 
ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, 
transarterial chemoembolization, transarterial embolization, SIRT etc.) are eligible 
provided the target lesion(s) have not been previously treated with local therapy or the 
target lesion(s) within the field of local therapy have subsequently progressed 
in accordance with RECIST version 1.1; 
 ECOG Performance Status of 0 or 1 within 7 days prior to recruitment; 
 Child-Pugh class A within 7 days prior to recruitment; 
 
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of 
varices (small to large) must be assessed and treated per local standard of care prior 
to enrollment. Patients who have undergone an EGD within 6 months of prior to 
initiation of study treatment do not need to repeat the procedure provided they had 
no active varices or varices at risk of bleeding; 
 Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to recruitment, unless otherwise specified: 
- ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor support; 
- Lymphocyte count  0.5  109/L (500/L); 
- PLT count  75  109/L (75,000/L) without transfusion;  
- Haemoglobin  90 g/L (9 g/dL); 
Patients may be transfused to meet this criterion. 
- AST, ALT, and alkaline phosphatase (ALP)  5  upper limit of normal (ULN); 
- Total bilirubin  3  ULN;  
- Serum creatinine  1.5  ULN or creatinine clearance  50 mL/min (calculated using 
the Cockcroft-Gault formula); 
- Serum albumin  28 g/L (2.8 g/dL) without transfusion; 

 
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- For patients not receiving therapeutic anticoagulation: INR and aPTT or PTT  1.5 
x ULN; 
- Urine dipstick for proteinuria  2 (within 7 days prior to initiation of study treatment); 
Patients discovered to have ≥ 2 proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection (or an alternative method such as 
protein:creatinine ratio, per local guidance) and must demonstrate  1 g of protein 
in 24 hours. 
 Resolution of any acute, clinically significant treatment-related toxicity from prior 
therapy to Grade  1 prior to study entry, with the exception of alopecia; 
 Negative HIV test at screening with the following exception: patients with a positive HIV 
test at screening are eligible provided they are stable on anti-retroviral therapy, have a 
CD4 count ≥ 200 µL, and have an undetectable viral load; 
 In patients with viral HCC, documented virology status of hepatitis, as confirmed by 
screening HBV and HCV serology test; 
 For patients with active hepatitis B virus (HBV):  
HBV DNA  500 IU/mL obtained within 28 days prior to initiation of study treatment, 
and 
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 
14 days prior to study entry and willingness to continue treatment for the length of 
the study; 
 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 must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year while they are receiving atezolizumab and bevacizumab and for 
5 months after the final dose of atezolizumab and for 6 months after the final dose 
of bevacizumab. Women must refrain from donating eggs during the same period. 
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 is not permanently infertile 
due to surgery (removal of ovaries, fallopian tubes and/or uterus) or another cause 
as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a 
woman with a tubal ligation is considered to be of childbearing potential. 

 
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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. 
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 acceptable methods of contraception. 
 For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 
With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of  1% per year during the treatment period and for 6 months after the last 
dose of bevacizumab. Men must refrain from donating sperm during this same 
period. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the last dose of bevacizumab to avoid 
exposing the embryo. 
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 acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 History of leptomeningeal disease or brain metastases; 
 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, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 

 
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Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met: 
- Rash must cover  10% of body surface area; 
- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids: 
- 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; 
 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. 
 Known active tuberculosis; 
 Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina;  
 History of congenital long QT syndrome or corrected QT interval 500 ms (calculated 
with use of the Fridericia method) at screening; 
 History of uncorrectable electrolyte disorder affecting serum levels of potassium, 
calcium, or magnesium; 
 Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the study; 
 History of malignancy other than HCC within 5 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate  90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine 
cancer; 
 Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that could impact patient safety; 

 
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 Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment; 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) or patients receiving 
Rifaximin as prevention of encephalopathy are eligible for the study.  
Antibiotics administered within 30 days prior to initiation of study treatment have to 
be recorded in eCRF. 
 Prior allogeneic stem cell or solid organ transplantation; 
 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; 
 Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the last dose of atezolizumab; 
 History of severe allergic anaphylactic reactions to chimeric or humanized antibodies 
or fusion proteins; 
 Known hypersensitivity to Chinese hamster ovary cell products or to any component of 
the atezolizumab or bevacizumab formulation;  
 Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment 
or within at least 5 months after the last dose of atezolizumab and 6 months after the 
last dose of bevacizumab;  
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
 Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; 
 Untreated or incompletely treated oesophageal and/or gastric varices with bleeding or 
high-risk for bleeding; 
 A prior bleeding event due to oesophageal and/or gastric varices within 6 months prior 
to initiation of study treatment; 
 Clinically evident moderate or severe ascites; 

 
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 At least one clinically evident episode of encephalopathy in the past three months;  
 Co-infection of HBV and HCV; 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV; 
 Co-infection with HBV and hepatitis D viral infection; 
 Symptomatic, untreated, or actively progressing central nervous system (CNS) 
metastases; 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met: 
- Measurable disease, per RECIST v1.1, must be present outside the CNS; 
- The patient has no history of intracranial haemorrhage or spinal cord 
haemorrhage; 
- Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord); 
- There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment; 
- The patient has not undergone stereotactic radiotherapy, whole-brain 
radiotherapy, and/or neurosurgical resection within 28 days prior to initiation of 
study treatment; 
- The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  
- If the patient is receiving anti-convulsivant therapy, the dose is considered 
stable; 
Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to repeat 
the screening brain scan. 
 Uncontrolled tumor-related pain; 
Patients requiring pain medication must be on a stable regimen at study entry. 

 
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Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment. Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 Clinically significant uncontrolled pleural effusion, pericardial effusion, or ascites 
requiring recurrent drainage procedures (once monthly or more frequently); 
Patients with indwelling catheters (e.g., PleurX) are allowed; 
 Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL or corrected serum calcium  ULN); 
 Treatment with investigational therapy within 28 days prior to initiation of study 
treatment; 
 Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies;  
 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; 
 Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF- agents) within 2 weeks prior to initiation of study treatment, or anticipation 
of need for systemic immunosuppressive medication during study treatment, with the 
following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 
hours of corticosteroids for a contrast allergy) are eligible for the study. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study. 

 
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 Inadequately controlled arterial hypertension (defined as systolic blood pressure 
(BP)  150 mmHg and/or diastolic blood pressure  100 mmHg), based on an average 
of  3 BP readings on  2 sessions; 
Anti-hypertensive therapy to achieve these parameters is allowable. 
 Prior history of hypertensive crisis or hypertensive encephalopathy; 
 Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment; 
 History of haemoptysis ( 2.5 mL of bright red blood per episode) within 1 month prior 
to initiation of study treatment; 
 Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation); 
 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; 
 Current or recent (within 10 days prior to study treatment start) use of full-dose oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose; 
Prophylactic anticoagulation for the patency of venous access devices is allowed 
provided the activity of the agent results in an INR  1.5  ULN and aPTT or PTT 
is within normal limits within 14 days prior to initiation of study treatment. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
allowed. However, the use of direct oral anticoagulant therapies such as 
dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to 
bleeding risk. Benefits and risks should be assessed and caution exercised for use 
of direct oral anticoagulants. The investigator should consider switching to other 
approved anticoagulants due to the risk of upper gastrointestinal (GI) bleeding in 
patients with HCC. 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to the first dose of bevacizumab; 
 
History of GI fistula, GI perforation, or intra-abdominal abscess within 6 months prior 
to initiation of study treatment; 

 
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 
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction 
including sub-occlusive disease related to the underlying disease or requirement for 
routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of 
study treatment; 
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at 
time of initial diagnosis may be enrolled if they had received definitive (surgical) 
treatment for symptom resolution. 
 Evidence of abdominal free air that is not explained by paracentesis or recent 
surgical procedure; 
 Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture: 
 Metastatic disease that involves major airways or blood vessels, or centrally located 
mediastinal tumor masses ( 30 mm from the carina) of large volume; 
Patients with vascular invasion of the portal or hepatic veins may be enrolled.   
 History of clinically significant intra-abdominal inflammatory process within 6 months 
prior to initiation of study treatment, including but not limited to complicated active 
peptic ulcer disease, diverticulitis, or colitis; 
 Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to 
initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days 
prior to initiation of study treatment; 
 Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic 
acid 
injection, 
cryoablation, 
high-intensity 
focused 
ultrasound, 
transarterial 
chemoembolization, transarterial embolization, SIRT etc.) within 28 days prior to 
initiation of study treatment or non-recovery from side effects of any such procedure; 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to initiation of study treatment, or abdominal surgery, abdominal interventions or 
significant abdominal traumatic injury within 60 days prior to initiation of study 
treatment or anticipation of need for major surgical procedure during the course of the 
study or non-recovery from side effects of any such procedure; 
 Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID); 
Occasional use of NSAIDs for the symptomatic relief of medical conditions such 
as headache or fever is allowed. 
 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment  
This is an open-label study. After written informed consent has been obtained, the study 
site will obtain the patient's identification number from the eCRF. 
 
4.2.2 
Blinding  
Not applicable. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS 
RELEVANT TO THE STUDY DESIGN 
The investigational medicinal products (IMP) for this study are atezolizumab + 
bevacizumab. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Atezolizumab  
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial. The vial contains approximately 20 mL (1200 mg) of atezolizumab solution. 
For information on the atezolizumab formulation, see the pharmacy manual and the 
Atezolizumab Investigator's Brochure. 
4.3.1.2 
Bevacizumab 
Bevacizumab will be supplied by the Sponsor as a sterile liquid in single-use 100-mg and 
400 mg preservative-free glass vials to deliver 4 mL or 16 mL bevacizumab (25 mg/mL). 
The vial contains approximately 4 mL or 16 mL of bevacizumab solution. 
For information on the bevacizumab formulation, see the pharmacy manual and the 
Bevacizumab Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Patients will receive treatment as outlined in Table 3 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).  
Table 3 
Study Treatment regimens 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
Atezolizumab 1200 mg IV on Day 1 
Bevacizumab 15 mg/kg IV on Day 1 
 

 
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Atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 
minutes between dosing. 
If scheduled dosing and study assessments are precluded because of a holiday, weekend, 
or other event, then dosing may be postponed to the soonest following date, with 
subsequent dosing continuing on a 21-day schedule. If treatment is postponed for fewer 
than 3 days, the patient can resume the original schedule. 
After six complete cycles, one of three cycles may be delayed by 1 week (28 days instead 
of 21 days for one cycle) to allow for vacations/holidays. Following the delay, the next 
cycle visit must be 21 days from the previous Day 1 Visit: two consecutive 28 cycles are 
not permitted. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). Cases of accidental 
overdose, or medication error, along with any associated adverse events, should be 
reported as described in Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Appendix 6 (Atezolizumab) and Appendix 5 
(Bevacizumab). 
4.3.2.1 
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 (see Section 3.1.1 for details). 
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 4. Atezolizumab 
infusions will be administered per the instructions outlined in Table 4. 

 
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Table 4 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted 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.a 
 
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 IRR 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 IRR, or 60 ( 15) 
minutes if the patient experienced an IRR 
with the previous infusion. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
IRR  infusion-related reaction 
aFor patients with borderline blood pressure, repeated measurements can be used to obtain an 
average blood pressure 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 6. 
No dose modification for atezolizumab is allowed. 
4.3.2.2 
Bevacizumab 
Bevacizumab will be administered by IV infusion at a fixed dose of 15 mg/kg on Day 1 of 
each 21-day Cycle (see Table 3). 
Administration of bevacizumab 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 4. 
Bevacizumab infusions will be administered per the instructions outlined in Table 5. 

 
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Table 5 
Administration of First and Subsequent Bevacizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
bevacizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
Bevacizumab should be infused over 
90 ( 15) minutes. 
 
Vital signs should be measured at the end 
of infusion and 2 ( 1) hour 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 IRR 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. 
 
Bevacizumab should be infused over 
60 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 90 ( 15) 
minutes if the patient experienced an IRR 
with the previous infusion. If the 60-
minute infusion was well tolerated, 
bevacizumab may be infused over 30 
(15) minutes thereafter 
 
Vital signs should be measured at the 
end of infusion and 2 ( 1) hour after the 
infusion. 
IRR  infusion-related reaction 
 
Guidelines for dosage modification and treatment interruption or discontinuation because 
of toxicities are provided in Appendix 5. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local regulations. The study site (i.e., investigator or other authorized 
personnel [e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the 
site, IMP inventory at the site, IMP use by each patient, and disposition or return of unused 
IMP, thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP. The study 
site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to confirm 
the shipment condition and content. Any damaged shipments will be replaced. The 
investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all IMPs received either by time monitoring (shipment arrival 
date and time) or temperature monitoring, for all IMPs received and that any discrepancies 
have been reported and resolved before use of the IMPs. All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 

 
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accordance with the labelled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may supply 
or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation. The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor. The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the atezolizumab and bevacizumab Investigator's 
Brochure for information on IMP handling, including preparation and storage, and 
accountability.  
4.3.4 
Continued Access to Atezolizumab and Bevacizumab 
The Sponsor will offer continued access to Roche IMPs (atezolizumab and bevacizumab) 
free of charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMPs (atezolizumab and bevacizumab) after 
completing the study if all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires continued 
Roche IMP treatment for his or her well-being; 
 
There are no appropriate alternative treatments available to the patient; 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive Roche IMPs (atezolizumab and bevacizumab) after 
completing the study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient); 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for unresectable HCC;  
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
unresectable HCC; 

 
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 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, 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 drug to the treatment discontinuation visit. All such medications should be reported 
to the investigator and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year (see Section 4.1.1); 
 
Hormone-replacement therapy; 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section 4.4.3). 
 
Megestrol acetate administered as an appetite stimulant; 
 
Mineralocorticoids (e.g., fludrocortisone); 
 
Inhaled or low-dose corticosteroids administered for COPD or asthma; 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency; 
 
Low-dose aspirin (< 325 mg/day) is permitted. Co-administration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage; 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease). Treatment with atezolizumab may be 

 
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continued during palliative radiotherapy. Treatment with bevacizumab should be 
suspended during palliative radiotherapy. 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
- 
The patient has no evidence of progression or haemorrhage after completion 
of CNS-directed therapy; 
- 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. 
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment. 
- 
Anti-convulsant therapy, if required, is administered at a stable dose. 
Note: Treatment with atezolizumab and bevacizumab should be withheld 
during CNS-directed radiation therapy. 
 Other local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, 
radiofrequency ablation) as outlined below: 
Patients experiencing a mixed response requiring local therapy for control of three or 
fewer non-target lesions may still be eligible to continue study treatment after Medical 
Monitor approval has been obtained. 
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 pre-existing conditions) 
with supportive therapies other than those defined as cautionary or prohibited therapies 
(see Sections 4.4.2 and 4.4.3) 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 
dyspnoea, 
hypotension, 
wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 

 
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managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and 
2-adrenergic agonists). Refer to Appendix 4 for Guidelies on Anaphylaxis Precautions. 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF- 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab. 
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered. If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications and TNF- inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when associated 
with atezolizumab therapy (refer to Appendix 6 for details). 
4.4.2.2 
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 4.4.3) may be used 
during the study at the discretion of the investigator. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether health authorityapproved or experimental, is prohibited for various time 
periods prior to starting study treatment, depending on the agent (see Section 4.1.2), 
and during study treatment, until disease progression is documented and the patient 
has discontinued study treatment, with the exception of palliative radiotherapy, 
radiotherapy to the brain and local therapy under certain circumstances (see Section 
4.4.1 for details); 
 
Investigational therapy 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 atezolizumab treatment, and for 5 months after the 
final dose of atezolizumab; 

 
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 
Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) are 
prohibited within 4 weeks or 5 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; 
 
Current use of full dose anticoagulants, thrombolytic therapy at therapeutic doses, or 
anti-platelet therapy are prohibited. 
Local label recommended doses for prophylactic use of anticoagulants or thrombolytic 
therapies are allowed. Benefits and risks should be assessed and caution exercised 
for use of direct oral anticoagulants. Other approved anticoagulants should be 
considered due the risk of upper GI bleeding in patients with HCC. 
Low-dose aspirin (< 325 mg/day) is permitted. Co-administration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage. 
If a patient experiences a venous thromboembolism (VTE) event while still receiving 
study drug treatment, it may still be possible for the patient to remain on study 
medication with atezolizumab only (see Section 4.1.2). 
 
Use of warfarin or Coumadin-like products (includes for prophylactic use) is prohibited. 
Prophylactic use of low dose anticoagulation, unfractionated heparin or LMWH is 
permitted. The preferred choice for anticoagulation treatment should be LMWH as per 
ASCO guidelines (Lyman et al. 2015). 
 
Concomitant chronic use of NSAIDs while receiving study drugs is prohibited, with the 
exception of chronic low-dose aspirin (<325 mg/day). However, for the symptomatic 
relief of medical conditions (e.g., headache, fever) intermittent or short-term intake of 
oral NSAIDs is allowed, when co-administered with proton pump inhibitors to reduce 
potential GI damage. 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities should be performed and documented for each patient.   
If scheduled dosing and study assessments are precluded because of a holiday, weekend, 
or other event, then dosing may be postponed to the soonest following date, with 
subsequent dosing continuing on a 21-day schedule. If treatment is postponed for fewer 
than 3 days, the patient can resume the original schedule. 

 
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After six complete cycles, one of three cycles may be delayed by 1 week (28 days instead 
of 21 days for one cycle) to allow for vacations/holidays. Following the delay, the next 
cycle visit must be 21 days from the previous Day 1 visit: two consecutive 28 cycles are 
not permitted. 
Patients will be closely monitored for safety and tolerability throughout the study. Patients 
should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
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 detailed record of 
all patients screened to document eligibility or record reasons for screening failure, as 
applicable. 
4.5.2 
Medical History, Baseline Conditions, 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 
any previous therapies or procedures linked to esophageal varices (if applicable) such as 
non-cardioselective beta-blockers, banding, sclerosing injections etc. will be recorded at 
baseline. Finally, infectious disease and pharmacological history (episodes of diarrhea, 
gastroenteritis, pneumonia, urinary tract infections, antibiotic treatments received and with 
which drugs) starting from three months before enrolment will be recorded. Moreover 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, or patient contact by means of 
telephone, 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 or ethnicity. 
4.5.3 
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 

 
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cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems. Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified post-
baseline 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 on the Adverse Event eCRF. 
As part of the tumor assessment, physical examinations should include the evaluation of 
the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic 
blood pressure, and temperature. Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF. At subsequent visits, record new 
or worsened clinically significant abnormalities on the Adverse Event eCRF. 
Vital signs are to be measured before, during, and after infusions as outlined in Table 6, 
and at other specified timepoints as outlined in the schedule of activities (see Appendix 1). 
Table 6 
Timing for Vital Sign Measurements for First and Subsequent 
Infusions 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Atezolizumab  Within 60 minutes prior to the 
atezolizumab infusion 
 Record patient's vital signs during or 
after the infusion if clinically 
indicated. 
 Within 60 minutes prior to the 
atezolizumab infusion 
 Record patient's vital signs during or 
after the infusion if clinically indicated 
Bevacizumab  Within 60 minutes prior to the 
bevacizumab infusion 
 At the end of infusion and 2  (± 1) 
hours after the infusion 
 Within 60 minutes prior to the 
bevacizumab infusion 
 At the end of infusion and 2  (± 1) 
hours after the infusion 
 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline, every 6 weeks (± 1 week) for the 
first 54 weeks following treatment initiation, and every 9 weeks (± 1 week) thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 or (for 
patients who continue treatment after radiographic disease progression) loss of clinical 
benefit as determined by the investigator (see Section 3.1.1 for details). Thus, tumor 

 
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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/or 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, so long as they meet criteria outlined below.   
4.5.5.1 
Radiographic Assessments 
Screening assessments must include CT scans with IV contrast (and oral contrast per site 
standard of care) or MRI scans of the chest, abdomen, and pelvis. A spiral CT scan of the 
chest may be obtained but is not a requirement. If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed and MRI scans of the abdomen and pelvis should be 
performed. A CT scan with contrast or MRI scan of the head must be done at screening 
to evaluate CNS metastasis in all patients (MRI scan must be performed if CT scan is 
contraindicated). An MRI scan of the head is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal CT scan. Bone scans and CT 
scans of the neck should also be performed if clinically indicated. At the investigator's 
discretion, other methods of assessment of measurable disease as per RECIST v1.1 may 
be used. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
All post-baseline imaging assessments will include CT scans with IV contrast (and oral 
contrast per site standard of care) or MRI scans of the chest, abdomen, and pelvis; scans 
of the head will be included per local practice or as clinically indicated.  
All measurable and/or evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation according to the schedule described above. 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).  To 
facilitate evaluation of post-progression tumor changes while treatment is ongoing tumor 
assessments must be continued after disease progression per RECIST v1.1 for patients 
who receive treatment beyond progression. This includes continued measurement of 
target lesions, evaluation of non-target lesions (including monitoring for further worsening 
of any non-target lesions that have shown unequivocal progression), and evaluation of 
any newly identified lesions (including measurements, if lesions are measurable) at all 
subsequent assessments. 

 
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The use of radiopharmaceutical products (e.g., 18F-FDG, Tc-99m, MIBG) and contrast 
agents (e.g., gadolinium-based or iodinated contrast media) in study imaging 
assessments will be consistent with standard/local practice, and will not involve a route of 
administration, dose, patient population, or any other factor that significantly increases the 
risk (or decreases the acceptability of the risk) to patients. The products employed in these 
procedures will be at the discretion of participating investigators, and shall be locally 
authorized or otherwise used in compliance with local regulations. The results of this study 
will not be used to support any new indication or change in labeling for these products. 
4.5.5.2 
Response Evaluation 
Objective response will be determined by the Investigator at specified timepoints 
according to RECIST v1.1 (see Appendix 2). Assessments should be performed by the 
same evaluator, if possible, to ensure internal consistency across visits. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Haematology:  WBC count, RBC count, haemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells); 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if considered 
standard of care for the region), serum troponin (at baseline, if considered standard of 
care/required per local clinical practice, and as clinically indicated during the study), 
sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, 
AST, and LDH; 
 
α-fetoprotein (AFP) 
 
Coagulation:  INR, and aPTT or PTT; 
 
Thyroid function testing:  thyroid-stimulating hormone (TSH), free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4); 
 
HIV serology:  HIV-1 antibody; 
 
HBV serology:  HBsAg, HBsAb, and total HBcAb, for all patients; HBV DNA for patients 
with negative HBsAg and HBsAb tests and a positive total HBcAb test; 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA; 

 
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 
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 post-menarchal, 
has not reached a postmenopausal state ( 12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis). 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted; 
The following samples will be stored locally, until shipment to a central laboratory (the Unit 
of Holobiont microbiome and microbiome engineering, Department of Pharmacy and 
Biotechnology, University of Bologna, Bologna, Italy) identified by the Sponsor, for 
microbiome analysis: 
 
Faeces samples for exploratory research on potential biomarkers; 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Faeces samples collected for biomarker research will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analyzed, unless the patient specifically requests that the samples be 
destroyed or local laws require destruction of the samples. However, if samples have been 
tested prior to withdrawal, results from those tests will remain as part of the overall 
research data. 
Data arising from sample analysis will be subject to the confidentiality standards described 
in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication. 

 
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4.5.7 
Electrocardiograms 
An ECG is required at screening and when clinically indicated. ECGs for each patient 
should be obtained from the same machine wherever possible. 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. Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. Any morphologic waveform changes or other ECG abnormalities must 
be documented on the eCRF. 
4.5.8 
Clinical Outcome Assessments 
Patient-reported outcome (PRO) instruments will be completed to more fully characterize 
the clinical profile of atezolizumab and bevacizumab. In addition, PRO instruments will 
enable the capture of each patient's direct experience with atezolizumab and 
bevacizumab. 
PRO data will be collected through use of the following instruments: PRO-CTCAE. 
4.5.9 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at home on Day 15 of each Cycle (see schedule 
of activities in Appendix 1). At the clinic, instruments will be administered before the patient 
receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment. 
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor in pre-printed booklets to enable the instrument to be administered in the 
correct order at each specified timepoint. The booklets will be labeled with the timepoint 
of administration. 
Patients should be given the following instructions for completing PRO instruments at 
home: 
 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 

 
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Site staff should review all completed instruments and should ask the patient to rectify any 
response that is not clearly marked in the appropriate location. If a response is missing, 
site staff should ask the patient to complete the item or confirm that the item was 
intentionally left blank. 
4.5.10 
Description of Clinical Outcome Assessments Instruments 
PRO-CTCAE 
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015). The PRO-CTCAE contains 124 questions that are rated either dichotomously (for 
determination of presence vs. absence) or on a 5-point Likert scale (for determination of 
frequency of occurrence, severity, and interference with daily function). Treatment 
toxicities can occur with observable signs (e.g., vomiting) or non-observable symptoms 
(e.g., nausea). The standard PRO-CTCAE recall period is the previous 7 days. 
A subset of 14 symptoms deemed most applicable to the current treatments has been 
selected for this study (see Appendix 7). Symptoms have been selected on the basis of 
toxicities associated with the drug's class, mechanism of action, or mode of administration 
and toxicities reported with the drug in another indication. 
4.5.11 
Blood Samples for Whole Genome Sequencing or Whole Exome 
Sequencing (Patients at Participating Sites) 
Not apllicable. 
4.6 
TREATMENT, 
PATIENT, 
STUDY, 
AND 
SITE 
DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (atezolizumab + bevacizumab) if 
any of the following criteria are met: 
 
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; 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient; 

 
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 
Use of another non-protocol anti-cancer therapy; 
 
Pregnancy; 
 
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 3.1.1 for details). 
If one component of study treatment (atezolizumab or bevacizumab) is discontinued 
permanently because of tolerability concerns, the patient may continue with the other 
components of study treatment until loss of clinical benefit as long as the patients are 
experiencing clinical benefit in the opinion of the investigator and after discussion with the 
Medical Monitor if agreed upon by the investigator and patient. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 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 final 
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). 
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study). 
Refer to the schedule of activities (see Appendix 1) for details on follow-up assessments to be 
performed for patients who permanently discontinue study treatment. If a patient requests to be 
withdrawn from treatment or follow-up assessments, this request must be documented in 
the source documents and signed by the investigator. 
4.6.2 
Patient Discontinuation from the 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 patient discontinuation from the study may include, but are not limited to, the 
following: 
 
Patient withdrawal of consent; 

 
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 
Study termination or site closure; 
 
Adverse event; 
 
Loss to follow-up; 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor. 
 
Every effort should be made to obtain a reason for patient discontinuation from the study. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF. If a patient requests 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. 
4.6.3 
Study Discontinuation 
The Sponsor 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. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment; 
 
Poor protocol adherence; 
 
Inaccurate or incomplete data recording; 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice; 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled). 
 

 
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5. 
ASSESSMENT OF SAFETY  
5.1 
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 5.1.1 and Section 5.1.2). 
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 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 criteria for treatment 
interruption or discontinuation, are provided in Appendix 5 (bevacizumab) and Appendix 
6 (atezolizumab). Refer to Sections 5.25.6 for details on safety reporting (e.g., adverse 
events, pregnancies) for this study. 
Patients with active infection are excluded from study participation. In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to and 
during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines 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 SARS-
CoV-2 infection, 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 SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated 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. In 
addition, immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH). Refer to Appendix 6 of the protocol and 
Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab. Guidelines for managing patients who 
experience anticipated adverse events are provided in Appendix 6.  

 
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5.1.2 
Risks Associated with Bevacizumab 
Bevacizumab has been associated with risks such as the following: gastrointestinal (GI) 
perforations, gall bladder perforation, bleeding/haemorrhage, pulmonary haemorrhage, 
arterial thromboembolic events (ATE), fistulae other than GI, wound-healing 
complications, hypertension, congestive heart failure (CHF), cardiac disorders (excluding 
CHF and ATE), neutropenia, infections, necrotizing fasciitis, thrombocytopenia, venous 
thromboembolic events, posterior reversible encephalopathy syndrome, pulmonary 
hypertension, ovarian failure, embryo fetal development disturbance, hypersensitivity 
reactions/infusion reactions, peripheral sensory neuropathy, osteonecrosis of the jaw, non 
mandibular osteonecrosis, thrombotic microangiopathy, and proteinuria. 
Refer to Appendix 5 of the protocol and Section 6 of the Bevacizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for Bevacizumab. 
5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Bevacizumab  
The risk of overlapping toxicities between atezolizumab and bevacizumab is anticipated 
to be minimal. Nevertheless, the attribution and management of certain adverse events 
that have been associated with each agent separately (e.g., haemorrhage, 
hypothyroidism, and GI toxicity) may not be unambiguous when the agents are 
administered together. It is theoretically possible that allergic or inflammatory adverse 
events associated with bevacizumab could be exacerbated by the immunostimulatory 
activity of atezolizumab. 
Toxicities should initially be managed according to the recommendations in Appendix 5 
(bevacizumab) and Appendix 6 (atezolizumab) with dose holds and modifications (if 
applicable) applied to the component of the study treatment judged to be the primary 
cause. If individual component causality for the toxicity cannot be adequately determined, 
then the most conservative management recommendation should be applied, refer to 
adverse event management guidelines in Appendix 5 (bevacizumab) and Appendix 6 
(atezolizumab) and in the most recent version of the Atezolizumab and Bevacizumab 
Investigator's Brochures). 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital signs, 
and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 
5.4. 

 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product; 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) (see Section 5.3.5.9 and Section 5.3.5.10 
for more information); 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline; 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment; 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies). 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death); 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death); 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11); 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient's ability to conduct normal life functions); 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment; 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 

 
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see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 
5.4.2 for reporting instructions). Adverse events of special interest for this study are as 
follows: 
 
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 (see Section 5.3.5.7); 
 
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. 
 
Systemic lupus erythematosus; 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH and MAS; 
 
Nephritis; 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis); 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis); 
 
Vasculitis 
 
Autoimmune haemolytic anaemia; 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  

 
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 
Grade 3 hypertension  
 
Grade 3 proteinuria  
 
Any grade GI perforation, abscess, or fistula  
 
Grade 2 non-GI fistula or abscess  
 
Grade 3 wound-healing complication  
 
Hemorrhage  
o Any grade CNS bleeding  
o Grade  2 hemoptysis 
o Other Grade  3 hemorrhagic event  
 
Any ATE  
 
Grade 3 venous thromboembolic event  
 
Any grade posterior reversible encephalopathy syndrome 
 
Grade 3 CHF  
 
5.3 
METHODS 
AND 
TIMING 
FOR 
CAPTURING 
AND 
ASSESSING SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
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 and on the Adverse Event eCRF. 
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 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
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 
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. 

 
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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
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?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 7 will be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. 
Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 

 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration (see also Table 8): 
 
Temporal relationship of event onset to the initiation of study treatment; 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as applicable); 
 
Known association of the event with study treatment or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event; 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
Table 8 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 

 
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The health care resources consumed for managing all Grade 3 and Grade 4 AEs will be 
identified and quantified in a dedicated section of the Adverse Event eCRF. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release 
syndrome (CRS). While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary. Differential diagnosis should be applied, 
particularly for late-onset CRS (occuring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, HLH, tumor lysis syndrome, early disease progression, or other 
manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured on the Adverse 
Event eCRF as a diagnosis (e.g., "infusion-related reaction") or "cytokine-release 
syndrome").  Avoid ambiguous terms such as "systemic reaction." Cases of late-onset 
CRS should be reported as "cytokine-release syndrome" on the Adverse Event eCRF. 
Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF or Cytokine Release Syndrome eCRF, as appropriate.  
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded as a separate event on the Adverse 
Event eCRF, with associated signs and symptoms also recorded separately on the 
dedicated Infusion-Related Reaction eCRF or Cytokine Release Syndrome eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 6. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF 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, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 

 
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5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of severe 
or serious secondary events. A medically significant secondary adverse event that is 
separated in time from the initiating event should be recorded as an independent event on 
the Adverse Event eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF; 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF; 
 
If a severe gastrointestinal haemorrhage leads to renal failure, both events should be 
reported separately on the eCRF; 
 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF; 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. If a persistent adverse event becomes more severe, the 
most extreme severity should also be recorded on the Adverse Event eCRF. If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 24 
hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions). The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints and 
subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms; 

 
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 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation); 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy; 
 
Is clinically significant in the investigator's judgement. 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 7.0 
mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details 
on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms; 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation); 
 
Results in a medical intervention or a change in concomitant therapy; 
 
Is clinically significant in the investigator's judgment. 
 
It is the investigator's responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 

 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details 
on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either an 
elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of unresectable HCC should be recorded on the Death 
Attributed to Progressive Disease eCRF. All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. The term "sudden death" should not be used 
unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 

 
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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of unresectable Hepatocellular 
Carcinoma  
Deterioration that is judged by the investigator to have unexpectedly worsened in severity 
or frequency or changed in nature (i.e., deterioration beyond the expected pattern of 
progression of the underlying disease) should be recorded as an adverse event. When 
recording an unanticipated worsening of HCC on the Adverse Event eCRF, it is important 
to convey the concept that the condition has changed by including applicable descriptors 
(e.g., "accelerated worsening of hepatocellular carcinoma"). 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. These data will be captured 
as efficacy assessment data only. In most cases, the expected pattern of progression will 
be based on RECIST v1.1 criteria. In rare cases, the determination of clinical progression 
will be based on symptomatic deterioration. However, every effort should be made to 
document progression through use of objective criteria. If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) or 
prolonged hospitalization should be documented and reported as a serious adverse event 
(per the definition of serious adverse event in Section 5.2.2), except as outlined below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care; 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study); 

 
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 
Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease; 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer. 
An event that leads to hospitalization under the following circumstances is not considered 
to be a serious adverse event, but should be reported as an adverse event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours. 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
Note: Special situations are not in themselves adverse events, but may result in adverse 
events. Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). For atezolizumab and becavizumab, adverse events associated 
with special situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term. Check the "Accidental overdose" 
and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event term. 
Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term. Check 
the "Accidental overdose" and "Medication error" boxes. 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 

 
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entry to report the headache. The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
In addition, all special situations associated with atezolizumab and bevacizumab, 
regardless of whether they result in an adverse event, should be recorded on the Adverse 
Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication error" 
boxes. Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication error" 
as the event term. Check the "Medication error" box. Enter a description of the error 
in the additional case details. 
Special situations and non serious AEs associated with special situations need to be 
reported on the Adverse Event eCRF within 30 calendar days after learning of the event  
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO-CTCAE data by the Sponsor. In 
addition, the Sponsor will make no attempt to reconcile patient reports of treatment-related 
symptoms (via PRO-CTCAE) with investigator reports of adverse events. Sites are not 
expected to review the PRO-CTCAE data for adverse events. 
5.4 
IMMEDIATE 
REPORTING 
REQUIREMENTS 
FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning of 
the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 

 
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For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more than 
24 hours after becoming aware of the information).  New significant information includes 
the following: 
 
New signs or symptoms or a change in the diagnosis; 
 
Significant new diagnostic test results; 
 
Change in causality based on new information; 
 
Change in the event's outcome, including recovery; 
 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
Medical Monitor Contact Information 
 
Medical Monitor: 
  
Mobile Telephone No.: 
  
Roche Medical Responsible: 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center will be available 
24 hours per day, 7 days per week, in case the above-listed contacts cannot be reached. 
The Emergency Medical Call Center will connect the investigator with an Emergency 
Medical Contact, provide medical translation service if necessary, and track all calls. 
Contact information, including toll-free numbers for the Emergency Medical Call Center, 
will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 

 
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5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until initiation 
of new systemic anti-cancer therapy, whichever occurs first. Investigators should record 
all case details that can be gathered immediately (i.e., within 24 hours after learning of the 
event) on the Adverse Event eCRF and submit the report via the electronic data capture 
(EDC) system. A report will be generated and sent to Roche Safety Risk Management by 
the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators. Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of atezolizumab or 6 months after the final dose of 
bevacizumab.  
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators. Pregnancy should not be recorded on the 
Adverse Event eCRF. The investigator should discontinue study treatment and counsel 
the patient, discussing the risks of the pregnancy and the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) 
should be reported on the Adverse Event eCRF. In addition, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information would 
need to be signed by one or both parents (as per local regulations) to allow for follow-up 
on the infant.  If the authorization has been signed, the infant's health status at birth should 

 
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be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the Sponsor may 
collect follow-up information on the infant's health status at 6 and 12 months after birth.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately inform 
the investigator if their partner becomes pregnant during the study or within 6 months after 
the final dose of bevacizumab. 
The investigator should report the pregnancy on the paper Clinical Trial Pregnancy 
Reporting Form and submit the form to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study treatment. When permitted 
by the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. If the 
authorization has been signed, the investigator should submit a Clinical Trial Pregnancy 
Reporting Form with additional information on the pregnant partner and the course and 
outcome of the pregnancy as it becomes available.  
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information would 
need to be signed by one or both parents (as per local regulations) to allow for follow-up 
on the infant.  If the authorization has been signed, the infant's health status at birth should 
be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the Sponsor may 
collect follow-up information on the infant's health status at 6 and 12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). A therapeutic or elective abortion 
performed for reasons other than an underlying maternal or embryofetal toxicity is not 
considered an adverse event. 

 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, or the event is assessed as stable by the investigator, or the patient is lost 
to follow-up, or the patient withdraws consent. Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 5.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient's 
medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until initiation 
of new systemic anti-cancer therapy, whichever occurs first), all deaths, regardless of 
cause, should be reported through use of the Long-Term Survival Follow-Up eCRF.   
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF. However, if the EDC system is not available, the 

 
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investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety information 
in the documents listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
Bevacizumab 
Bevacizumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
No hypothesis testing is intended, as the focus of the statistical analyses is on the 
precision of the obtained estimate of the incidence of this key safety parameter. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study will enroll approximately a sample of convenience (Lohr 2010) of 150 patients 
across 21 Italian sites, possibly according to a competitive enrolment scheme (Kim et al. 
2017). 
According to  the results of the YO40245 (IMbrave150) trial (Cheng et al. 2019), the 
incidence of Grade 3-5 bleeding events is 7.9% (that is, 6.4% incidence of Grade 3-4 
bleeding events plus 1.5% incidence of Grade 5 bleeding events) during a 10.4 months 
timespan (that is, 7.4 months of median treatment duration plus 90 days or 3 months of 
follow-up). 

 
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Therefore, assuming a fixed rate with respect to time, the overall Grade 3-5 bleeding 
events rate (r) per month is (Miller and Homan 1984; Briggs et al. 2006): 
𝑟= −
[ln(1 −0.079)]
10.4
 
or 0.007913, that, considering a convenience sample (Lohr 2010) of 150 patients and a 
12-month lasting year (Wilkins 1990), can be converted into an annual probability (one 
year p) - or incidence - of Grade 3-5 bleeding events as follows (Miller and Homan 1984; 
Briggs et al. 2006): 
𝑜𝑛𝑒 𝑦𝑒𝑎𝑟 𝑝= [1 −exp(−0.007913x12)] 
or 0.090587. 
According to this incidence point estimate and assuming no missing 1-year patient time 
and that each patient can experience only one Grade 3-5 bleeding event per year (that is, 
ruling out for sake of simplicity shared frailty issues, such as multiple occurrence of 3-5 
bleeding events experienced by the same patient) (Therneau and Grambsch 2000), the 
expected number (#) of patients with Grade 3-5 bleeding event per year out of a 
convenience sample size (Lohr 2010) of 150 evaluable subjects can be calculated as 
follows: 
# 𝑜𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑏𝑙𝑒𝑒𝑑𝑖𝑛𝑔 𝑒𝑣𝑒𝑛𝑡𝑠 𝑝𝑒𝑟 𝑦𝑒𝑎𝑟= (0.090587x150) 
or about 14 patients with the event per year. 
The achievable precision (width of 95% CI) for the incidence of Grade 3-5 bleeding events 
is illustrated separately (Table 9). The sample variance of the binomial distribution is 
conditional on its sample mean (Agresti 2002) and both these statistics enter the formula 
for calculating the standard error of the sample distribution of the mean (Agresti 2002). 
Therefore, given the same sample size, a low incidence of Grade 3-5 bleeding events 
leads to a small width of the 95% CI, whereas a higher incidence of Grade 3-5 bleeding 
events results in a wider 95% CI. 
In order to investigate the precision of the point estimate for the incidence of Grade 3-5 
bleeding events under different scenarios, the Clopper-Pearson method (Clopper and 
Pearson 1934; Agresti 2002; Fleiss et al. 2003) for calculating incidence binomial exact 
95% CI has been applied (Table 9). 

 
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Table 9 
Clopper-Pearson 95% CI for the Incidence of Grade 3-5 Bleeding 
Events, Based on 150 Evaluable Subjects 
# Patients with 
events 
Incidence 
 (%) 
Precision -      
CI Width (%)    
LL 95% CI  
(%) 
UL 95% CI  
(%) 
0 
0 
2.43 
0 
2.43 
1 
0.67 
3.65 
0.02 
3.67 
2 
1.33 
4.57 
0.16 
4.73 
3 
2.00 
5.32 
0.41 
5.73 
4 
2.67 
5.96 
0.73 
6.69 
5 
3.33 
6.52 
1.09 
7.61 
6 
4.00 
7.02 
1.48 
8.50 
7 
4.67 
7.48 
1.90 
9.38 
8 
5.33 
7.90 
2.33 
10.23 
9 
6.00 
8.30 
2.78 
11.08 
10 
6.67 
8.67 
3.24 
11.91 
11 
7.33 
9.03 
3.71 
12.74 
12 
8.00 
9.36 
4.20 
13.56 
13 
8.67 
9.66 
4.70 
14.36 
14 
9.33 
9.96 
5.20 
15.16 
  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrolment, study drug administration, and discontinuation from the study will be 
summarized for the ITT population, defined as all recruited patients. The reasons for study 
drug discontinuation will also be tabulated. Major protocol deviations, including major 
deviations with regard to the inclusion and exclusion criteria, will be summarized for the 
ITT population. 
All safety analyses will be conducted in the SAP, defined as all enrolled patients who had 
at least one administration of atezolizumab +bevacizumab. 
All efficacy analyses will be conducted on the ITT population. 
6.3 
SUMMARIES 
OF 
DEMOGRAPHIC 
AND 
BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, and baseline 
disease characteristics, e.g., ECOG performance status) will be summarized using means, 

 
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standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  
Missing values will be classified and managed using the methods outlined in Section 6.7. 
6.4 
SAFETY ANALYSES 
The safety SAP consists of all enrolled patients who had at least one full or 
partial administration of atezolizumab + bevacizumab. 
Primary analysis 
The overall incidence of Grade 3-5 NCI CTCAE v5.0 bleeding events will be calculated for 
the SAP, along with Clopper-Pearson (Clopper and Pearson 1934; Agresti 2002; Fleiss et 
al. 2003) 95% CI. 
No hypothesis testing is intended, as the focus of the statistical analyses is on the 
precision of the obtained estimate of the incidence of this key safety parameter. 
For the primary safety endpoint, that is overall Grade 3-5 bleeding events, in addition to 
the incidence of Grade 3-5 bleeding events, the annual and overall bleeding rate (BR) will 
be calculated as follows:  
𝐵𝑅= #𝑒𝑣𝑒𝑛𝑡𝑠/𝑃𝑌 
where #events is the total number of Grade 3-5 bleeding events (including multiple 
occurrences per patient), and PY is the total number of patient-years under observation. 
The BR point estimate will be provided along with 95% CI, assuming a Poisson distribution 
(Poisson 1837; Agresti 2001; Hilbe 2014) for the underlying number of related events. 
Secondary analysis 
Safety will be also assessed through summaries of exposure to study treatment, adverse 
events, deaths, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, dose intensity, 
number of cycles and dose modifications) will be summarized with descriptive statistics. 
Laboratory data with values outside the normal ranges will be identified. In addition, 
selected laboratory data will be summarized by grade with descriptive statistics. 
Descriptive statistics will be used to summarize changes in vital signs. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded according 
to NCI CTCAE v5.0. All adverse events, serious adverse events, adverse events leading 

 
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to death, adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment-emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade. For events of varying severity, the highest 
grade will be used in the summaries. Deaths with causes of death reported during the 
study will be summarized. 
The following events occurring during or after the first dose of study treatment will be 
summarized by NCI CTCAE grade v5.0: 
- All Adverse Events (AEs) 
- 
All severe AEs (Grade 3-4) 
- All treatment related AEs;  
- 
All severe treatment-related AEs (Grade 3 -4) 
- All serious AEs 
- 
All treatment-related serious AEs 
- All immune-mediated AEs 
- 
 All severe immune-mediated AEs (Grade 3-4) 
- All adverse events leading to withdrawal from any component 
- All adverse events leading to withdrawal from atezolizumab 
- All adverse events leading to withdrawal from bevacizumab 
- All Grade 5 AEs 
- 
All treatment related Grade 5 AE 
- All adverse event of special interest (AESIs) of atezolizumab 
- 
All severe AESIs of atezolizumab (Grade 3-4) 
- All adverse event of special interest (AESIs) of bevacizumab  
- 
All severe AESIs of atezolizumab (Grade 3-4) 
- All adverse events leading to dose  temporary interruption of any component 
- All adverse events leading to dose temporary interruption of atezolizumab 
- All adverse events leading to dose temporary interruption of bevacizumab 
Multiple occurrences of the same event will be counted once at the maximum severity. 
The following descriptive statistics on the selected items will be reported (Pagano and 
Gavreau 2000): 

 
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- Continuous and count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Summary statistical tables including number of and patients with adverse events along 
with 95% CI assuming an underlying Poisson distribution (Poisson 1837; Agresti 2001; 
Hilbe 2014) as well as number absolute and relative frequencies of adverse events along 
with Clopper-Pearson 95% CI (Clopper and Pearson 1934; Agresti 2002; Fleiss et al. 2003) 
will be produced.  
Additional analyses may be performed as indicated. 
Missing values will be classified and managed using the methods outlined in Section 6.7. 
According to its relevance to possible AEs experienced by patients on atezolizumab + 
bevacizumab, a subset of the about 80 items included in the Italian translation of the Item 
Library Version 1.0 of the NCI-PRO-CTCAE™ questionnaire (Appendix 7) (Smith et al. 
2016; National Cancer Institute, 2017) will be selected by a working group composed of 
study investigators and patient advocates. 
The following descriptive statistics on the selected items (possibly grouping in domains 
items that share common features) (Brazier et al.2017) of the Italian translation of the Item 
Library Version 1.0 of the NCI-PRO-CTCAE™ questionnaire version 1.0 of the NCI-PRO-
CTCAE™ questionnaire will be reported (Pagano and Gavreau 2000): 
- Ordinal count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Missing data for items and patients will be summarized to improve results interpretation 
(National Cancer Institute, 2020). 
6.5 
EFFICACY ANALYSES 
Efficacy analysis includes both secondary and exploratory objectives. 
Analysis of main and other secondary endpoints 
All baseline summaries and efficacy analyses will be based on the ITT analysis set defined 
as all recruited patients. 
Time-dependent variables OS, PFS, TTP, Duration of Response (DOR) and PPS will be 
analyzed using Kaplan-Meier (K-M) methods (Kaplan and Meier 1958) and Greenwood’s 

 
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formula (Greenwood 1926). Medians and the quartiles with 95% confidence interval (CI) 
will be derived from the K-M curves. K-M plots with a 95% CI for OS, PFS, DOR and PPS 
will be prepared. 
ORR will simply be summarised. The ORR will be calculated as the percentage of patients 
who have a CR or PR before any evidence of progression. A 95% CI will be derived for 
the ORR using Wilson score intervals (CIs for a single proportion) (Wilson 1927). 
Analysis of exploratory endpointsFollowing disease progression, patients will be 
followed to evaluate whether the patterns of tumor progression (growth versus new lesion, 
intrahepatic versus extrahepatic) have a different impact on OS and PPS. OS and PPS 
will be described based on the following patterns of progression:  
- >20% increase in tumor size against a known baseline lesion (intrahepatic growth [IHG] 
or extrahepatic growth [EHG]) 
- new intrahepatic lesion (NIH)  
- new extrahepatic lesion (NEH) and/or vascular invasion 
To evaluate if post-study treatments have impact on OS following disease progression, 
patients will be followed-up for anti-cancer therapies and survival with a descriptive 
analysis. In details, number and rate of patients starting second or further lines of 
treatment will be described indicating time and duration of each post-study treatment. OS 
based on type and duration of each post-study treatments will be described. 
To evaluate if reason of treatment withdrawal has impact on OS, OS based on the 
following reasons of treatment withdrawal will be described: 
- Progressive disease (PD) vs adverse event (AE) vs deteriorating liver function/clinical 
conditions. 
Missing values will be classified and managed using the methods outlined in Section 6.7. 
6.6 
BIOMARKER ANALYSES  
For all fecal samples, the gut microbiota composition will be profiled by 16S rRNA gene-
based next-generation sequencing, as previously described (Ayeni et al., 2018). Briefly, 
microbial DNA will be extracted from faeces and the 16S rRNA V3-V4 region will be 
sequenced on Illumina MiSeq platform. Bioinformatics analysis for alpha/beta diversity 
and taxonomic assignment will be carried out using the QIIME pipeline (Bolyen et al., 
2019). To get species-level and functional insights, a subset of samples, selected based 
on 16S rDNA data, will be subjected to shotgun metagenomics on Illumina NextSeq. 
Sequenced metagenomes will be analysed by de novo assembling using available 

 
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software (e.g. Meta-Velvet) and ORF annotation using web servers (e.g. MG-RAST) 
against GenBank or KEGG database, and/or by direct read mapping on NCBI database, 
using bowtie2 or bwa algorithms (Rampelli et al., 2020). Viral and fungal components of 
the gut microbiome (i.e., the gut virome and mycobiome, respectively) will be searched as 
well, by using dedicated pipelines, such as ViromeScan (Rampelli et al., 2016) and 
HumanMycobiomeScan (Soverini et al., 2019). Publicly available microbiome sequencing 
data from healthy age/gender-matched subjects possibly from the same geographical 
location will be downloaded (e.g. from MG-RAST or NCBI SRA) and used for comparative 
purposes. 
The effect of host variables (e.g. gender, age, BMI, dietary pattern, drugs use, etc.) on the 
gut microbiota will be modelled using regression analysis. Clusters of microbiota 
structures will be identified by hierarchical clustering and their co-occurrence/co-inhibition 
networks and temporal dynamics will be reconstructed. Correlations between microbial 
taxa/genes and host metadata will be sought by uni/multivariate methods, including simple 
correlation tests, dimension-reduction techniques and multivariate correlation methods. 
Machine-learning methods, including Random Forests, will be used to identify 
discriminating taxa/genes. All statistical analysis will be performed in R. P-values will be 
corrected for multiple comparisons using the Benjamini–Hochberg method when 
appropriate. A p-value ≤ 0.05 will be considered statistically significant. 
Exploratory biomarker analyses will be performed in an effort to increase the 
understanding of HCC disease evolution under atezolizumab + bevacizumab treatment. 
PFS and OS will be analyzed using the methods outlined in Section 6.5. This may include 
appropriate multivariate analyses. Further details will be provided in the statistical analysis 
plan (SAP). 
6.7 
HEALTHECONOMIC ANALYSIS 
The health care resources consumed for managing Grade 3 and 4 AE related to the 
administration of atezolizumab + bevacizumab by the sample of convenience (Lohr 2010) 
of approximately 150 patients enrolled in 21 Italian clinical sites will be prospectively 
identified and quantified, using the ITT analysis population.  
Following the Italian National Health Service (INHS) viewpoint (Drummond et al. 2015), 
the abovementioned health care resources will be valued and detailed via a partial 
technique of economic evaluation of health care programmes (Drummond et al. 2015), 
named cost description (Drummond et al. 2015). Cost description describes the health 
care resources cost but neither takes their effects on patient’s health state into account, 
nor informes any choice among different health care programmes (Drummond et al. 2015).  
The cost description will focus on the following INHS-funded health care resources 
(Lazzaro et al. 2013; Lazzaro et al. 2018; Lazzaro et al. 2019): 

 
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- Laboratory tests; 
- Diagnostic imaging;  
- Instrumental tests; 
- Drugs (posology; number of administrations per diem; length of treatment); 
- Other medications (eg, oxygen therapy); 
- Transfusions (RBC and/or PLTs); 
- Specialist follow-up visits; 
- Hospitalizations: 
✓ day-hospital setting (type of ward; number of accesses); 
✓ inward setting (type of ward; number of episodes; number of days per episode); 
- Emergency room (number of admittances). 
The cost description will be carried out via a three-step approach that encompasses (i) 
INHS-funded health care resources identification and (ii) quantification, followed by (iii) 
their valuation. INHS-funded health care resources consumed by patients for managing 
Grade 3 and Grade 4 AEs related to the administration of atezolizumab + bevacizumab 
will be identified and quantified via the Adverse Event eCRF. 
INHS-funded health care resources valuation will be performed via multiplying by an item-
specific unitary cost the volume of INHS-funded health care resources consumed by 
patients for managing Grade 3 and Grade 4 AEs related to the administration of 
atezolizumab + bevacizumab. 
Since the cost description will follow the INHS standpoint: 
- Drugs will be valued at consumer price (Lazzaro et al. 2019). 
- For health care services that differ from drugs, INHS tariffs will be used to value health 
care resources consumed for managing Grade 3 and Grade 4 AEs related to the 
administration of atezolizumab + bevacizumab (Ministero della Salute, 2012; 
Conferenza Permanente per i Rapporti tra lo Stato le Regioni e le Province Autonome 
di Trento e Bolzano, 2019). 
The monetary standards will be consistent with the delivery setting of each health care 
procedure (outpatient; day-hospital; inward). 

 
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It is expected that INHS-funded health care resources consumed by patients for managing 
Grade 3 and Grade 4 AEs related to the administration of atezolizumab + bevacizumab 
(visits, diagnostic imaging and tests) will be mostly valued as outpatient procedures via 
the Italian Ministry of Health tariffs in force for outpatient setting (Ministero della Salute 
2012).   
Had any of the abovementioned health care procedures been performed in day-hospital 
or inpatient setting, only the hotel cost for hospital stay (Conferenza Permanente per i 
Rapporti tra lo Stato le Regioni e le Province Autonome di Trento e Bolzano, 2019) will be 
added to the cost of the health care procedure itself calculated according to the Italian 
Ministry of Health tariffs in force for outpatient setting (Ministero della Salute 2012). 
Emergency room admittance will be valued according to a dedicated INHS tariff (Ministero 
della Salute 2007). 
As the reference literature on the economic evaluation of health care programmes 
(Drummond et al 2015) requires that the resource costing procedure refers to the same 
and, preferably, the most recent year (imposing a proper inflation rate, when necessary), 
all costs will be reported in € at 2020 values.The following descriptive statistics concerning 
INHS-funded health care resources consumption (type and volume) and valuation (cost) 
due to Grade 3 and 4 AEs related to the administration of atezolizumab + bevacizumab 
management will be reported (Pagano and Gavreau 2000): 
- Continuous and count variables: 
✓ location measures: mean and median; 
✓ dispersion measures: standard deviation and range; 
- Categorical variables: absolute and relative frequencies. 
Both base case statistical analyses and cost description (Drummond et al. 2015) will be 
performed on all the evaluable patients included in the study database (Complete Case 
Analysis - CCA) (Little and Rubin 2002). If the CCA sample will prove to be too limited, an 
available case analysis (ACA) (Little and Rubin 2002) will replace CCA. 
The frequency of missing data will be reported for all analyzed variables and patients.  
Missing data will be diagnosed and classified according to their underlying missing 
mechanism (Missing Completely At Random - MCAR; Missing At Random - MAR; Missing 
Not At Random - MNAR) and pattern (monotonic; generalized; univariate) (Van Buuren et 
al. 1999; Little and Rubin 2002; Van Buuren 2018).  

 
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Missing data will be dealt with via one or more multiple imputation regression models 
and/or other statistical methods consistent with their underlying missing mechanism (Van 
Buuren et al. 1999; Little and Rubin 2002; Van Buuren 2018). 
Therefore CCA (or ACA) and fully imputed descriptive statistics for quantitative non-
monetary and quantitative monetary variables (Anthony and Young 2002) will be 
presented. 
Non-parametric bootstrap method will be applied to INHS-funded health care sector-
related costs data for calculating 95% CIs in CCA (or ACA) (Efron and Tibshirani 1993; 
Desgagné et al. 1998; Barber and Thompson 2000). 
Statistical analyses will be supported by Stata/SE software v 16.0 (StataCorp LP, College 
Station, TX, USA). 
In order to carry out the cost description and statistical analyses concerning the 
abovementioned INHS-funded health care resources consumed by patients for managing 
Grade 3 and Grade 4 AEs related to the administration of atezolizumab + bevacizumab, 
a dedicated excerpt of the original database will be provided by the Sponsor of the study. 
6.8 
EXPLORATORY ANALYSES OF PRO-CTCAE DATA  
PRO-CTCAE analyses will be primarily descriptive, with a focus on characterizing the 
pattern of symptomatic treatment toxicities over the course of the study. Results from 
these exploratory analyses will be presented separately from the other safety analyses.  
PRO-CTCAE data will be analyzed at the item level in line with current NCI 
recommendations for data handling (Basch et al. 2014). 
PRO-CTCAE data will be summarized over time. The proportion of missing data at each 
assessment timepoint will also be summarized to facilitate interpretation of data. 
The number and percentage of patients reporting each symptom and the change from 
baseline by category (frequency of occurrence, severity, interference) will be summarized 
at each assessment timepoint by treatment arm. For items that are rated on a 5-point 
Likert scale, the maximum post-baseline score and change from baseline will be 
summarized by treatment arm. 
Graphical representation of PRO-CTCAE data over time will also be provided. 
6.9 
INTERIM ANALYSES 
6.9.1 
Planned Interim Analyses 
An interim analysis of safety will be performed at the time of 50 recruited patients, 
estimated to occur at approximately 6 months after FPI.  A second interim analysis will be 
performed when patients have completed a period of follow-up of approximately 10 

 
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months. This follow-up period corresponds to that reported in the published YO40245 
(IMbrave150) trial (Cheng et al. 2019; Finn et al. NEJM 2021), which has been taken into 
consideration in the sample size calculation for this study with regard to the expected 
incidence of Grade 3-5 bleeding events. This second interim analysis will take into account 
all the efficacy and safety endpoints  with descriptive purposes. 
7. 
DATA COLLECTION AND MANAGEMENT  
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study. A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data. Data entered manually will be collected via EDC through use 
of eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.   
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO's data management plans and specifications. Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor's standard 
procedures will be used to handle and process the electronic transfer of these data.   
eCRFs and correction documentation will be maintained in the EDC system's audit trail. 
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO's standard procedures.  
PRO data will be collected on paper questionnaires. The data from the questionnaires will 
be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records. Acknowledgement of receipt of 
the data is required. 

 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy 
for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review. The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail that 
shows the original data as well as the reason for the change, name of the person making 
the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, electronic or paper PRO data (if applicable), Informed Consent Forms, 
laboratory test results, medication inventory records, and images, must be retained by the 

 
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Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to another 
party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, whichever 
is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the ICH 
E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). Studies conducted in the European Union or European Economic 
Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, 
regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC submission. 
The final IRB/ECapproved Consent Forms must be provided to the Sponsor for health 
authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. Patients 
will be told that they are free to refuse to participate and may withdraw their consent at 
any time for any reason. A separate, specific signature will be required to document a 
patient's agreement to participate in optional procedures. Patients who decline to 
participate will not provide a separate signature. 

 
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The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the study, 
the patient or a legally authorized representative must re-consent by signing the most 
current version of the Consent Forms or the addendum, in accordance with applicable 
laws and IRB/EC policy. For any updated or revised Consent Forms, the case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.76). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor. Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health authority 
requirements and the policies and procedures established by their IRB/EC, and archived 
in the site's study file.  

 
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization 
for use and disclosure of personal health information) signed by the patient, 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. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.65). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, representatives, 
and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to government 
or other health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study. These data may be 
combined with or linked to other data and used for research purposes, to advance science 
and public health, or for analysis, development, and commercialization of products to treat 
and diagnose disease. In addition, redacted Clinical Study Reports and other summary 
reports will be provided upon request (see Section 9. 65). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 

 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
including an audit trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. Prior 
to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.   
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for inspection 
of study data, patients' medical records, and eCRFs. The investigator will permit national 
and local health authorities; Sponsor monitors, representatives, and collaborators; and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Roche S.p.A, 20900 Monza, Italy.  
The Sponsor will provide clinical operations management, data management, and medical 
monitoring. 
Twenty-one sites in Italy will participate in the study to enroll approximately 150 patients. 
Screening and enrollment will occur through an IxRS.   

 
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Central facilities will be used for certain study assessments throughout the study 
(e.g., biomarker analyses). Accredited local laboratories will be used for routine monitoring; 
local laboratory ranges will be collected. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summary reports of clinical study results may 
be available in health authority databases for public access, as required by local regulation, 
and will be made available upon request. For more information, refer to the Roche Global 
Policy on Sharing of Clinical Study Information at the following website: 
 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within 6 months after the availability of the respective 
Clinical Study Report. In addition, for all clinical trials in patients involving an IMP for which 
a marketing authorization application has been filed or approved in any country, the 
Sponsor aims to publish results from analyses of additional endpoints and exploratory 
data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the appropriate 
Sponsor personnel. 

 
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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information). 

 
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Appendix 1  
Schedule of Activities 
Assessment Window (Days) a  
Screening b  
Treatment Phase (Q3W)  
Treatment 
Discontinuation c  
Survival 
Follow-Up 
–28 to –1  
–7 to –1  
Day 1 of Each Cycle a (± 3 days) 
≤ 30 Days after 
Last Dose 
 
Signed Informed Consent Form(s) b  
x  
 
 
 
 
Review of eligibility criteria  
x  
 
 
 
 
Medical, surgical, and cancer histories, 
including demographic information d  
x  
 
 
 
 
Infectious disease and pharmacological 
history (episodes of diarrhea, 
gastroenteritis, pneumonia, urinary tract 
infections, antibiotic treatments received 
and with which drugs) starting from three 
months before enrolment  
x 
 
 
 
 
Complete physical examination e  
x  
 
 
 
 
Limited physical examination f  
 
 
x g  
x  
 
Child-Pugh score 
x 
 
 
 
 
ECOG Performance Status  
 
x  
x g  
x  
 
Tumor assessment h  
x  
 
See footnote h  
x  
x  
Vital signs i  
x  
 
x  
x  
 
Weight  
x  
 
x j  
x  
 
Height  
x  
 
 
 
 
12-lead ECG k  
x  
 
Perform as clinically indicated  
 
EGD l  
x  
 
 
 
 
Previous therapies or procedures linked 
to esophageal varices (if applicable) such 
x 
 
 
 
 

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Assessment Window (Days) a  
Screening b  
Treatment Phase (Q3W)  
Treatment 
Discontinuation c  
Survival 
Follow-Up 
–28 to –1  
–7 to –1  
Day 1 of Each Cycle a (± 3 days) 
≤ 30 Days after 
Last Dose 
 
as non-cardioselective beta-blockers, 
banding, sclerosing injections etc. 
Haematology m, y  
 
x  
x g  
x  
 
Serum chemistry n, y  
 
x  
x g  
x  
 
HIV, HBV, HCV serology o 
x 
 
 
 
 
Quantitative HBsAg, HBV DNA, HCV 
RNA p  
x  
 
x  
x  
 
α-fetoprotein (AFP) 
x  
 
x  
x  
 
Coagulation panel (aPTT or PTT, INR) y  
 
x  
x g  
x  
 
Urinalysis q, y 
 
x  
x g  
x  
 
TSH, free T3, free T4  
x  
 
Cycles 5, 9, 13, etc. (every 4 cycles)  
x  
 
Pregnancy test  
 
x r  
x s  
x  
 
Faeces for microbiome evaluation z 
x  
 
x z 
 
 
Concomitant medications t  
 
x  
x  
x  
 
Adverse events u  
x  
 
x  
x  
x 
Identification and quantification of health 
care resources consumed for managing 
Grade 3 and 4 AEs 
 
 
x 
x 
 
Study treatment infusion v  
 
 
x  
 
 
PRO w 
 
 
x 
 
 
Survival and anti-cancer therapy follow-
up x 
 
 
 
 
x 
CT = computed tomography; EGD = esophagogastroduodenscopy; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg 
= hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; MRI = magnetic resonance imaging; PET = positron emission 

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tomography; PRO = patient-reported outcome; Q3W = every 3 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; T3 
= triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
Note: Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. Each cycle 
is 21 days in length. 
a All visits and infusions may be administered with a window of ± 3 days. 
b Written informed consent can be obtained up to 30 days prior to study entry and is required before performing any study-specific tests or procedures. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and per protocol relevant window may be used for 
screening assessments rather than repeating such tests. Screening local laboratory assessments obtained ≤ 96 hours prior to the initiation of study 
treatment do not have to be repeated for Cycle 1. Test results should be reviewed prior to administration of study treatment. 
c Patients will be asked to return to the clinic 30 days after the last dose of study treatment for an end-of-treatment visit. After this visit, serious adverse 
events and protocol defined adverse events of special interest, regardless of attribution, will be recorded until 90 days after the last dose of study 
treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first. Ongoing adverse events thought to be related to study 
treatment will be followed until the event has resolved to baseline grade or better, the event is assessed by the investigator as stable, new anti-cancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it is determined that the study treatment or participation is not 
the cause of the adverse event. Scans performed within 6 weeks prior to the treatment discontinuation visit do not need to be repeated. 
d Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Demographic information includes age and self-reported 
race/ethnicity. Reproductive status and alcohol history should also be captured. 
e A complete physical examination at screening should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. Changes in abnormalities noted at baseline should be recorded 
at the end of the visit. New or worsened abnormalities should be recorded as adverse events if appropriate. 
f A limited physical examination will be performed at other visits to assess changes from baseline abnormalities and any new abnormalities and to 
evaluate patient reported symptoms. New or worsened abnormalities should be recorded as adverse events if appropriate.  
g ECOG Performance Status, limited physical examination and local laboratory assessments may be obtained ≤ 96 hours before Day 1 of each cycle. 
h All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic imaging performed during the screening 
period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis and brain, 2) bone scan or PET scan as clinically indicated, and 3) any other 
imaging studies (CT scan of the neck, plain films, etc.) as clinically indicated by the treating physician. The same radiographic procedures and 
technique must be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performer during screening, then she 
should subsequently undergo CT performed using the same radiologic protocol throughout the remainder of the study). Results must be reviewed by 
the investigator before dosing at the next cycle. Tumor assessments will be performed at baseline, every 6 weeks (± 1 week) for the first 54 weeks 

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following the initiation of study treatment, and every 9 weeks (± 1 week) thereafter, with additional scans as clinically indicated. All known sites of 
disease documented at screening should be re-assessed at each subsequent tumor evaluation. Tumor response will be evaluated by the investigator 
using RECIST Version 1.1. In the absence of disease progression, tumor assessments should continue regardless of whether patients discontinue 
study treatment or start new anti-cancer treatment, unless the patient dies, withdraws consent, or the study is terminated by the Sponsor, whichever 
occurs first. 
j Vital signs include heart rate, respiratory rate, blood pressure, and temperature. On days of study treatment administration (atezolizumab and 
bevacizumab), the patient's vital signs should be determined up to 60 minutes before all infusions. Vital signs will be measured at the end of 
bevacizumab infusion and 2 (± 1) hours after end of the infusion and will also be collected during and after every infusion of atezolizumab if clinically 
indicated. 
j The dose of bevacizumab will be based on the patient's weight (in kilograms) measured ≤ 14 days prior to baseline (the initiation of study treatment) 
and will remain the same throughout the study unless there is a weight change of > 10% from baseline. If re-baseline is needed the latest baseline 
weight should always be used to calculate percent change in weight for all subsequent doses. 
k Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection.  
l All patients must undergo an EGD and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. 
m Haematology consists of CBC, including RBC count, haemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count. A manual differential can be done if clinically indicated. 
n Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), serum troponin (at baseline, if 
considered standard of care/required per local clinical practice, and as clinically indicated during the study), sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH . 
o All patients will be tested for HIV locally prior to the inclusion into the study and if not in contradiction with local legislation; patients with a positive 
HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥200µL, and have an undetectable viral load. 
HBsAg, HBsAb, and total HBcAb should be collected during screening and tested locally. HBV DNA must be collected prior to Cycle 1, Day 1 in 
patients who have negative serology for HBsAg and HBsAb tests and a total HBcAb. 
p Only if patient tests positive for HBsAg, HBcAb, quantitative HBsAg and HBV DNA will be tested during screening; Cycle 5, Day 1; Cycle 9, Day 1; 
and at treatment discontinuation. Quantitative HBsAg will be tested locally. If a patient tests positive for HCV antibody at screening, quantitative HCV 
RNA must be tested locally at screening, Cycle 5 Day 1, Cycle 9 Day 1, and at treatment discontinuation. If local quantitative HBsAg test is not 
available, a qualitative HBsAg followed by quantitative HBV DNA can be performed as an alternative. 
q Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood and should be repeated before every cycle during treatment. Urine 
dipstick for proteinuria must be < 2+ within 7 days prior to initiation of study treatment. Patients discovered to have ≥ 2+ proteinuria on dipstick 

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urinalysis at baseline should undergo a 24-hour urine collection (or protein creatinine ratio as an alternative per local guidance) and must demonstrate 
< 1 g of protein in 24 hours. 24 hour urine collection (or protein:creatinine ratio as an alternative per local guidance) should be done prior to 
bevacizumab administration according to the guidelines in Appendix 5. 
r Serum pregnancy test within 14 days before Cycle 1, Day 1. 
s Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications the patient has used 
within the 7 days prior to initiation of study treatment should be documented. At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded. 
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study treatment 
or until initiation of another anti-cancer therapy, whichever occurs first and serious adverse events and adverse events of special interest will continue 
to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware 
of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6). 
. The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, new systemic anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it is determined that the 
study treatment or participation is not the cause of the adverse event. Every effort should be made to follow all serious adverse events considered to 
be related to study drug or study-related procedures until a final outcome can be reported.  
v The initial dose of atezolizumab will be delivered over 60 (± 15) minutes. If the first infusion is tolerated without infusion-associated adverse events, 
the second infusion may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (± 10) minutes. The initial dose of bevacizumab will be delivered over 90 (± 15) minutes. If the first infusion is tollerate without infusion-
associated adverse events, the second infusion may be delivered over 60 (± 10) minutes. If the 60-minute infusion is well tolerated, all subsequent 
infusions may be delivered over 30 (± 10) minutes. Atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 minutes 
between dosing. In the absence of unacceptable toxicity, patients may continue study treatment until there is evidence of disease progression or lack 
of clinical benefit. 
w The NCI-CTCAE questionnaire (Appendix 7) will be completed by all patients on paper starting on Day 15 of each Cycle. All PRO questionnaires 
are scheduled for self-administration at home and are required to be completed by the patient, to avoid any potential bias to patients’ responses to 
ensure that the validity of the instrument is not compromised. Interview assessment by a family member will be allowed if the patient is not able to 
complete the measure on their own. Study personnel should review all questionnaires for completeness before the patient leaves the investigational 
site and record responses in eCRF.   

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x Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (± 21 
days) until death, loss to follow-up, or until study termination by the Sponsor. All patients will be followed for survival and new anti-cancer therapy 
(including targeted therapy and immunotherapy) information unless the 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. 
y Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle.  
z Faeces samples from 150 subjects will be collected in sterile containers (1-5 grams are sufficient), stored locally (preferably at -80°C), and then 
shipped to a central laboratory (the Unit of Holobiont microbiome and microbiome engineering, Department of Pharmacy and Biotechnology, 
University of Bologna, Bologna, Italy) for analysis, where they will be stored at -80°C until processing. For each patient, faecal samples will be 
collected at screening, and at weeks 3, 6, 12, and 51 during treatment (within 3 days). 
 
 

 
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Appendix 2  
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 and 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. 

Appendix 2: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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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 lungs, 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, positron emission tomography (PET) 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. 
 
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.  
 

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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 not usually more than 4 weeks prior to the beginning of the treatment. 
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, because 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 IV 
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (with or without MRI 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 (with or without MRI IV contrast) 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 

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lesions on a different modality, because the same lesion may appear to have a different 
size using a new modality. 
ENDOSCOPY, 
LAPAROSCOPY, 
ULTRASOUND, 
TUMOR 
MARKERS, 
CYTOLOGY, AND HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
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 should 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) 

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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"). 
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, given that 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 is 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). 

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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 during 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 the 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. 
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 the 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 "unequivocal 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 following 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 at prior timepoints 
(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 
 

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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  
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  
 
PD:  Unequivocal progression of existing non-target lesions 
 
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 truly represents truly new disease. If repeat scans 

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confirm there is definitely a new lesion, progression should be declared as of 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. 
Table 1 
Criteria for Overall Response at a Single Timepoint 
Target Lesions 
Non-Target Lesions 
New Lesions 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD or NE 
No 
PR 
PR 
CR, non-CR/Non-PD, or 
NE 
No 
PR 
SD 
CR, non-CR/Non-PD, or 
NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR 
NED b 
No 
CR 
PR 
NED b 
No 
PR 
SD 
NED b 
No 
SD 
NED a 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NED a 
CR 
No 
CR 
NED a 
NE 
No 
NE 
NED a 
NED b 
No 
NED 
CR  complete response; NE  not evaluable; NED  not evaluable disease; PD  progressive 
disease; PR  partial response; SD  stable disease. 
a No target lesions identified at baseline  
b No non-target lesions identified at baseline. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging or measurement is performed 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 

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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 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 treatment. 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. 
Fluorodeoxyglucose (FDG)-PET is not yet validated for use in clinical trials to 
determine response but may complement CT/MRI in the assessment of progression. 
FDG-PET imaging to identify new lesions is described in the following table. 

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Baseline FDG-PET 
Post-Baseline FDG-PET  
Determination 
Negative FDG-PET 
Positive FDG-PET  
New lesion (PD) 
None 
Positive FDG-PET corresponds 
to a new site of disease 
confirmed by CT/MRI 
New lesion (PD) 
None 
Positive FDG-PET not 
confirmed as a new site of 
disease on CT/MRI 
Additional follow-up CT/MRI scans 
are needed to determine if there is 
truly progression occurring at that 
site. 
If so, new lesion (PD) with the date of 
PD being the date of the initial 
abnormal FDG-PET scan date 
If not, it is not a new lesion. 
None 
Positive FDG-PET that 
corresponds to a preexisting 
site of disease on CT/MRI that 
is not progressing on the basis 
of the anatomic images 
Not a new lesion 
CT  computed tomography; FDG  fluorodeoxyglucose; MRI  magnetic resonance imaging; 
PD  progressive disease; PET  positron emission tomography. 
Note:  A positive FDG-PET scan lesion indicates one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
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. 
Schwartz LH., Litiére S, de Vries SE, et al. RECIST 1.1update and clarification: from 
RECIST Committee. Eur J Cancer 2016; 62:1327. 
  

 
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Appendix 3  
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). Caution should be used when considering atezolizumab for 
patients who have previously experienced a severe or life-threatening skin adverse 
reaction or pericardial disorder while receiving another immunostimulatory anti-cancer 
agent. The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions. 
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 myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 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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 Crohn disease  
 

 
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Appendix 4  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local or 
institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion in a clinical setting: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, 
and thermometer 
 
Oxygen 
 
Epinephrine for intramuscular (preferred route), subcutaneous, intramuscular, 
intravenous, or 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. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as required 
by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 5  
Guidelines for Management of Adverse Events Associated with 
Atezolizumab + Bevacizumab 
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 ≤ 10 mg/day oral prednisone or 
equivalent 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 the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.  
Bevacizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If the event resolves to Grade ≤ 1, 
bevacizumab may be restarted at the same dose level. If bevacizumab is delayed due to 
toxicity for > 42 days beyond when the next dose should have been given, the patient 
must be permanently discontinued from bevacizumab. Bevacizumab can be resumed after 
being withheld for > 42 days if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit. 
Atezolizumab and/or bevacizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on of the investigator’s benefitrisk assessment  and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption. 
If either study drug is withheld or discontinued, the other study drug can be continued as 
long as the patient is experiencing clinical benefit, as determined by the investigator per 
medical judgment. 
Refer to Section 4.3.2 for information on dose interruptions for reasons other than toxicity. 

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MANAGEMENT GUIDELINES 
Guidelines for management of patients who experience adverse events associated with 
atezolizumab and bevacizumab are provided in Appendix 6 (Tables 1-14) and Appendix 
5 (Table 1), respectively. 
For cases in which management guidelines are not covered in the atezolizumab or 
bevacizumab Investigator's Brochures or this protocol, patients should be managed as 
deemed appropriate by the investigator according to best medical judgment. 
Atezolizumab 
Appendix 6 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated adverse events (e.g., pulmonary, 
hepatic, gastrointestinal, endocrine, ocular, myocarditis, pericardial disorders, pancreatic, 
dermatologic, neurologic, meningoencephalitis, renal, myositis, hemophagocytic 
lymphohistiocytosis). 
Bevacizumab 
Table 1 provides guidelines for the management of patients who experience adverse 
events associated with bevacizumab. 
 
 
 

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Event 
Action to Be Taken 
Bowel obstruction, Grade 3-4 
 Hold bevacizumab for complete obstruction. 
 If surgery is necessary, patient may restart bevacizumab 
after full recovery from surgery and at investigator's 
discretion. 
Hypersensitivity, allergic reactions 
 Permanently discontinue bevacizumab. 
Hypertension 
 
General guidance 
 Grade 2 or above, start hypertensive therapy 
Hypertension Grade 2 
 Hold bevacizumab. 
 Once blood pressure < 150/100 mmHg, patient may continue 
bevacizumab therapy. 
Hypertension Grade 3 
 If blood pressure is not controlled < 150/100 mmHg with 
medication, discontinue bevacizumab. 
Hypertension Grade 4 (includes 
hypertensive encephalopathy) 
 Discontinue bevacizumab. 
Hemorrhage 
 
Grade ≥ 2 hemoptysis (≥ 2.5 mL of 
bright red blood pre episode) 
 Discontinue bevacizumab. 
Grade 3-4 bleeding 
 Discontinue bevacizumab. 
Bleeding in patients on full-dose 
anticoagulant therapy 
 Discontinue bevacizumab.a 
CNS bleeding, any grade 
 Discontinue bevacizumab. 
Venous thromboembolic events 
 
Venous thromboembolic event, 
Grade ≥ 3 
 For Grade 3 thromboembolic events, hold bevacizumab for 
3 weeks. Bevacizumab treatment may be resumed during 
the period of therapeutic-dose anticoagulant therapy once 
the level of anticoagulation therapy is stabilized: 
 Anticoagulant treatment should be administered per 
institutional guidelines. 
 After administration of bevacizumab is restarted, if the 
patient experiences another Grade 3 venous 
thromboembolic event, bevacizumab should be discontinued. 
 For Grade 4 thromboembolic events, discontinue 
bevacizumab. 
Arterial thromboembolic events 
 
Arterial thromboembolic event, any 
grade 
 Discontinue bevacizumab. 
 
 

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Proteinuria 
 
Grade 1 (1 + proteinuria, urinary 
protein < 1.0 g/24 hr) 
 Administer bevacizumab 
Grade 2 (2 + proteinuria, urinary 
protein 1.0-3.4 g/24 hr) 
 For 2 dipstick: may administer bevacizumab and collect 24-
hour urine prior to subsequent bevacizumab administration. 
 For 3 dipstick: must obtain 24-hour urine prior to 
administering bevacizumab. 
 Withhold bevacizumab for urinary protein 2 g/24 hr. 
Resume bevacizumab when proteinuria is 2 g/24 hr. 
Grade 3 (urinary protein > 3.5 g/24 
hr) 
 Withhold bevacizumab. Resume bevacizumab when 
proteinuria is 2 g/24 hr. 
Proteinuria with diagnosis of 
nephritic syndrome 
 Permanently discontinue bevacizumab. 
Fistula 
 
Tracheoesophageal fistula, any 
grade 
 Discontinue bevacizumab. 
Fistula (non tracheoesophageal), 
Grade 4 
 Discontinue bevacizumab. 
Wound dehiscence 
 
Wound dehiscence, any grade 
requiring medical or surgical 
therapy 
 Discontinue bevacizumab. 
Posterior Reversible Encephalopathy Syndrome/Reversible Posterior Leukoencephalopathy Syndrome 
PRES/LPRS, any grade confirmed by 
MRI 
 Discontinue bevacizumab. 
IRR infusion-related reaction; MRI magnetic resonance imaging. 
a Follow guidelines of the treating institution. 

 
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Appendix 6  
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 
when clinically indicated. 
Although most immune-mediated adverse events observed with atezolizumab 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-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible immune-
related adverse events prior to initiating therapy and throughout treatment and survival 
follow-up.  There should be a high level of suspicion that new symptoms are treatment 
related. 
 
 The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in the following subsections. 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider withholding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.5−1 mg/kg/day of prednisone or equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as 
a Grade 3 event.   
 
Withhold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1−2 mg/kg/day oral prednisone or equivalent).  Corticosteroids 
should be tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours 
of high-dose corticosteroid use, other immunosuppressants may be offered for 
some toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 

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hormonereplacement therapy.The investigator should consider the benefitrisk 
balance for a given patient prior to further administration of atezolizumab. 
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 
benefitrisk assessment and documented by the investigator. The Medical Monitor 
is available to advise as needed.   
Guidelines for managing patients who experience selected adverse events are provided 
in the following sections. Management guidelines are presented by adverse event severity 
based on the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 5.0. 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, 
dyspnea,fatigue, hypoxia, pneumonitis, and pulmonary infiltrates. 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 COVID-19 evaluation should be performed per institutional guidelines where 
relevant. Management guidelines for pulmonary events are provided in Table 1. 

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Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 

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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. 
 Consider resuming on radiographic evidence of improvement. 
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 with or without transbronchial biopsy 
 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 and contact 
Medical Monitor. c,d 
 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 and contact Medical 
Monitor. c, d 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 
Bronchoscopy or BAL with or without transbronchial biopsy 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. 

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Event 
Management 
BAL  bronchoscopic alveolar lavage. NCI CTCAE v5.0: National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on of the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
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 the investigator’s benefitrisk assessment 
and documented by the investigator. The Medical Monitor is available to advise as 
needed.  
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; 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. 

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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. 
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 and contact the Medical 
Monitor. c 
AST or ALT increases 
to > 10 x ULN or total bilirubin 
increases to > 3 x ULN 
 
● Permanently discontinue atezolizumab and contact the 
Medical Monitor. 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; ULN = upper limit of normal. 
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 the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is available to 
advise as needed. 
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 the investigator’s benefitrisk assessment and 
documented by the investigator. The Medical Monitor is available to advise as needed.  
 
 

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GASTROINTESTINAL EVENTS 
Management guidelines for diarrhoea or colitis are provided in Table 3. 
All events of diarrhoea or colitis should be thoroughly evaluated for other more common 
aetiologies. 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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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 

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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. 
 If strong clinical suspicion for immune-mediated colitis, initiate empiric 
IV corticosteroids while waiting for definitive diagnosis. 
 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 does not 
improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. 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 does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 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 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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GI  gastrointestinal. NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on of the investigator’s  benefitrisk assessment  and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
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 the investigator’s benefitrisk assessment and 
documented by the investigator. The Medical Monitor is available to advise as needed.  
 
 
 

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ENDOCRINE EVENTS 
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. Patients 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 

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Event 
Management 
Hypothyroidism  
Grade 1  
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 
Consider withholding 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 and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
Hyperthyroidism  
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 Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Hyperthyroidism  
Grade 2  
 
Consider withholding atezolizumab. 
 
Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
 
Consider patient referral to an 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 drug 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 and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism.c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. NCI CTCAE v5.0: 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on of the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
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 the investigator’s benefitrisk 
assessment and documented by the investigator. The Medical Monitor is available to 
advise as needed. 

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Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 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 and 
contact Medical Monitor. 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. NCI CTCAE v5.0: 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of 
assessment by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
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 the investigator’s benefitrisk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 

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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 and contact the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 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. NCI CTCAE v5.0: 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on  the investigator’s benefitrisk assessment  and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
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 the investigator’s  benefitrisk 
assessment and documented by the investigator. The Medical Monitor is available to 
advise as needed. 

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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 and contact 
the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 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. 
NCI CTCAE v5.0 : National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
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 the investigator’s  benefitrisk assessment 
and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
 

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IMMUNE-MEDIATED CARDIAC EVENTS 
In high-risk patients (including those with abnormal baseline cardiac troponin levels, 
when available), transthoracic echocardiogram (TTE) monitoring should be 
considered, as clinically indicated, and based on local clinical practice.  
Management guidelines for cardiac events are provided in Table 6. 
 
IMMUNE-MEDIATED MYOCARDITIS 
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., 
troponin, 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 immune-
mediated 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 pre-existing 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, a TTE for evaluation of left ventricular 
injection fraction and global longitudinal strain, 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 
aetiology, should be treated according to the guidelines in Table 6. 
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 immune-
mediated 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 (e.g. metastatic disease ), cancer treatment (e.g., chest 

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radiotherapy), cardiac injury (e.g. injury due to myocardial infarction or iatrogenesis), 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, TTE, 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. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-
4 
or 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. a 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider anti-
arrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 1g/kg/day IV 
methylprednisolone for 3-5 days and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 24 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. NCI CTCAE v5.0: 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE v5.0. 
 
 
 
 

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INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome 
(CRS) with atezolizumab may receive premedication with antihistamines, anti-pyretic 
medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions. 
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of 
cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab 
administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(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. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-γ (Merad and Martin 
2020). If a patient develops suspected CRS during the study, a differential diagnosis 
should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment. If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
 
 

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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
Grade 1a  
Fever b with or 
without 
constitutional 
symptoms 
 Immediately interrupt infusion  
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If 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-pyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
requiring low-
flow oxygen d by 
nasal cannula 
or blow-by 
 Immediately interrupt infusion. 
  Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 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, and contact the Medical Monitor. 
 
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-pyretic medications, 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 Medical Monitor. 

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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 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. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 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 and in 
consultation with the Medical Monitor. 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely. Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
 Hospitalize patient until complete resolution of symptoms. 

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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
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:  The management guidelines have been adapted from the NCCN guidelines for the  
management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v 5.0 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-pyretic medications, 
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 the investigator’s  benefitrisk 
assessment and documented by the investigator . The Medical Monitor is available to 
advise as needed.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretic medications, 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). 
 
 
 
 

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PANCREATIC EVENTS 
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. 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis  

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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 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 and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 
GI  gastrointestinal. NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is available 
to advise as needed. 
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 the investigator’s benefitrisk assessment and documented 
by the investigator. The Medical Monitor is available to advise as needed. 

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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 and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 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. NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment  and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed. 
.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 the investigator’s benefitrisk assessment and documented 
by the investigator. The Medical Monitor is available to advise as needed.  
 

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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab 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 for evaluation and, if 
indicated, biopsy. 
 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 for evaluation and, if indicated, 
biopsy. 
 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 and contact 
Medical Monitor. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor.c 
Stevens-
Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis; 
 Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if 
indicated, biopsy; 
 Follow the applicable treatment and management guidelines above; 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab 

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NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be based on of the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
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 the investigator’s benefitrisk 
assessment and documented by the investigator. The Medical Monitor is available to 
advise as needed. 
 
 
 

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NEUROLOGIC DISORDERS 
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 aetiologies. Myasthenia may be associated with myositis (see section on 
immune-mediated myositis) and patients should be managed accordingly.  Management 
guidelines for neurologic disorders are provided in Table 10, with specific guidelines for 
myelitis provided in Table 111. 
Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-
mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab.Investigate etiology.  
 
Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-
mediated 
neuropathy, 
including facial 
paresis, 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. 
 For general immune-mediated neuropathy: 
– If event resolves to Grade 1 or better, resume atezolizumab. b 
– If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
• 
For facial paresis: 
– 
Initial observation OR initiate prednisone 12 mg/kg/day (if 
progressing from mild).  Initiate treatment with gabapentin, 
pregabalin, or duloxetine, for pain. 
– 
If event resolves fully, resume atezolizumab b 
– 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines and proceed as 
per Guillain-Barré syndrome management.. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to 12 mg/kg/day 

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oral or IV prednisone. 
 Consider IVIG or plasmapheresis in patients with rapid 
progression with development of bulbar and/or respiratory 
symptoms. 
 In life-threatening cases, consider IV methylprednisone 1 g/day 
for 35 days and consider other immunosuppressive agent. 
NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
IVIG  intravenous immunoglobulin. 
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 the investigator’s  benefitriskassessment  and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
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 
the 
investigator’sbenefitrisk assessment and documented by the investigator . The 
Medical Monitor is available to advise as needed. 
 
Table 11 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-
mediated 
myelitis, Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to neurologist.  
Immune-
mediated 
myelitis, Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to neurologist. 
 
Rule out infection. 
 
Initiate 
treatment 
with 
corticosteroids 
equivalent 
to 
1-2 mg/kg/day oral prednisone. 
Immune-
mediated 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 

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myelitis, Grade 3 
or 4 
 
Initiate non-opioid treatment (e.g., pregabalin, gabapentin, 
duloxetine) for pain. 
 
Hospitalize patient. 
– 
Initiate treatment with corticosteroids equivalent to 
1 g/day IV methylprednisolone. 
– 
If event does not improve or there is worsening of 
symptoms 
within 
3 days, 
consider 
IVIG 
or 
plasmapheresis and manage as per institutional 
guidelines. 
 
Refer patient to neurologist. 
IVIG  intravenous immunoglobulin. 
 
 
 

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IMMUNE-MEDIATED MENINGOENCEPHALITIS 
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 . 
Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 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. 
NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE v5.0. 
 
 
RENAL EVENTS 
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 

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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 113. 
Table 113 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function closely, including creatinine and urine 
protein, 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 and 
contact the Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 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. 
NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on of the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 the investigator’s 
benefitrisk assessment and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed. 
 
 
 

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IMMUNE-MEDIATED MYOSITIS 
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/creatine 
phosphokinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy. Patients may initially present with low grade nondescript 
symptoms including mild pain and weakness; thus, there should be a low threshold for 
suspicion of myositis.  Patients with possible myositis should be referred to a 
rheumatologist or neurologist.  Patients with possible myositis should be monitored for 
signs of myocarditis (see section on immune-mediated myocarditis) and myasthenia 
gravis (bulbar symptoms such as dysphagia, dysphonia, and dyspnea; see section on 
neurologic disorders). 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table . 
Table 14 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. 
Immune-
mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
 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 and 
contact the Medical Monitor. c 

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Table 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Immune-
mediated 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
 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. 
 Consider IVIG or plasmapheresis.  
 If event does not improve within 24-48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor.  
 
For recurrent events, treat as a Grade 4 event. Permanently 
discontinue atezolizumab and contact the Medical Monitor.  
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 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. 
 Consider IVIG or plasmapheresis.  
 If event does not improve within 24-48 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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NCI CTCAE v5.0: National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
IVIG  intravenous immunoglobulin. 
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 of the investigator’s benefitrisk assessmentand in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 the investigator’s 
benefitrisk assessment and documented by the investigator . The Medical Monitor is 
available to advise as needed. 
 
 
 

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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
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 IL-2 receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 

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Patients with suspected HLH should be treated according to the guidelines in Table . 
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis  
Event 
Management 
Suspected HLH  
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and 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;. 
 
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 [resource 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. 

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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. 
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. 

Appendix 7: NCI-PRO CTCAE ITEMS (Item Library Version 1.0) 
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Appendix 7  
NCI-PRO CTCAE ITEMS (Item Library Version 1.0) 
As individuals go through treatment for their cancer they sometimes experience  
different symptoms and side effects. For each question, please check or mark an in the 
one box that best describes your experiences over the past 7 days. 
 
 
 

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